Science.gov

Sample records for agonist ro 60-0175

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

    PubMed

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

    2000-01-10

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

  2. Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig.

    PubMed

    McLeod, Robbie L; Jia, Yanlin; Fernandez, Xiomara; Parra, Leonard E; Wang, Xin; Tulshian, Deen B; Kiselgof, Eugenia J; Tan, Zheng; Fawzi, Ahmad B; Smith-Torhan, April; Zhang, Hongtao; Hey, John A

    2004-07-01

    We have previously shown that N/OFQ, the endogenous peptide ligand for the 'opioid-like' NOP receptor, inhibits cough in guinea pigs and cats. In the present study we sought to continue our characterization of the cough-suppressant effects of NOP stimulation by profiling the pulmonary and antitussive effects of a novel non-peptide NOP agonist, Ro-64-6198, in guinea pigs. In receptor-binding assays, we confirmed that Ro-64-6198 selectively binds to NOP receptors over other opioid receptors. The Ki values for Ro-64-6198 at NOP, MOP, KOP and DOP receptors was 0.3, 36, 214 and 3,787 nmol/l, respectively. In GTPgammaS-binding assays, Ro-64-6198 displayed >900-fold functional selectivity at NOP relative to MOP receptors. We evaluated the effects of Ro-64-6198 (3 and 10 micromol/l) in isolated guinea pig nodose ganglia cells on the increases in intracellular Ca2+ concentration evoked by capsaicin stimulation (1 x 10(-8)-1 x 10(-6) mol/l). Similar to previously reported data with N/OFQ, Ro-64-6198 (3 and 10 micromol/l) significantly attenuated Ca2+ responses in nodose ganglia cells produced by exposure to capsaicin. The effect of Ro-64-6198 (3 micromol/l) on capsaicin-induced intracellular Ca2+ responses was blocked by the NOP antagonist, J113397 (3 micromol/l). In guinea pig in vivo studies, aerosolized capsaicin (10-300 micromol/l) produced a dose-dependent increase in cough number. Ro-64-6198 given i.p. significantly inhibited cough due to capsaicin (300 micromol/l) exposure. In a duration study we found that the maximum antitussive effect (42 +/- 8% inhibition) of Ro-64-6198 (3 mg/kg) was observed at 1 h after i.p. administration. Also at 1 h after administration, Ro-64-6198 (0.003-3.0 mg/kg, i.p.) produced a dose-dependent inhibition of cough. The antitussive effect of Ro-64-6198 (3 mg/kg, i.p.) was blocked by J113397 (12 mg/kg, i.p.) but not by the classical opioid antagonist naltrexone (10 mg/kg, i.p.). Although the antitussive action of Ro-64-6198 may be mediated

  3. Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys

    PubMed Central

    Zelenock, Kathy A.; Lindsey, Angela M.; Sulima, Agnieszka; Rice, Kenner C.; Prinssen, Eric P.; Wichmann, Jürgen; Woods, James H.

    2016-01-01

    Nociceptin/orphanin FQ receptor (NOP) agonists have been reported to produce antinociceptive effects in rhesus monkeys with comparable efficacy to μ-opioid receptor (MOP) agonists, but without their limiting side effects. There are also known to be species differences between rodents and nonhuman primates (NHPs) in the behavioral effects of NOP agonists. The aims of this study were the following: 1) to determine if the NOP agonist Ro 64-6198 could be trained as a discriminative stimulus; 2) to evaluate its pharmacological selectivity as a discriminative stimulus; and 3) to establish the order of potency with which Ro 64-6198 produces discriminative stimulus effects compared with analgesic effects in NHPs. Two groups of rhesus monkeys were trained to discriminate either fentanyl or Ro 64-6198 from vehicle. Four monkeys were trained in the warm-water tail-withdrawal procedure to measure antinociception. Ro 64-6198 produced discriminative stimulus effects that were blocked by the NOP antagonist J-113397 and not by naltrexone. The discriminative stimulus effects of Ro 64-6198 partially generalized to diazepam, but not to fentanyl, SNC 80, ketocyclazocine, buprenorphine, phencyclidine, or chlorpromazine. Fentanyl produced stimulus effects that were blocked by naltrexone and not by J-113397, and Ro 64-6198 did not produce fentanyl-appropriate responding in fentanyl-trained animals. In measures of antinociception, fentanyl, but not Ro 64-6198, produced dose-dependent increases in tail-withdrawal latency. Together, these results demonstrate that Ro 64-6198 produced stimulus effects in monkeys that are distinct from other opioid receptor agonists, but may be somewhat similar to diazepam. In contrast to previous findings, Ro 64-6198 did not produce antinociception in the majority of animals tested even at doses considerably greater than those that produced discriminative stimulus effects. PMID:26801398

  4. Characterization of the Discriminative Stimulus Effects of a NOP Receptor Agonist Ro 64-6198 in Rhesus Monkeys.

    PubMed

    Saccone, Phillip A; Zelenock, Kathy A; Lindsey, Angela M; Sulima, Agnieszka; Rice, Kenner C; Prinssen, Eric P; Wichmann, Jürgen; Woods, James H

    2016-04-01

    Nociceptin/orphanin FQ receptor (NOP) agonists have been reported to produce antinociceptive effects in rhesus monkeys with comparable efficacy to μ-opioid receptor (MOP) agonists, but without their limiting side effects. There are also known to be species differences between rodents and nonhuman primates (NHPs) in the behavioral effects of NOP agonists. The aims of this study were the following: 1) to determine if the NOP agonist Ro 64-6198 could be trained as a discriminative stimulus; 2) to evaluate its pharmacological selectivity as a discriminative stimulus; and 3) to establish the order of potency with which Ro 64-6198 produces discriminative stimulus effects compared with analgesic effects in NHPs. Two groups of rhesus monkeys were trained to discriminate either fentanyl or Ro 64-6198 from vehicle. Four monkeys were trained in the warm-water tail-withdrawal procedure to measure antinociception. Ro 64-6198 produced discriminative stimulus effects that were blocked by the NOP antagonist J-113397 and not by naltrexone. The discriminative stimulus effects of Ro 64-6198 partially generalized to diazepam, but not to fentanyl, SNC 80, ketocyclazocine, buprenorphine, phencyclidine, or chlorpromazine. Fentanyl produced stimulus effects that were blocked by naltrexone and not by J-113397, and Ro 64-6198 did not produce fentanyl-appropriate responding in fentanyl-trained animals. In measures of antinociception, fentanyl, but not Ro 64-6198, produced dose-dependent increases in tail-withdrawal latency. Together, these results demonstrate that Ro 64-6198 produced stimulus effects in monkeys that are distinct from other opioid receptor agonists, but may be somewhat similar to diazepam. In contrast to previous findings, Ro 64-6198 did not produce antinociception in the majority of animals tested even at doses considerably greater than those that produced discriminative stimulus effects. PMID:26801398

  5. Benzodiazepine recognition site inverse agonists Ro-15-4513 and FG 7142 both antagonize the EEG effects of ethanol in the rat

    SciTech Connect

    Marrosu, F.; Mereu, G.; Giorgi, O.; Corda, M.G.

    1988-01-01

    The aim of the present study was to compare the ability of Ro 15-4513 and FG 7142, two inverse agonists for benzodiazepine recognition sites, to antagonize the EEG effects of ethanol in freely moving rats. Ethanol induced sedation and ataxia associated with a progressive suppression of the fast cortical activities and an enhancement of low frequencies in both cortical and hippocampal tracings. In contrast, Ro 15-4513 and FG 7142 both caused a state of alertness associated with desynchronized cortical activity and theta hippocampal rhythm as well as spiking activity which was predominantly observed in the cortical tracings. When rats were treated with FG 7142 or Ro 15-4513 either before or after ethanol, a reciprocal antagonism of the behavioral and EEG effects of ethanol and of the partial inverse agonists was observed. These data support the view that the anti-ethanol effects of Ro 15-4513 may be related to its partial inverse agonist properties.

  6. The anti-inflammatory selective melanocortin receptor subtype 4 agonist, RO27-3225, fails to prevent acoustic trauma-induced tinnitus in rats.

    PubMed

    Zheng, Yiwen; McPherson, Kate; Reid, Peter; Smith, Paul F

    2015-08-15

    In preliminary studies we have observed a massive microglial activation in the cochlear nucleus following acoustic trauma-induced tinnitus in rats, which suggests that inflammatory responses within the central auditory system may be involved in the development and maintenance of tinnitus. Recently, the anti-inflammatory properties of melanocortins (MCs), have gained increasing interest in pharmacology due to their promising therapeutic potential in the treatment of inflammatory-mediated diseases. Among the five subtypes of the MC receptor, MC3 and MC4 receptors are the predominant brain receptors and are thought to play an important role in brain inflammation and neuroprotection. Importantly, MC4 receptors have been found in the mouse and rat central auditory systems. In this study we investigated whether the MC4 receptor agonist, RO27-3225, injected s.c at a dose of 90 or 180µg/kg, 30min before acoustic trauma and then every 12h for 10 days, could prevent the development of acoustic trauma-induced tinnitus in rats, using a conditioned behavioural suppression model. Although evidence of tinnitus developed in the exposed-vehicle group compared to the sham-vehicle group (P≤0.03), in response to a 32kHz tone, there were no significant drug effects from treatment with RO27-3225, indicating that it did not confer any protection against the development of tinnitus in this animal model. This result suggests that the anti-inflammatory effects of MC4 receptor agonists may not be sufficient to prevent tinnitus. PMID:25977231

  7. Determination of the partial benzodiazepine receptor agonist Ro 16-6028 in plasma by capillary gas chromatography with nitrogen-selective detection after conversion into the ethyl ester derivative.

    PubMed

    Timm, U; Fischer, G; Zell, M; Zumbrunnen, R

    1989-09-29

    A highly sensitive capillary gas chromatographic method was developed to determine plasma levels of a novel partial benzodiazepine receptor agonist in man following the very low therapeutic doses required for anxiolysis. The compound was isolated from plasma by liquid-liquid extraction at basic pH, converted into the ethyl ester analogue by a two-step procedure, separated from plasma constituents by capillary gas chromatography and quantified by means of nitrogen-selective detection. Because of the thermolabile tert.-butyl ester function, the agonist could not be gas chromatographed without degradation. Formation of the far more stable ethyl ester analogue was achieved by treatment with hydrogen chloride in ethanol, followed by an ethylation step with diazoethane. The high sensitivity of the new method (about 100 pg/ml, using 1-ml plasma specimens) allowed the monitoring of plasma levels of the agonist for up to 8 h (about three elimination half-lives) after a single 0.1-mg oral dose to human volunteers. The practicability of the procedure was demonstrated by the analysis of more than 600 plasma samples from clinical studies performed with human volunteers. PMID:2573608

  8. Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia.

    PubMed

    Beyeler, A; Kadiri, N; Navailles, S; Boujema, M Ben; Gonon, F; Moine, C Le; Gross, C; De Deurwaerdère, P

    2010-08-11

    Serotonin2C (5-HT(2C)) receptors act in the basal ganglia, a group of sub-cortical structures involved in motor behavior, where they are thought to modulate oral activity and participate in iatrogenic motor side-effects in Parkinson's disease and Schizophrenia. Whether abnormal movements initiated by 5-HT(2C) receptors are directly consequent to dysfunctions of the motor circuit is uncertain. In the present study, we combined behavioral, immunohistochemical and extracellular single-cell recordings approaches in rats to investigate the effect of the 5-HT(2C) agonist Ro-60-0175 respectively on orofacial dyskinesia, the expression of the marker of neuronal activity c-Fos in basal ganglia and the electrophysiological activity of substantia nigra pars reticulata (SNr) neuron connected to the orofacial motor cortex (OfMC) or the medial prefrontal cortex (mPFC). The results show that Ro-60-0175 (1 mg/kg) caused bouts of orofacial movements that were suppressed by the 5-HT(2C) antagonist SB-243213 (1 mg/kg). Ro-60-0175 (0.3, 1, 3 mg/kg) dose-dependently enhanced Fos expression in the striatum and the nucleus accumbens. At the highest dose, it enhanced Fos expression in the subthalamic nucleus, the SNr and the entopeduncular nucleus but not in the external globus pallidus. However, the effect of Ro-60-0175 was mainly associated with associative/limbic regions of basal ganglia whereas subregions of basal ganglia corresponding to sensorimotor territories were devoid of Fos labeling. Ro-60-0175 (1-3 mg/kg) did not affect the electrophysiological activity of SNr neurons connected to the OfMC nor their excitatory-inhibitory-excitatory responses to the OfMC electrical stimulation. Conversely, Ro-60-0175 (1 mg/kg) enhanced the late excitatory response of SNr neurons evoked by the mPFC electrical stimulation. These results suggest that oral dyskinesia induced by 5-HT(2C) agonists are not restricted to aberrant signalling in the orofacial motor circuit and demonstrate discrete

  9. Serotonin2C receptors modulate dopamine transmission in the nucleus accumbens independently of dopamine release: behavioral, neurochemical and molecular studies with cocaine.

    PubMed

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

    2015-05-01

    In keeping with its ability to control the mesoaccumbens dopamine (DA) pathway, the serotonin2C receptor (5-HT2C R) plays a key role in mediating the behavioral and neurochemical effects of drugs of abuse. Studies assessing the influence of 5-HT2C R agonists on cocaine-induced responses have suggested that 5-HT2C Rs can modulate mesoaccumbens DA pathway activity independently of accumbal DA release, thereby controlling DA transmission in the nucleus accumbens (NAc). In the present study, we assessed this hypothesis by studying the influence of the 5-HT2C R agonist Ro 60-0175 on cocaine-induced behavioral, neurochemical and molecular responses. The i.p. administration of 1 mg/kg Ro 60-0175 inhibited hyperlocomotion induced by cocaine (15 mg/kg, i.p.), had no effect on cocaine-induced DA outflow in the shell, and increased it in the core subregion of the NAc. Furthermore, Ro 60-0175 inhibited the late-onset locomotion induced by the subcutaneous administration of the DA-D2 R agonist quinpirole (0.5 mg/kg), as well as cocaine-induced increase in c-Fos immunoreactivity in NAc subregions. Finally, Ro 60-0175 inhibited cocaine-induced phosphorylation of the DA and c-AMP regulated phosphoprotein of Mr 32 kDa (DARPP-32) at threonine residues in the NAc core, this effect being reversed by the selective 5-HT2C R antagonist SB 242084 (0.5 mg/kg, i.p.). Altogether, these findings demonstrate that 5-HT2C Rs are capable of modulating mesoaccumbens DA pathway activity at post-synaptic level by specifically controlling DA signaling in the NAc core subregion. In keeping with the tight relationship between locomotor activity and NAc DA function, this interaction could participate in the inhibitory control of cocaine-induced locomotor activity. PMID:24661380

  10. Activation of serotonin(2C) receptors in the lateral habenular nucleus increases the expression of depression-related behaviors in the hemiparkinsonian rat.

    PubMed

    Han, Ling-Na; Zhang, Li; Li, Li-Bo; Sun, Yi-Na; Wang, Yong; Chen, Li; Guo, Yuan; Zhang, Yu-Ming; Zhang, Qiao-Jun; Liu, Jian

    2015-06-01

    The roles of lateral habenular nucleus (LHb) glutamate neurons and serotonin2C (5-HT2C) receptors in depression are poorly understood, particularly in Parkinson's disease-associated depression. Here we assessed the importance of LHb glutamate neurons and 5-HT2C receptors for depressive-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. The lesion induced depressive-like responses compared to sham-operated rats. Intra-LHb injection of potent, selective 5-HT2C receptor agonist Ro60-0175 decreased sucrose consumption and increased immobility time in sham-operated rats, indicating the induction of depressive-like responses, and intra-LHb injection of Ro60-0175 further increased the expression of depressive-like behaviors in the lesioned rats. Activation of LHb 5-HT2C receptors by the local administration of Ro60-0175 increased the firing rate of EAAC1 (a neuronal glutamate transporter)-positive neurons and percentage of the neurons with burst-firing pattern in the two groups of rats. Compared to sham-operated rats, the duration of Ro60-0175 action on the firing rate of EAAC1-positive neurons was markedly prolonged in the lesioned rats. Intra-LHb injection of Ro60-0175 decreased dopamine, 5-HT and noradrenaline levels in the medial prefrontal cortex, habenula, hippocampus and amygdala in sham-operated and the lesioned rats. The lesion did not change the percentage of EAAC1/5-HT2C receptor co-expressing neurons in the LHb. These findings indicate that activation of 5-HT2C receptors in the LHb increases firing activity of LHb glutamate neurons and then decreases monoamine levels in several brain regions, which increase the expression of depressive-like behaviors. Further, our results also suggest that the lesion leads to hyperfunctionality of 5-HT2C receptors on glutamate neurons of the LHb. PMID:25661701

  11. 46 CFR 111.105-40 - Additional requirements for RO/RO vessels.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... RO/RO vessels. (a) Each RO/RO vessel must meet ABS Steel Vessel Rules (incorporated by reference; see 46 CFR 110.10-1), section 4-8-4/27.3.2. (b) Each item of installed electrical equipment must meet the... 1 hazardous location. (c) Where the ventilation requirement of ABS Steel Vessel Rules section...

  12. Effect of an imidazobenzodiazepine, Ro15-4513, on the incoordination and hypothermia produced by ethanol and pentobarbital.

    PubMed

    Hoffman, P L; Tabakoff, B; Szabó, G; Suzdak, P D; Paul, S M

    1987-08-01

    The imidazobenzodiazepine, Ro15-4513, which is a partial inverse agonist at brain benzodiazepine receptors, reversed the incoordinating effect of ethanol in mice, as measured on an accelerating Rotarod. This effect was blocked by benzodiazepine receptor antagonists. In contrast, Ro15-4513 had no effect on ethanol-induced hypothermia in mice. However, Ro15-4513 reversed the hypothermic effect of pentobarbital, and, at a higher dose, also reversed the incoordinating effect of pentobarbital in mice. The data support the hypothesis that certain of the pharmacological effects of ethanol are mediated by actions at the GABA-benzodiazepine receptor-coupled chloride channel. PMID:3600196

  13. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

  14. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 7 2012-07-01 2012-07-01 false Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25). 1918.86 Section 1918.86 Labor Regulations Relating to Labor... REGULATIONS FOR LONGSHORING Handling Cargo § 1918.86 Roll-on roll-off (Ro-Ro) operations (see also §...

  15. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 7 2014-07-01 2014-07-01 false Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25). 1918.86 Section 1918.86 Labor Regulations Relating to Labor... REGULATIONS FOR LONGSHORING Handling Cargo § 1918.86 Roll-on roll-off (Ro-Ro) operations (see also §...

  16. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 7 2013-07-01 2013-07-01 false Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25). 1918.86 Section 1918.86 Labor Regulations Relating to Labor... REGULATIONS FOR LONGSHORING Handling Cargo § 1918.86 Roll-on roll-off (Ro-Ro) operations (see also §...

  17. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 7 2011-07-01 2011-07-01 false Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25). 1918.86 Section 1918.86 Labor Regulations Relating to Labor... REGULATIONS FOR LONGSHORING Handling Cargo § 1918.86 Roll-on roll-off (Ro-Ro) operations (see also §...

  18. Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells

    PubMed Central

    Liang, Yayun; Mafuvadze, Benford; Aebi, Johannes D; Hyder, Salman M

    2016-01-01

    Standard treatment for primary prostate cancer includes systemic exposure to chemotherapeutic drugs that target androgen receptor or antihormone therapy (chemical castration); however, drug-resistant cancer cells generally emerge during treatment, limiting the continued use of systemic chemotherapy. Patients are then treated with more toxic standard therapies. Therefore, there is an urgent need for novel and more effective treatments for prostate cancer. The cholesterol biosynthetic pathway is an attractive therapeutic target for treating endocrine-dependent cancers because cholesterol is an essential structural and functional component of cell membranes as well as the metabolic precursor of endogenous steroid hormones. In this study, we have examined the effects of RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate; Roche Pharmaceuticals internal reference: RO0488071) (RO), which is an inhibitor of 2, 3-oxidosqualene cyclase (a key enzyme in the cholesterol biosynthetic pathway), on prostate cancer cells. Exposure of both hormone-dependent and castration-resistant human prostate cancer cells to RO reduced prostate cancer cell viability and induced apoptosis in vitro. RO treatment reduced androgen receptor protein expression in hormone-dependent prostate cancer cells and increased estrogen receptor β (ERβ) protein expression in both hormone-dependent and castration-resistant prostate cancer cell lines. Combining RO with an ERβ agonist increased its ability to reduce castration-resistant prostate cancer cell viability. In addition, RO effectively suppressed the growth of aggressive castration-resistant human prostate cancer cell xenografts in vivo without any signs of toxicity to experimental animals. Importantly, RO did not reduce the viability of normal prostate cells in vitro. Our study is the first to demonstrate that the cholesterol biosynthesis inhibitor RO effectively suppresses growth of human prostate cancer cells

  19. Behavioral and biochemical characterization of benzodiazepine receptor partial agonists in pigeons.

    PubMed

    Witkin, J M; Acri, J B; Wong, G; Gleeson, S; Barrett, J E

    1996-04-01

    The ability of benzodiazepine receptor partial agonists to exhibit full efficacy in preclinical anxiolytic tests, in conjunction with initial clinical results, has suggested the possibility of a reduced clinical side-effect profile compared to benzodiazepine receptor full agonists like diazepam. Because punished behavior of pigeons has been useful in detecting effects of novel anxiolytic drugs, effects of imidazobenzodiazepine and beta-carboline benzodiazepine receptor partial agonists and some related compounds were evaluated in this species. The abilities of these compounds to substitute for the discriminative stimulus effects of the full agonists midazolam also was determined. Intrinsic efficacy was assessed by the degree to which gamma-aminobutyric acid increased ligand potency to displace [(3)H]Ro15-1788 (flumazinil) from membranes of pigeon cerebrum, and ranged from full agonist-like efficacy (Ro 19-5470; 7-(3-cyclopropyl-1,2,4-oxodiazol-5-yl)-5,6-dihydro-5-methyl-4H- imidazo[1,5a]-thieno[3,2-f]diazin-4-one) to minimal gamma-aminobutyric acid potentiations close to that of the antagonist flumazenil (abecarnil and Ro 41-7812; 7-chloro-4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a] -[1,4 ]benzodiazepine-6-one). Punished responding was increased markedly by midazolam and by all partial agonists, except Ro 41-7812 and Ro 42-8773 (7-chloro-3-[3-(cyclopropylmethoxy)-1-propynyl]-4,5-dihyro-5 -methyl-6H-imidaz o[1,5-a][1,4]benzodiazepine-6-one), at doses that did not affect nonpunished responding. In contrast to the full substitution generally observed in mammals, all of the partial agonists produced incomplete substitution (40-70%) in the midazolam drug discrimination procedure in pigeons. A positive relationship was observed between the degree of substitution and intrinsic efficacy. The benzodiazepine antagonists, flumazenil and ZK 93,426 (ethyl-5-isopropoxy-4-methoxymethyl-beta-carboline-3-carboxylate), neither increased punished responding nor

  20. AstRoMap European Astrobiology Roadmap

    PubMed Central

    Horneck, Gerda; Westall, Frances; Grenfell, John Lee; Martin, William F.; Gomez, Felipe; Leuko, Stefan; Lee, Natuschka; Onofri, Silvano; Tsiganis, Kleomenis; Saladino, Raffaele; Pilat-Lohinger, Elke; Palomba, Ernesto; Harrison, Jesse; Rull, Fernando; Muller, Christian; Strazzulla, Giovanni; Brucato, John R.; Rettberg, Petra; Capria, Maria Teresa

    2016-01-01

    Abstract The European AstRoMap project (supported by the European Commission Seventh Framework Programme) surveyed the state of the art of astrobiology in Europe and beyond and produced the first European roadmap for astrobiology research. In the context of this roadmap, astrobiology is understood as the study of the origin, evolution, and distribution of life in the context of cosmic evolution; this includes habitability in the Solar System and beyond. The AstRoMap Roadmap identifies five research topics, specifies several key scientific objectives for each topic, and suggests ways to achieve all the objectives. The five AstRoMap Research Topics are • Research Topic 1: Origin and Evolution of Planetary Systems• Research Topic 2: Origins of Organic Compounds in Space• Research Topic 3: Rock-Water-Carbon Interactions, Organic Synthesis on Earth, and Steps to Life• Research Topic 4: Life and Habitability• Research Topic 5: Biosignatures as Facilitating Life Detection It is strongly recommended that steps be taken towards the definition and implementation of a European Astrobiology Platform (or Institute) to streamline and optimize the scientific return by using a coordinated infrastructure and funding system. Key Words: Astrobiology roadmap—Europe—Origin and evolution of life—Habitability—Life detection—Life in extreme environments. Astrobiology 16, 201–243. PMID:27003862

  1. AstRoMap European Astrobiology Roadmap.

    PubMed

    Horneck, Gerda; Walter, Nicolas; Westall, Frances; Grenfell, John Lee; Martin, William F; Gomez, Felipe; Leuko, Stefan; Lee, Natuschka; Onofri, Silvano; Tsiganis, Kleomenis; Saladino, Raffaele; Pilat-Lohinger, Elke; Palomba, Ernesto; Harrison, Jesse; Rull, Fernando; Muller, Christian; Strazzulla, Giovanni; Brucato, John R; Rettberg, Petra; Capria, Maria Teresa

    2016-03-01

    The European AstRoMap project (supported by the European Commission Seventh Framework Programme) surveyed the state of the art of astrobiology in Europe and beyond and produced the first European roadmap for astrobiology research. In the context of this roadmap, astrobiology is understood as the study of the origin, evolution, and distribution of life in the context of cosmic evolution; this includes habitability in the Solar System and beyond. The AstRoMap Roadmap identifies five research topics, specifies several key scientific objectives for each topic, and suggests ways to achieve all the objectives. The five AstRoMap Research Topics are • Research Topic 1: Origin and Evolution of Planetary Systems • Research Topic 2: Origins of Organic Compounds in Space • Research Topic 3: Rock-Water-Carbon Interactions, Organic Synthesis on Earth, and Steps to Life • Research Topic 4: Life and Habitability • Research Topic 5: Biosignatures as Facilitating Life Detection It is strongly recommended that steps be taken towards the definition and implementation of a European Astrobiology Platform (or Institute) to streamline and optimize the scientific return by using a coordinated infrastructure and funding system. PMID:27003862

  2. Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys.

    PubMed

    Ko, Mei-Chuan; Woods, James H; Fantegrossi, William E; Galuska, Chad M; Wichmann, Jürgen; Prinssen, Eric P

    2009-08-01

    Behavioral effects of a nonpeptidic NOP (nociceptin/orphanin FQ Peptide) receptor agonist, Ro 64-6198, have not been studied in primate species. The aim of the study was to verify the receptor mechanism underlying the behavioral effects of Ro 64-6198 and to systematically compare behavioral effects of Ro 64-6198 with those of a mu-opioid receptor agonist, alfentanil, in monkeys. Both Ro 64-6198 (0.001-0.06 mg/kg, s.c.) and alfentanil (0.001-0.06 mg/kg, s.c.) produced antinociception against an acute noxious stimulus (50 degrees C water) and capsaicin-induced allodynia. An NOP receptor antagonist, J-113397 (0.01-0.1 mg/kg, s.c.), dose-dependently produced rightward shifts of the dose-response curve of Ro 64-6198-induced antinociception. The apparent pA(2) value of J-113397 was 8.0. Antagonist studies using J-113397 and naltrexone revealed that Ro 64-6198 produced NOP receptor-mediated antinociception independent of mu-opioid receptors. In addition, alfentanil dose-dependently produced respiratory depression and itch/scratching responses, but antinociceptive doses of Ro 64-6198 did not produce such effects. More important, Ro 64-6198 did not produce reinforcing effects comparable with those of alfentanil, cocaine, or methohexital under self-administration procedures in monkeys. These results provide the first functional evidence that the activation of NOP receptors produces antinociception without reinforcing effects in primates. Non-peptidic NOP receptor agonists may have therapeutic value as novel analgesics without abuse liability in humans. PMID:19279568

  3. Characterisation of RO fouling in an integrated MBR/RO system for wastewater reuse.

    PubMed

    Moreno, J; Monclús, H; Stefani, M; Cortada, E; Aumatell, J; Adroer, N; De Lamo-Castellví, S; Comas, J

    2013-01-01

    Membrane filtration has gradually gained acceptance as the preferred pre-treatment for reverse osmosis (RO). In this paper, an integrated membrane bioreactor (MBR)/RO system for wastewater reuse treating real sewage water has been evaluated and the RO fouling has been characterised. The MBR achieved low values of organic matter, total nitrogen, PO(4)(3-), total organic carbon, turbidity and conductivity. Filtration with two different RO commercial membranes was performed after the MBR pre-treatment and the same average fouling rate (0.08 bar day(-1)) was noted. These results gained from the characterisation of the high quality MBR/RO permeate show its potential for water reuse. Inorganic precipitation appears to be the predominant form of fouling in the RO membranes. Calcium phosphate and alumino-silicates were identified by a scanning electron microscope combined with an energy dispersive X-ray and polysaccharides, amide and aliphatic structures were detected with attenuated total reflection infrared microspectroscopy. PMID:23306255

  4. Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory

    PubMed Central

    Liu, Jian-Feng; Thorn, David A; Zhang, Yanan

    2016-01-01

    Background: As a modulator of dopaminergic system, trace amine-associated receptor 1 has been shown to play a critical role in regulating the rewarding properties of additive drugs. It has been demonstrated that activation of trace amine-associated receptor 1 decreased the abuse-related behaviors of cocaine in rats. However, the role of trace amine-associated receptor 1 in specific stages of cocaine reward memory is still unclear. Methods: Here, using a cocaine-induced conditioned place preference model, we tested the effects of a selective trace amine-associated receptor 1 agonist RO5166017 on the expression, reconsolidation, and extinction of cocaine reward memory. Results: We found that RO5166017 inhibited the expression but not retention of cocaine-induced conditioned place preference. RO5166017 had no effect on the reconsolidation of cocaine reward memory. Pretreatment with RO5166017 before extinction hindered the formation of extinction long-term memory. RO5166017 did not affect the movement during the conditioned place preference test, indicating the inhibitory effect of RO5166017 on the expression of cocaine-induced conditioned place preference was not caused by locomotion inhibition. Using a cocaine i.v. self-administration model, we found that the combined trace amine-associated receptor 1 partial agonist RO5263397 with extinction had no effect on the following cue- and drug-induced reinstatement of cocaine-seeking behavior. Repeated administration of the trace amine-associated receptor 1 agonist during extinction showed a continually inhibitory effect on the expression of cocaine reward memory both in cocaine-induced conditioned place preference and cocaine self-administration models. Conclusions: Taken together, these results indicate that activation of trace amine-associated receptor 1 specifically inhibited the expression of cocaine reward memory. The inhibitory effect of trace amine-associated receptor 1 agonists on cocaine reward memory suggests

  5. 29 CFR 1918.86 - Roll-on roll-off (Ro-Ro) operations (see also § 1918.2, Ro-Ro operations, and § 1918.25).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... clearly marked and barricaded. (f) Air brake connections. Each tractor shall have all air lines connected... weight of the cargo. (i) Tractors. Tractors used in Ro-Ro operations shall have: (1) Sufficient power...

  6. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs. PMID:19275609

  7. Melanocortin MC4 receptor agonists alleviate brain damage in abdominal compartment syndrome in the rat.

    PubMed

    Liu, Dong; Zhang, Hong-Guang; Zhao, Zi-Ai; Chang, Ming-Tao; Li, Yang; Yu, Jian; Zhang, Ye; Zhang, Lian-Yang

    2015-02-01

    Intra-abdominal hypertension (IAH) is accompanied by high morbidity and mortality in surgical departments and ICUs. However, its specific pathophysiology is unclear. IAH not only leads to intra-abdominal tissue damage but also causes dysfunction in distal organs, such as the brain. In this study, we explore the protective effects of melanocortin 4 receptor agonists in IAH-induced brain injury. The IAH rat models were induced by hemorrhagic shock/resuscitation (with the mean arterial pressure (MAP) maintained at 30 mm Hg for 90 min followed by the reinfusion of the withdrawn blood with lactated Ringer's solution). Then, air was injected into the peritoneal cavity of the rats to maintain an intra-abdominal pressure of 20 mm Hg for 4 h. The effects of the melanocortin 4 receptor agonist RO27-3225 in alleviating the rats' IAH brain injuries were observed, which indicated that RO27-3225 could reduce brain edema, the expressions of the IL-1β and TNF-α inflammatory cytokines, the blood-brain barrier's permeability and the aquaporin4 (AQP4) and matrix metalloproteinase 9 (MMP9) levels. Moreover, the nicotinic acetylcholine receptor antagonist chlorisondamine and the selective melanocortin 4 receptor antagonist HS024 can negate the protective effects of the RO27-3225. The MC4R agonist can effectively reduce the intracerebral proinflammatory cytokine gene expression and alleviate the brain injury caused by blood-brain barrier damage following IAH. PMID:25616531

  8. Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to α4/6β3δ GABAA receptors

    PubMed Central

    Hanchar, H. Jacob; Chutsrinopkun, Panida; Meera, Pratap; Supavilai, Porntip; Sieghart, Werner; Wallner, Martin; Olsen, Richard W.

    2006-01-01

    Although GABAA receptors have long been implicated in mediating ethanol (EtOH) actions, receptors containing the “nonsynaptic” δ subunit only recently have been shown to be uniquely sensitive to EtOH. Here, we show that δ subunit-containing receptors bind the imidazo-benzodiazepines (BZs) flumazenil and Ro15-4513 with high affinity (Kd < 10 nM), contrary to the widely held belief that these receptors are insensitive to BZs. In immunopurified native cerebellar and recombinant δ subunit-containing receptors, binding of the alcohol antagonist [3H]Ro15-4513 is inhibited by low concentrations of EtOH (Ki ≈ 8 mM). Also, Ro15-4513 binding is inhibited by BZ-site ligands that have been shown to reverse the behavioral alcohol antagonism of Ro15-4513 (i.e., flumazenil, β-carbolinecarboxylate ethyl ester (β-CCE), and N-methyl-β-carboline-3-carboxamide (FG7142), but not including any classical BZ agonists like diazepam). Experiments that were designed to distinguish between a competitive and allosteric mechanism suggest that EtOH and Ro15-4513 occupy a mutually exclusive binding site. The fact that only Ro15-4513, but not flumazenil, can inhibit the EtOH effect, and that Ro15-4513 differs from flumazenil by only a single group in the molecule (an azido group at the C7 position of the BZ ring) suggest that this azido group in Ro15-4513 might be the area that overlaps with the alcohol-binding site. Our findings, combined with previous observations that Ro15-4513 is a behavioral alcohol antagonist, suggest that many of the behavioral effects of EtOH at relevant physiological concentrations are mediated by EtOH/Ro15-4513-sensitive GABAA receptors. PMID:16581914

  9. Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to alpha4/6beta3delta GABAA receptors.

    PubMed

    Hanchar, H Jacob; Chutsrinopkun, Panida; Meera, Pratap; Supavilai, Porntip; Sieghart, Werner; Wallner, Martin; Olsen, Richard W

    2006-05-30

    Although GABA(A) receptors have long been implicated in mediating ethanol (EtOH) actions, receptors containing the "nonsynaptic" delta subunit only recently have been shown to be uniquely sensitive to EtOH. Here, we show that delta subunit-containing receptors bind the imidazo-benzodiazepines (BZs) flumazenil and Ro15-4513 with high affinity (K(d) < 10 nM), contrary to the widely held belief that these receptors are insensitive to BZs. In immunopurified native cerebellar and recombinant delta subunit-containing receptors, binding of the alcohol antagonist [(3)H]Ro15-4513 is inhibited by low concentrations of EtOH (K(i) approximately 8 mM). Also, Ro15-4513 binding is inhibited by BZ-site ligands that have been shown to reverse the behavioral alcohol antagonism of Ro15-4513 (i.e., flumazenil, beta-carbolinecarboxylate ethyl ester (beta-CCE), and N-methyl-beta-carboline-3-carboxamide (FG7142), but not including any classical BZ agonists like diazepam). Experiments that were designed to distinguish between a competitive and allosteric mechanism suggest that EtOH and Ro15-4513 occupy a mutually exclusive binding site. The fact that only Ro15-4513, but not flumazenil, can inhibit the EtOH effect, and that Ro15-4513 differs from flumazenil by only a single group in the molecule (an azido group at the C7 position of the BZ ring) suggest that this azido group in Ro15-4513 might be the area that overlaps with the alcohol-binding site. Our findings, combined with previous observations that Ro15-4513 is a behavioral alcohol antagonist, suggest that many of the behavioral effects of EtOH at relevant physiological concentrations are mediated by EtOH/Ro15-4513-sensitive GABA(A) receptors. PMID:16581914

  10. SyRoTek--Distance Teaching of Mobile Robotics

    ERIC Educational Resources Information Center

    Kulich, M.; Chudoba, J.; Kosnar, K.; Krajnik, T.; Faigl, J.; Preucil, L.

    2013-01-01

    E-learning is a modern and effective approach for training in various areas and at different levels of education. This paper gives an overview of SyRoTek, an e-learning platform for mobile robotics, artificial intelligence, control engineering, and related domains. SyRoTek provides remote access to a set of fully autonomous mobile robots placed in…

  11. RoMPS concept review automatic control of space robot

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The Robot operated Material Processing in Space (RoMPS) experiment is being performed to explore the marriage of two emerging space commercialization technologies: materials processing in microgravity and robotics. This concept review presents engineering drawings and limited technical descriptions of the RoMPS programs' electrical and software systems.

  12. Ro/SSA inhibits the autologous mixed lymphocyte reaction.

    PubMed Central

    Karsh, J; Harley, J B; Goldstein, R; Lazarovits, A I

    1993-01-01

    To test the hypothesis that the Ro/SSA autoantigen can be recognized as antigenic by the human immune system, lymphocytes obtained from normal volunteers were used in in vitro assays evaluating the ability of Ro/SSA (mol. wt 60 kD) to induce B and/or T cell responses. Bovine Ro/SSA strongly inhibited the autologous mixed lymphocyte reaction in a dose-dependent manner without similar effects on concurrently performed allogeneic mixed lymphocyte reactions or T cell proliferation induced by phytohaemagglutinin. Using three colour FACS analysis, Ro/SSA was found to decrease the percentage of CD4+CD45+RA+ T cells in the proliferative, S+(G2+M), phase of the cell cycle. Associated with the decrease in the percentage of suppressor-inducer cells, was the finding that Ro/SSA was able to augment RF production in pokeweed mitogen stimulated cultures of peripheral blood lymphocytes. PMID:7678209

  13. Classification of CoRoT Exoplanet Light Curves

    NASA Astrophysics Data System (ADS)

    Sarro, L. M.; Debosscher, J.; Aerts, C.

    2006-11-01

    We describe the methodology developed for the classification of the exoplanet light curves to be assembled by the CoRoT space mission. A supervised classification method will be used to deliver the N3 data products to the CoRoT Additional Programme community. Unsupervised classification will also be performed, but at a later stage of the mission. In the current paper, we provide the class definitions and attributes under consideration for the fast supervised classification. These definitions and attributes will be improved after each long run of CoRoT.

  14. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  15. Assuring the Legacy of the CoRoT Planets

    NASA Astrophysics Data System (ADS)

    Deeg, H. J.; Klagyivik, P.; Alonso, R.; Hoyer, S.

    2015-09-01

    For the long-lasting impact of CoRoT's planet findings, precise knowledge of the times of their transits is of vital importance for any future observing campaigns. Here we give the motivation and first results of a systematic revisit of the transits of most CoRoT planets to refine their ephemeris. As secondary objectives, more precise planet characterisations, from period or transit shape variations on/and from use of a well-defined passband may be obtained.

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

    PubMed Central

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

    2014-01-01

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

  17. GCM simulated geopotential heights compared to GPS RO data

    NASA Astrophysics Data System (ADS)

    Molodtsov, S.; Kirilenko, A.; Olsen, D.

    2012-12-01

    Accurate, high-quality, global coverage data is required for global climate monitoring. It also provides possibility of additional validation of the general circulation models (GCMs). GPS Radio occultation (GPS RO) measurements have potential of becoming a new benchmark in data acquisition, providing new high-quality profiles of the parameters of the atmosphere, such as the temperature, water vapor pressure, and geopotential heights. In our study we use GPS RO data with a purpose to test global circulation models (GCMs). We study how climate change signal emerges in the GPS RO data and how these signals are reflected in GCM simulations. We use temperature and geopotential height profiles from 2001-2006 CHAMP and 2006-2011 COMIC acquisitions to validate the output from twelve IPCC AR4 GCMs run under A1B SRES scenario. We found that the 2001-2011 trends of the temperature and geopotential height derived from the IPCC AR4 GCMs show the same pattern with trends derived from GPS RO data - warming of the upper troposphere (UT) and cooling of the lower stratosphere (LS). There is some discrepancy between trends in lower troposphere (LT) between models and GPS RO data: some GCMs show decreasing temperature and geopotential height trends while the GPS RO trends are positive. The statistical analysis of these trends will be reported.

  18. Anti-ENA profiles related with anti-SS-A/Ro. The detection of Ro52 and Ro60 according to the presence of SS-B/La, and ANA pattern and titer.

    PubMed

    González, D Almeida; Rodríguez, C Casañas; Armas, L Magdalena; Varela, A Roces; Rodríguez, I Marcelino; Duarte, M Troche; de León, A Cabrera

    2014-09-01

    Anti-Ro52 (Ro52) and anti-Ro60 (Ro60) antibodies are associated with different clinical entities. We investigated their relationship with the presence of anti-SS-B/La (SSB) antibody, the pattern and titer of antinuclear antibody (ANA), and the variations in antibody profiles related with anti-SS-A/Ro (SSA) positivity. Our aim was to develop a strategy to increase the efficiency of anti-extractable nuclear antigen (ENA) determinations. Statistical analyses were based on the Chi-squared test for categorical variables, the Mann-Whitney U test to compare profiles, and the odds ratio (OR) and 95% confidence interval (95% CI) to estimate the risk of variability. We analyzed 800 SSA-positive samples with Ro52 or Ro60 reactivity. The most frequent profiles were Ro52+Ro60+SSB (n=349, 43.6%); Ro52+Ro60 (n=126, 15.8%); Ro52 (n=121, 15.1%) and Ro60 (n=71, 8.9%). In samples positive only for SSA and an ANA titer ≤1:640, the most likely profile was positivity for either Ro52 or Ro60, whereas when the ANA titer was >1:640, positivity for both Ro52 and Ro60 simultaneously was more likely (p<0.001). In samples positive for both SSA and SSB, the most likely profile was Ro52+Ro60+SSB regardless of the ANA titer (p=0.001). When only SSA was positive and the ANA staining pattern was nucleolar, centromeric or cytoplasmic, Ro52 positivity was most likely (p<0.001). When both SSA and SSB were positive, both Ro52 and Ro60 were likely to be positive regardless of the ANA staining pattern. In 28.7% of the patients the profile was variable. Variability was significantly greater in those with the SSA profile (23/67) than with the SSA+SSB profile (15/105; OR=1.9, 95% CI=1.1-3.3; p=0.025), and the difference in variability was greatest between the Ro52+Ro60 profile (8/23) and the Ro52+Ro60+SSB profile (8/68; OR=4.2, 95% CI=1.9-9.5; p<0.001). We conclude that to increase efficiency in the immunology laboratory, positivity for Ro52 and Ro60 individually or simultaneously can be deduced from SSB

  19. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  20. Stellar cycles from photometric data: CoRoT stars

    NASA Astrophysics Data System (ADS)

    Ferreira Lopes, C. E.; Leão, I. C.; de Freitas, D. B.; Canto Martins, B. L.; Catelan, M.; De Medeiros, J. R.

    2015-11-01

    Context. Until a few years ago, the amplitude variation in the photometric data had been explored to a limited extent mainly because of time resolution and photometric sensitivity limitations. This investigation is now possible thanks to the Kepler and CoRoT databases which provide a unique set of data for studying the nature of stellar variability cycles. Aims: The present study characterizes the amplitude variation in a sample of main-sequence stars with light curves collected using CoRoT exofield CCDs. Methods: We analyze potential stellar activity cycles by studying the variability amplitude over small boxes. The cycle periods and amplitudes were computed based on the Lomb-Scargle periodogram, harmonic fits, and visual inspection. As a first application of our approach, we considered the photometric data for 16 CoRoT FGK main sequence stars, revisited during the IRa01, LRa01 and LRa06 CoRoT runs. Results: The 16 CoRoT stars appear to follow the empirical relations between activity cycle periods (Pcyc) and the rotation period (Prot) found by previous works. In addition to the so-called A (active) and I (inactive) sequences previously identified, there is a possible third sequence, here named S (short-cycles) sequence. However, recovery fractions estimated from simulations suggest that only a half of our sample has confident cycle measurements. Therefore, more study is needed to verify our results, and Kepler data will clearly be useful for such a study. Overall, our procedure provides a key tool for exploring the CoRoT and Kepler databases to identify and characterize stellar cycle variability. The CoRoT space mission was developed and is operated by the French space agency CNES, with the participation of ESA's RSSD and Science Programmes, Austria, Belgium, Brazil, Germany, and Spain.

  1. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  2. CoRoT data reduction by example

    NASA Astrophysics Data System (ADS)

    Weingrill, J.

    2015-02-01

    Data reduction techniques published so far for the CoRoT N2 data product were targeted primarily on the detection of extrasolar planets. Since the whole dataset has been released, specific algorithms are required to process the lightcurves from CoRoT correctly. Though only unflagged datapoints must be chosen for scientific processing, some flags might be reconsidered. The reduction of data along with improving the signal-to-noise ratio can be achieved by applying a one dimensional drizzle algorithm. Gaps can be filled by linear interpolated data without harming the frequency spectrum. Magnitudes derived from the CoRoT color channels might be used to derive additional information about the targets. Depending on the needs, various filters in the frequency domain remove either the red noise background or high frequency noise. The autocorrelation function or the least squares periodogram are appropriate methods to identify periodic signals. The methods described here are not strictly limited to CoRoT data but may also be applied on Kepler data or the upcoming PLATO mission. The CoRoT space mission, launched on 2006 December 27, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain.

  3. Evaluation of RO modules for the SSP ETC/LSS.

    NASA Technical Reports Server (NTRS)

    Jasionowski, W. J.; Bambenek, R. A.

    1973-01-01

    During the past eight years the NASA Manned Spacecraft Center has supported the development of an Integrated Water and Waste Management System for use in the Space Station Prototype (SSP) Environmental Thermal Control/Life-Support System (ETC/LSS). This system includes the reverse osmosis (RO) process for recycling wash water and the compression distillation process for recovering useable water from urine, urinal flush water, humidity condensate, commode flush water and the wash water concentrated by RO. This paper summarizes the experimental work performed during the past four years to select the best commercially available RO module for this system and to also define which surfactants and germicides are most compatible with the selected module.

  4. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  5. Treatment of RO brine-towards sustainable water reclamation practice.

    PubMed

    Ng, H Y; Lee, L Y; Ong, S L; Tao, G; Viawanath, B; Kekre, K; Lay, W; Seah, H

    2008-01-01

    Treatment and disposal of RO brine is an important part in sustaining the water reclamation practice. RO brine generated from water reclamation contains high concentration of organic and inorganic compounds. Cost-effective technologies for treatment of RO brine are still relatively unexplored. Thus, this study aim to determine a feasible treatment process for removal of both organic and inorganic compounds in RO brine generated from NEWater production. The proposed treatment consists of biological activated carbon (BAC) column followed by capacitive deionization (CDI) process for organic and inorganic removals, respectively. Preliminary bench-scale study demonstrated about 20% TOC removal efficiency was achieved using BAC at 40 mins empty bed contact time (EBCT) while the CDI process was able to remove more than 90% conductivity reducing it from 2.19 mS/cm to only about 164 microS/cm. More than 90% cations and anions in the BAC effluent were removed using CDI process. In addition, TOC and TN removals of 78% and 91%, respectively were also attained through this process. About 90% water recovery was achieved. This process shows the potential of increased water recovery in the reclamation process while volume for disposal can be further minimized. Further studies on the sustainable operation and process optimization are ongoing. PMID:18776632

  6. Removing Arsenic with a Softening/RO Combo

    EPA Science Inventory

    This paper provides a very short summary of the arsenic demonstration program and the limited test results from the point-of-use (POU), reverse osmosis (RO) project in Homedale, ID. Preformance data is presented on the effectiveness of the POU treatment system to remove arseni...

  7. AmeriFlux US-Ro3 Rosemount- G19

    SciTech Connect

    Baker, John; Griffis, Tim

    2016-01-01

    This is the AmeriFlux version of the carbon flux data for the site US-Ro3 Rosemount- G19. Site Description - This tower is located in a farm field farmed in accordance with the cominant farming practice in the region: a corn/soybean rotation with chisel plow tillage in the fall following corn harvest and in the spring following soybeans.

  8. AmeriFlux US-Ro1 Rosemount- G21

    SciTech Connect

    Baker, John; Griffis, Tim; Griffis, Timothy

    2016-01-01

    This is the AmeriFlux version of the carbon flux data for the site US-Ro1 Rosemount- G21. Site Description - This tower is located in a farm field farmed in accordance with the dominant farming practice in the region: a corn/soybean rotation with chisel plow tillage in the fall following corn harvest and in the spring following soybeans.

  9. Asteroseismology of OB stars with CoRoT

    NASA Astrophysics Data System (ADS)

    Degroote, P.; Aerts, C.; Samadi, R.; Miglio, A.; Briquet, M.; Auvergne, M.; Baglin, A.; Baudin, F.; Catala, C.; Michel, E.

    2010-12-01

    The CoRoT satellite is revolutionizing the photometric study of massive O-type and B-type stars. During its long runs, CoRoT observed the entire main sequence B star domain, from typical hot β Cep stars, via cooler hybrid p- and g-mode pulsators to the SPB stars near the edge of the instability strip. CoRoT lowers the sensitivity barrier from the typical mmag-precision reached from the ground, to the μmag-level reached from space. Within the wealth of detected and identified pulsation modes, relations have been found in the form of multiplets, combination of frequencies, and frequency- and period spacings. This wealth of observational evidence is finally providing strong constraints to test current models of the internal structure and pulsations of hot stars. Aside from the expected opacity driven modes with infinite lifetime, other unexpected types of variability are detected in massive stars, such as modes of stochastic nature. The simultaneous observation of all these light curve characteristics implies a challenge for both observational asteroseismology and stellar modelling. The CoRoT space mission was developed and is operated by the French space agency CNES, with participation of ESA's RSSD and Science Programmes, Austria, Belgium, Brazil, Germany, and Spain.

  10. Is ultraviolet radiation on haemodialysis RO water beneficial?

    PubMed

    Stragier, A

    2005-01-01

    The quality of dialysis fluids has become increasingly important in the treatment of HD patients. Purified water represents over 95% of its volume. Bacterial and endotoxin content of Reverse Osmosis (RO) water is usually kept under control by bacterial filters, inserted in the distribution departure loop, and by monthly disinfection of the distribution circuit; the simpler the circuit, the better. This paper reports 12 years experience during which Ultraviolet Irradiation (UV) has replaced bacterial filters. To keep the bacterial growth under control in a complex RO water circuit (including a tank and multiple loops) a simple UV lamp was inserted in the departure line. It proved sufficient to keep bacterial count within AAMI norms. Failure of the UV lamp was associated with a rise of up to 500 cfu/ml in the last (fourth week) before routine disinfection. Normal levels were again obtained after replacement of the UV lamp. Six years later, a second UV lamp was added on the return loop. Bacterial counts and endotoxin levels in RO water promptly fell to <1 cfu/ml and <0.125 EU, till today. It is concluded that UV lamps should be favoured over bacterial filters in systems that are not disinfected daily, such as the RO water circuit. The principle of UV irradiation is explained and its advantage over bacterial filters is discussed. Future possible applications of UV are presented. PMID:16551024

  11. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  12. Piperidine derivatives as nonprostanoid IP receptor agonists.

    PubMed

    Hayashi, Ryoji; Sakagami, Hideki; Koiwa, Masakazu; Ito, Hiroaki; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-05-01

    The discovery of a new class of nonprostanoid prostaglandin I2 receptor (IP receptor) agonists is reported. Among them, the unique piperidine derivative 31b (2-((1-(2-(N-(4-tolyl)benzamido)ethyl)piperidin-4-yl)oxy)acetic acid) was a good IP receptor agonist and was 50-fold more selective for the human IP receptor than for other human prostanoid receptors. This compound showed good pharmacokinetic properties in dog. PMID:26996371

  13. In vitro and in vivo evaluation of iodine-123-Ro 16-0154: A new imaging agent for SPECT investigations of benzodiazepine receptors

    SciTech Connect

    Beer, H.F.; Blaeuenstein, P.A.H.; Hasler, P.H.; Delaloye, B.; Riccabona, G.; Bangerl, I.; Hunkeler, W.; Bonetti, E.P.; Pieri, L.; Richards, J.G. )

    1990-06-01

    The flumazenil analogue, Ro 16-0154, a benzodiazepine partial inverse agonist, has been labeled by halogen exchange to enable SPECT investigations of central benzodiazepine receptors in the human brain. The purified {sup 123}I-Ro 16-0154 was found to be stable in rat brain preparations and to be metabolized in rat liver preparations. Its pharmacologic properties were comparable to those of flumazenil. The biodistribution in rats (1 hr postinjection) resulted in a high brain-to-blood ratio of 16. Clinical studies revealed images of the benzodiazepine receptor density in the brain. Since the receptor labeling was markedly reduced by injection of flumazenil, it was considered to be specific. Storage defects due to pathologic cerebral blood flow and changed receptor density were detected; this shows the potential usefulness of the substance for diagnostic purposes, e.g., the differential diagnosis of various forms of epilepsy.

  14. Cold molecules: Formation, ro-vibrational cooling and electronic conversion

    NASA Astrophysics Data System (ADS)

    Horchani, R.

    2016-05-01

    The possibility of controlling all the motion as well as the internal quantum state of a sample of molecules is a long term goal in the cold molecules field. Although many different techniques have been used to produce ultra-cold molecules, in this paper, we will concentrate on the optical pumping technique successfully used to achieve rotational and vibrational cooling of Cs2 molecules. We will review the different photo-association schemes for molecule formation, the detection schemes through photoionization, the ro-vibrational cooling into a single level and finally the electronic conversion. In addition, we will present a theoretical model for both ro-vibrational cooling and electronic conversion that can be used for the preparation of different experiments.

  15. Validation of Robotic Surgery Simulator (RoSS).

    PubMed

    Kesavadas, Thenkurussi; Stegemann, Andrew; Sathyaseelan, Gughan; Chowriappa, Ashirwad; Srimathveeravalli, Govindarajan; Seixas-Mikelus, Stéfanie; Chandrasekhar, Rameella; Wilding, Gregory; Guru, Khurshid

    2011-01-01

    Recent growth of daVinci Robotic Surgical System as a minimally invasive surgery tool has led to a call for better training of future surgeons. In this paper, a new virtual reality simulator, called RoSS is presented. Initial results from two studies - face and content validity, are very encouraging. 90% of the cohort of expert robotic surgeons felt that the simulator was excellent or somewhat close to the touch and feel of the daVinci console. Content validity of the simulator received 90% approval in some cases. These studies demonstrate that RoSS has the potential of becoming an important training tool for the daVinci surgical robot. PMID:21335803

  16. THE MASS OF CoRoT-7b

    SciTech Connect

    Hatzes, Artie P.; Wuchterl, Guenther; Fridlund, Malcolm; Gandolfi, Davide; Nachmani, Gil; Mazeh, Tsevi; Valencia, Diana; Hebrard, Guillaume; Borde, Pascal; Carone, Ludmila; Paetzold, Martin; Udry, Stephane; Bouchy, Francois; Deleuil, Magali; Moutou, Claire; Barge, Pierre; Deeg, Hans; Tingley, Brandon; Dvorak, Rudolf; Ferraz-Mello, Sylvio E-mail: malcolm.fridlund@esa.int; and others

    2011-12-10

    The mass of CoRoT-7b, the first transiting super-Earth exoplanet, is still a subject of debate. A wide range of masses have been reported in the literature ranging from as high as 8 M{sub Circled-Plus} to as low as 2.3 M{sub Circled-Plus }. This range in mass is largely due to the activity level of the star that contributes a significant amount of radial velocity (RV) 'jitter' and how the various methods correct this jitter. Although most mass determinations give a density consistent with a rocky planet, the lower value permits a bulk composition that can be up to 50% water. We present an analysis of the CoRoT-7b RV measurements that uses very few and simple assumptions in treating the activity signal. By analyzing those RV data for which multiple measurements were made in a given night, we remove the activity related RV contribution without any a priori model. We argue that the contribution of activity to the final RV curve is negligible and that the K-amplitude due to the planet is well constrained. This yields a mass of 7.42 {+-} 1.21 M{sub Circled-Plus} and a mean density of {rho} = 10.4 {+-} 1.8 gm cm{sup -3}. CoRoT-7b is similar in mass and radius to the second rocky planet to be discovered, Kepler-10b, and within the errors they have identical bulk densities-they are virtual twins. These bulk densities lie close to the density-radius relationship for terrestrial planets similar to what is seen for Mercury. CoRoT-7b and Kepler-10b may have an internal structure more like Mercury than the Earth.

  17. CoRoT space photometry of seven Cepheids

    NASA Astrophysics Data System (ADS)

    Poretti, E.; Le Borgne, J. F.; Rainer, M.; Baglin, A.; Benkő, J. M.; Debosscher, J.; Weiss, W. W.

    2015-11-01

    A few Galactic classical Cepheids were observed in the programmes of space missions as Coriolis, MOST, and Kepler. An appealing opportunity was to detect additional non-radial modes, thus opening the possibility to perform asteroseismic studies and making the pulsational content of Galactic Cepheids more similar to that of Magellanic Clouds ones. However, only hints of cycle-to-cycle variations were found, without any strict periodicity. In this context the potential of the CoRoT exoplanetary data base was not fully exploited despite the wide area covered on the Galactic plane. Therefore, we investigated all the candidate Cepheids pointed out by the automatic classification of the CoRoT curves. At the end, we could identify seven bona fide Cepheids. The light curves were investigated to remove some instrumental effects. The frequency analysis was particularly delicate since these small effects can be enhanced by the large amplitude, resulting in the presence of significant, but spurious, peaks in the power spectrum. Indeed, the careful evaluation of a very attracting peak in the spectra of CoRoT 0102618121 allowed us to certify its spurious origin. Once that the instrumental effects were properly removed, no additional mode was detected. On the other hand, cycle-to-cycle variations of the Fourier parameters were observed, but very small and always within ±3σ. Among the seven Cepheids, there are two Pop. I first-overtone pulsators, four Pop. I fundamental mode pulsators, and one Pop. II star. The CoRoT colours allowed us to measure that times of maximum brightness occur a little earlier (about 0.01 period) at short wavelengths than at long ones.

  18. The Mass of CoRoT-7b

    NASA Astrophysics Data System (ADS)

    Hatzes, Artie P.; Fridlund, Malcolm; Nachmani, Gil; Mazeh, Tsevi; Valencia, Diana; Hébrard, Guillaume; Carone, Ludmila; Pätzold, Martin; Udry, Stephane; Bouchy, Francois; Deleuil, Magali; Moutou, Claire; Barge, Pierre; Bordé, Pascal; Deeg, Hans; Tingley, Brandon; Dvorak, Rudolf; Gandolfi, Davide; Ferraz-Mello, Sylvio; Wuchterl, Günther; Guenther, Eike; Guillot, Tristan; Rauer, Heike; Erikson, Anders; Cabrera, Juan; Csizmadia, Szilard; Léger, Alain; Lammer, Helmut; Weingrill, Jörg; Queloz, Didier; Alonso, Roi; Rouan, Daniel; Schneider, Jean

    2011-12-01

    The mass of CoRoT-7b, the first transiting super-Earth exoplanet, is still a subject of debate. A wide range of masses have been reported in the literature ranging from as high as 8 M ⊕ to as low as 2.3 M ⊕. This range in mass is largely due to the activity level of the star that contributes a significant amount of radial velocity (RV) "jitter" and how the various methods correct this jitter. Although most mass determinations give a density consistent with a rocky planet, the lower value permits a bulk composition that can be up to 50% water. We present an analysis of the CoRoT-7b RV measurements that uses very few and simple assumptions in treating the activity signal. By analyzing those RV data for which multiple measurements were made in a given night, we remove the activity related RV contribution without any a priori model. We argue that the contribution of activity to the final RV curve is negligible and that the K-amplitude due to the planet is well constrained. This yields a mass of 7.42 ± 1.21 M ⊕ and a mean density of ρ = 10.4 ± 1.8 gm cm-3. CoRoT-7b is similar in mass and radius to the second rocky planet to be discovered, Kepler-10b, and within the errors they have identical bulk densities—they are virtual twins. These bulk densities lie close to the density-radius relationship for terrestrial planets similar to what is seen for Mercury. CoRoT-7b and Kepler-10b may have an internal structure more like Mercury than the Earth.

  19. Submillimeter Astronomy from the South Pole (AST/RO)

    NASA Astrophysics Data System (ADS)

    Stark, Antony A.

    2013-01-01

    The Antarctic Submillimeter Telescope and Remote Observatory (AST/RO), a 1.7 m diameter offset Gregorian telescope for astronomy and aeronomy studies at wavelengths between 200 and 2000 μm, saw first light in 1995 and operated until 2005. It was the first radio telescope to operate continuously throughout the winter on the Antarctic Plateau. It served as a site testing instrument and prototype for later instruments, as well as executing a wide variety of scientific programs that resulted in six doctoral theses and more than one hundred scientific publications. The South Pole environment is unique among observatory sites for unusually low wind speeds, low absolute humidity, and the consistent clarity of the submillimeter sky. Especially significant are the exceptionally low values of sky noise found at this site, a result of the small water vapor content of the atmosphere. Multiple submillimeter-wave and Terahertz detector systems were in operation on AST/RO, including heterodyne and bolometric arrays. AST/RO's legacy includes comprehensive submillimeter-wave site testing of the South Pole, spectroscopic studies of 492 GHz and 809 GHz neutral atomic carbon and 460 GHz and 806 GHz carbon monoxide in the Milky Way and Magellanic Clouds, and the first detection of the 1.46 THz [N II] line from a ground-based observatory.

  20. Discoveries in the Atmospheres of roAp Stars

    NASA Astrophysics Data System (ADS)

    Kurtz, D. W.; Freyhammer, L. M.; Elkin, V. G.; Mathys, G.

    2007-11-01

    We have obtained a large amount of data on over 40 roAp stars and potential roAp stars with the Ultraviolet and Visual Echelle Spectrograph (UVES) on the VLT with time resolution typically around 1 min and radial velocity precision as high as 1 m s-1. Abundance stratification caused by atomic diffusion in the presence of strong global magnetic fields gives promise of three-dimensional maps of the pulsation amplitude and phase, and of the abundance distributions of many ions that may provide the strongest observational tests of atomic diffusion theory. Studies of individual spectral lines and of line profile variability sample the observable atmospheres of roAp stars from continuum optical depth τ5000~1 to as high as τ5000~10-5, revealing fascinating new pulsational behaviour not observed in other types of pulsating stars, including, inter alia, line profile variability in rare earth elements lines interpreted by as evidence for shock waves in the high atmosphere of these stars, an intriguing range of line bisector shapes, and a new pulsational diagnostic for resolved Zeeman components for the most strongly magnetic stars.

  1. VizieR Online Data Catalog: CoRoT/Exoplanet fields with MATISSE (Gazzano+, 2010)

    NASA Astrophysics Data System (ADS)

    Gazzano, J.-C.; de Laverny, P.; Deleuil, M.; Recio-Blanco, A.; Bouchy, F.; Moutou, C.; Bijaoui, A.; Ordenovic, C.; Gandoli, D.; Loeillet, B.

    2010-11-01

    Atomic data modifications from VALD initial request, atmospheric parameters for 1227 CoRoT targets, radial velocity for 1534 CoRoT targets, and Vsini for 1604 CoRoT targets in three CoRoT/Exoplanet fields LRa01, LRc01, and SRc01. The reported uncertainties are only internal errors. (6 data files).

  2. Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [11C]Ro15-4513 PET images

    PubMed Central

    Myers, James FM; Rosso, Lula; Watson, Ben J; Wilson, Sue J; Kalk, Nicola J; Clementi, Nicoletta; Brooks, David J; Nutt, David J; Turkheimer, Federico E; Lingford-Hughes, Anne R

    2012-01-01

    This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume (VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant VT decrease (∼10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect α1-subtype binding, but not another (13%±22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands. PMID:22214903

  3. Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study.

    PubMed

    Stokes, Paul R A; Myers, Jim F; Kalk, Nicola J; Watson, Ben J; Erritzoe, David; Wilson, Sue J; Cunningham, Vincent J; Riano Barros, Daniela; Hammers, Alexander; Turkheimer, Federico E; Nutt, David J; Lingford-Hughes, Anne R

    2014-10-01

    The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [(11)C]Ro15-4513 binding in 12 male participants using a paired, double blind, placebo-controlled protocol. Spectral analysis was used to examine synaptic α1 and extrasynaptic α5 GABA-BZR subtype availability in brain regions with high levels of [(11)C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [(11)C]Ro15-4513 binding in a separate cohort of 4 participants using the same spectral analysis protocol. Tiagabine administration produced significant reductions in hippocampal, parahippocampal, amygdala and anterior cingulate synaptic α1 [(11)C]Ro15-4513 binding, and a trend significance reduction in the nucleus accumbens. These reductions were greater than test-retest reliability, indicating that they are not the result of chance observations. Our results suggest that acute increases in endogenous synaptic GABA are detectable in the living human brain using [(11)C]Ro15-4513 PET. These findings have potentially major implications for the investigation of GABA function in brain disorders and in the development of new treatments targeting this neurotransmitter system. PMID:24844747

  4. Effects of (−)-RO363 at human atrial β-adrenoceptor subtypes, the human cloned β3-adrenoceptor and rodent intestinal β3-adrenoceptors

    PubMed Central

    Molenaar, Peter; Sarsero, Doreen; Arch, Jonathan R S; Kelly, John; Henson, Sian M; Kaumann, Alberto J

    1997-01-01

    Chronic treatment of patients with β-blockers causes atrial inotropic hyperresponsiveness through β2-adrenoceptors, 5-HT4 receptors and H2-receptors but apparently not through β1-adrenoceptors despite data claiming an increased β1-adrenoceptor density from homogenate binding studies. We have addressed the question of β1-adrenoceptor sensitivity by determining the inotropic potency and intrinsic activity of the β1-adrenoceptor selective partial agonist (−)-RO363 and by carrying out both homogenate binding and quantitative β-adrenoceptor autoradiography in atria obtained from patients treated or not treated with β-blockers. In the course of the experiments it became apparent that (−)-RO363 also may cause agonistic effects through the third atrial β-adrenoceptor. To assess whether (−)-RO363 also caused agonistic effects through β3-adrenoceptors we studied its relaxant effects in rat colon and guinea-pig ileum, as well as receptor binding and adenylyl cyclase stimulation of chinese hamster ovary (CHO) cells expressing human β3-adrenoceptors. β-Adrenoceptors were labelled with (−)-[125I]-cyanopindolol. The density of both β1- and β2-adrenoceptors was unchanged in the 2 groups, as assessed with both quantitative receptor autoradiography and homogenate binding. The affinities of (−)-RO363 for β1-adrenoceptors (pKi=8.0–7.7) and β2-adrenoceptors (pKi=6.1–5.8) were not significantly different in the two groups. (−)-RO363 increased atrial force with a pEC50 of 8.2 (β-blocker treated) and 8.0 (non-β-blocker treated) and intrinsic activity with respect to (−)-isoprenaline of 0.80 (β-blocker treated) and 0.54 (non-β-blocker treated) (P<0.001) and with respect to Ca2+ (7 mM) of 0.65 (β-blocker treated) and 0.45 (non-β-blocker treated) (P<0.01). The effects of (−)-RO363 were resistant to antagonism by the β2-adrenoceptor antagonist, ICI 118,551 (50 nM). The effects of 0.3–10 nM (−)-RO363 were antagonized by 3–10 nM of the

  5. Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development

    PubMed Central

    2013-01-01

    The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development. PMID:24900784

  6. Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development.

    PubMed

    Zhang, Zhuming; Chu, Xin-Jie; Liu, Jin-Jun; Ding, Qingjie; Zhang, Jing; Bartkovitz, David; Jiang, Nan; Karnachi, Prabha; So, Sung-Sau; Tovar, Christian; Filipovic, Zoran M; Higgins, Brian; Glenn, Kelli; Packman, Kathryn; Vassilev, Lyubomir; Graves, Bradford

    2014-02-13

    The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development. PMID:24900784

  7. Antioxidative properties of ginsenoside Ro against UV-B-induced oxidative stress in human dermal fibroblasts.

    PubMed

    Kang, Hyun Ji; Oh, Yuri; Lee, Sihyeong; Ryu, In Wang; Kim, Kyunghoon; Lim, Chang-Jin

    2015-01-01

    Ginsenoside Ro (Ro), an oleanolic acid-type ginsenoside, exhibited suppressive activities on reactive oxygen species (ROS) and matrix metalloproteinase-2 (MMP-2) elevation in UV-B-irradiated fibroblasts. Ro could overcome the reduction of the total glutathione (GSH) contents in UV-B-irradiated fibroblasts. Ro could not interfere with cell viabilities in UV-B-irradiated fibroblasts. Collectively, Ro possesses a potential skin anti-photoaging property against UV-B radiation in fibroblasts. PMID:26214051

  8. Radiosensitivity of CD45RO{sup +} memory and CD45RO{sup {minus}} naive T cells in culture

    SciTech Connect

    Uzawa, Akiko; Suzuki, Gen; Nakata, Yukiko; Akashi, Makoto; Ohyama, Harumi; Akanuma, Atsuo

    1994-01-01

    Radiosensitivities of various human T-cell subsets were investigated by a proliferation assay and by a single-cell gel electrophoresis assay. Each T-cell subset was purified using a cell sorter and was induced to proliferate by ionomycin and interleukin 2. Unsorted T cells showed biphasic dose-survival curves, indicating the heterogeneity of T cells in terms of radiosensitivity. Purified CD4{sup +} helper and CD8{sup +} killer T cells showed similar biphasic dose-survival curves. Hence both T-cell subsets were composed of cells of different radiosensitivity. The T-cell subsets belonging to different activation stages such as CD45RO{sup +} memory and CD45RO{sup {minus}} naive T cells had different dose-survival curves. The former was more radiosensitive than the latter. The high radiosensitivity of CD45RO{sup +} cells was also demonstrated by single-cell gel electrophoresis after irradiation. This is the first demonstration that a particular cell surface marker on T cells is correlated with greater radiosensitivity. 27 refs., 7 figs., 1 tab.

  9. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  10. Dispersion and nonlinear effects in OFDM-RoF system

    NASA Astrophysics Data System (ADS)

    Alhasson, Bader H.; Bloul, Albe M.; Matin, M.

    2010-08-01

    The radio-over-fiber (RoF) network has been a proven technology to be the best candidate for the wireless-access technology, and the orthogonal frequency division multiplexing (OFDM) technique has been established as the core technology in the physical layer of next generation wireless communication system, as a result OFDM-RoF has drawn attentions worldwide and raised many new research topics recently. At the present time, the trend of information industry is towards mobile, wireless, digital and broadband. The next generation network (NGN) has motivated researchers to study higher-speed wider-band multimedia communication to transmit (voice, data, and all sorts of media such as video) at a higher speed. The NGN would offer services that would necessitate broadband networks with bandwidth higher than 2Mbit/s per radio channel. Many new services emerged, such as Internet Protocol TV (IPTV), High Definition TV (HDTV), mobile multimedia and video stream media. Both speed and capacity have been the key objectives in transmission. In the meantime, the demand for transmission bandwidth increased at a very quick pace. The coming of 4G and 5G era will provide faster data transmission and higher bit rate and bandwidth. Taking advantages of both optical communication and wireless communication, OFDM Radio over Fiber (OFDM-RoF) system is characterized by its high speed, large capacity and high spectral efficiency. However, up to the present there are some problems to be solved, such as dispersion and nonlinearity effects. In this paper we will study the dispersion and nonlinearity effects and their elimination in OFDM-radio-over-fiber system.

  11. Introduction of a single isomer beta agonist.

    PubMed

    Rau, J L

    2000-08-01

    The release of levalbuterol offers the first approved single-isomer beta agonist for oral inhalation. Data from in vitro studies support the concept that S albuterol is not inactive and may have properties antagonistic to bronchodilation. There is some variability in the results of clinical studies with the separate isomers of albuterol, which suggests the need for further study. The introduction of levalbuterol into general clinical use in managing asthma and chronic obstructive disease should begin to offer additional information on the effects of a single isomer beta agonist in comparison to previous racemic mixtures. PMID:10963321

  12. Effect of dopamine D4 receptor agonists on sleep architecture in rats.

    PubMed

    Nakazawa, Shunsuke; Nakamichi, Keiko; Imai, Hideaki; Ichihara, Junji

    2015-12-01

    Dopamine plays a key role in the regulation of sleep-wake states, as revealed by the observation that dopamine-releasing agents such as methylphenidate have wake-promoting effects. However, the precise mechanisms for the wake-promoting effect produced by the enhancement of dopamine transmission are not fully understood. Although dopamine D1, D2, and D3 receptors are known to have differential effects on sleep architecture, the role of D4 receptors (D4Rs), and particularly the influence of D4R activation on the sleep-wake state, has not been studied so far. In this study, we investigated for the first time the effects of two structurally different D4R agonists, Ro 10-5824 and A-412997, on the sleep-wake states in rats. We found that both D4R agonists generally increased waking duration, and conversely, reduced non-rapid eye movement (NREM) sleep duration in rats. The onset of NREM sleep was also generally delayed. However, only the A-412997 agonist (but not the Ro 10-5824) influenced rapid eye movement sleep onset and duration. Furthermore, these effects were accompanied with an enhancement of EEG spectral power in the theta and the gamma bands. Our results suggest the involvement of dopamine D4R in the regulation of sleep-wake states. The activation of the D4R could enhance the arousal states as revealed by the behavioral and electrophysiological patterns in this study. Dopamine D4R may contribute to the arousal effects of dopamine-releasing agents such as methylphenidate. PMID:25985889

  13. The driving mechanism of roAp stars

    NASA Astrophysics Data System (ADS)

    Dupret, M.-A.; Théado, S.; Noels, A.

    2008-10-01

    We analyse in detail the driving mechanism of roAp stars and present the theoretical instability strip predicted by our models with solar metallicity. A particular attention is given to the interpretation of the role played by the different eigenfunctions in the stabilization of the modes at the red edge of the instability strip. The gradient of temperature in the HI opacity bump appears to play a major role in this context. We also consider the particular and complex role played by the shape of the eigenfunctions (location of the nodes, ...).

  14. Long period oscillations in roAp stars

    NASA Astrophysics Data System (ADS)

    Riley, J. D.; Kurtz, D. W.; Cunha, M. S.

    2004-12-01

    We present the results of observations made over three weeks using the UCT CCD Photometer on the 0.75-m telescope at the South African Astronomical Observatory. Candidate long period roAp stars were identified from their positions on the H-R diagram and observed for a typical period of 4 hr to test for the existence of pulsations, with particular emphasis on pulsations with periods in excess of 15 min. Although 13 stars were successfully observed, none exhibited significant pulsations.

  15. Comparison of antibody assays for detection of autoantibodies to Ro 52, Ro 60 and La associated with primary Sjögren's syndrome.

    PubMed

    Trier, Nicole Hartwig; Nielsen, Inger Ødum; Friis, Tina; Houen, Gunnar; Theander, Elke

    2016-06-01

    Anti-Ro(52/60) and anti-La constitute the hallmark autoantibodies in primary Sjögren's syndrome, being present in 40-70% of sera. Several anti-Ro/La assays exist, but antibody detection appears to be assay-specific, thus the aim of this study was to compare several anti-Ro/La assays. In total, 96 sera from individuals with primary Sjögren's syndrome and 114 healthy controls were tested for anti-Ro 52/60 and anti-La in 17 immunoassays. Especially the immunoassays used for detection of anti-Ro 52 differed in their sensitivity (48-79%), while only small differences in sensitivities were observed for the anti-Ro 60 (69-77%) anti-La (39-44%) assays. Concordances of 65%, 79% and 73% for the anti-Ro 52, anti-Ro 60 and anti-La assays were found, respectively. The majority of the assays yielded high specificities, primarily ranging from 97 to 100%, except from a single anti-Ro 60 assay, which yielded a specificity of 79%. Occasionally, reactivity levels were increased in a few assays, indicating that false-positive results can be obtained when applying assays of reduced specificity. In general, the commercial assays appeared to perform better than the in-house analyses. When correcting the in-house assays for background reactivity, sensitivities were reduced by approximately 7%, 17%, and 19% for anti-Ro 52, anti-Ro 60 and anti-La assays, respectively, illustrating the pitfalls when applying immunoassays for detection of autoantibodies, which in theory may apply to commercial assays as well. Finally, increased total sensitivities were obtained when combining assays. These studies contribute to clarify the clinical utility of immunoassays for detection of autoantibodies of Ro 52, Ro 60 and La and illustrate that the most efficient strategy to maximize antibody sensitivity is to combine several assays. PMID:26956184

  16. Virus removal and integrity in aged RO membranes.

    PubMed

    Pype, Marie-Laure; Donose, Bogdan C; Martí, Llucia; Patureau, Dominique; Wery, Nathalie; Gernjak, Wolfgang

    2016-03-01

    Membrane ageing reduces the quality of the filtered water. Therefore, in order to warrant public health, monitoring membrane performances are of utmost importance. Reverse osmosis (RO) membranes are generally used to remove viruses and salt. However, there is no detailed study demonstrating the impact of aged membrane on the rejection of viruses and of membrane integrity indicators. In this paper, the impact of hypochlorite induced RO ageing on the rejection of a virus surrogate (MS2 phage) and four membrane integrity indicators (salt, dissolved organic matter, rhodamine WT and sulphate) was evaluated. Hypochlorite exposure was either active (under filtration) or passive (soaking), and the changes of the membrane surface chemistry were characterised using several autopsy techniques. Under this accelerated ageing condition, the introduction of chlorine in the membrane chemistry and the breakage of amide bonds caused an increase of the water permeability and a decrease of the virus surrogate's and indicators' rejection. Ageing resulted in a more negatively charged membrane and also in a higher hydrophobicity, which lead to the adsorption of MS2 phage. Despite severe physical membrane damage leading to a reduction of salt rejection to 1.2 log (94%), the minimum rejection of MS2 phage stayed on or above 4 log. PMID:26724450

  17. Removal of organic contaminants by RO and NF membranes

    NASA Technical Reports Server (NTRS)

    Yoon, Yeomin; Lueptow, Richard M.

    2005-01-01

    Rejection characteristics of organic and inorganic compounds were examined for six reverse osmosis (RO) membranes and two nanofiltration (NF) membranes that are commercially available. A batch stirred-cell was employed to determine the membrane flux and the solute rejection for solutions at various concentrations and different pH conditions. The results show that for ionic solutes the degree of separation is influenced mainly by electrostatic exclusion, while for organic solutes the removal depends mainly upon the solute radius and molecular structure. In order to provide a better understanding of rejection mechanisms for the RO and NF membranes, the ratio of solute radius (r(i,s)) to effective membrane pore radius (r(p)) was employed to compare rejections. An empirical relation for the dependence of the rejection of organic compounds on the ratio r(i,s)/r(p) is presented. The rejection for organic compounds is over 75% when r(i,s)/r(p) is greater than 0.8. In addition, the rejection of organic compounds is examined using the extended Nernst-Planck equation coupled with a steric hindrance model. The transport of organic solutes is controlled mainly by diffusion for the compounds that have a high r(i,s)/r(p) ratio, while convection is dominant for compounds that have a small r(i,s)/r(p) ratio. c2005 Elsevier B.V. All rights reserved.

  18. Reciprocity of agonistic support in ravens

    PubMed Central

    Fraser, Orlaith N.; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim’s likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  19. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  20. Small molecule TSHR agonists and antagonists.

    PubMed

    Neumann, S; Gershengorn, M C

    2011-04-01

    TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule "drug-like" ligands. Recombinant human TSH (rhTSH, Thyrogen(®)) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves' disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential. PMID:21511239

  1. Reciprocity of agonistic support in ravens.

    PubMed

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

    Cooperative behaviour through reciprocation or interchange of valuable services in primates has received considerable attention, especially regarding the timeframe of reciprocation and its ensuing cognitive implications. Much less, however, is known about reciprocity in other animals, particularly birds. We investigated patterns of agonistic support (defined as a third party intervening in an ongoing conflict to attack one of the conflict participants, thus supporting the other) in a group of 13 captive ravens, Corvus corax. We found support for long-term, but not short-term, reciprocation of agonistic support. Ravens were more likely to support individuals who preened them, kin and dominant group members. These results suggest that ravens do not reciprocate on a calculated tit-for-tat basis, but aid individuals from whom reciprocated support would be most useful and those with whom they share a good relationship. Additionally, dyadic levels of agonistic support and consolation (postconflict affiliation from a bystander to the victim) correlated strongly with each other, but we found no evidence to suggest that receiving agonistic support influences the victim's likelihood of receiving support (consolation) after the conflict ends. Our findings are consistent with an emotionally mediated form of reciprocity in ravens and provide additional support for convergent cognitive evolution in birds and mammals. PMID:22298910

  2. The CoRoT transit candidate catalog

    NASA Astrophysics Data System (ADS)

    Aigrain, S.; Deleuil, M.

    2013-09-01

    We present a full catalog of all the candidate transiting planets identified by the CoRoT space mission during its first 5 years of operations, including homogeneously derived transit parameters, validation diagnostics and a summary of the outcome of follow-up observations, where available.The catalog includes confirmed planets, clear false alarms (mainly blended or grazing eclipsing binaries), but also dozens of unconfirmed cases, where the follow-up was either inconclusive (hot stars, fast rotators) or incomplete (owing to limited telescope time and the relatively faint nature of the CoRoT targets). The catalog is intended primarily as a resource for the community, for example as a starting point for completeness and population studies. The candidate detection and selection processes have evolved significantly over the course of the mission. Several teams independently analyse the light curves from each observing run, searching for transits and providing ranked candidate lists, which are subsequently merged and ranked manually. This enables the use of some specialist methods, which are better suited to the detection of only certain types of transits, but makes it difficult to provide an overall assessment of the sensitivity of the mission to transits of different depths and periods. However, we note the transit search methods used by the different teams have gradually converged since launch, and there are now fewer teams actively involved in the transit search, with more overlap between the resulting candidate lists. For each CoRoT observing run, one team member coordinates the selection of candidates for followup, with input from the other team members. The set of criteria used to perform this selection have also evolved over the years, becoming more homogeneous. In particular, the light curve fitting tools used to produce the transit parameters and other diagnostics, which are included in the present catalog, are now routinely used to validate candidates and

  3. Transiting exoplanets from the CoRoT space mission. XXVI. CoRoT-24: a transiting multiplanet system

    NASA Astrophysics Data System (ADS)

    Alonso, R.; Moutou, C.; Endl, M.; Almenara, J.-M.; Guenther, E. W.; Deleuil, M.; Hatzes, A.; Aigrain, S.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Cavarroc, C.; Cabrera, J.; Carpano, S.; Csizmadia, Sz.; Cochran, W. D.; Deeg, H. J.; Díaz, R. F.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Fruth, T.; Gandolfi, D.; Gillon, M.; Grziwa, S.; Guillot, T.; Hébrard, G.; Jorda, L.; Léger, A.; Lammer, H.; Lovis, C.; MacQueen, P. J.; Mazeh, T.; Ofir, A.; Ollivier, M.; Pasternacki, T.; Pätzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Tadeu dos Santos, M.; Tingley, B.; Titz-Weider, R.; Weingrill, J.; Wuchterl, G.

    2014-07-01

    We present the discovery of a candidate multiply transiting system, the first one found in the CoRoT mission. Two transit-like features with periods of 5.11 and 11.76 d are detected in the CoRoT light curve around a main sequence K1V star of r = 15.1. If the features are due to transiting planets around the same star, these would correspond to objects of 3.7 ± 0.4 and 5.0 ± 0.5 R⊕ , respectively. Several radial velocities serve to provide an upper limit of 5.7 M⊕ for the 5.11 d signal and to tentatively measure a mass of 28+11-11 M⊕ for the object transiting with a 11.76 d period. These measurements imply low density objects, with a significant gaseous envelope. The detailed analysis of the photometric and spectroscopic data serves to estimate the probability that the observations are caused by transiting Neptune-sized planets as much as over 26 times higher than a blend scenario involving only one transiting planet and as much as over 900 times higher than a scenario involving two blends and no planets. The radial velocities show a long-term modulation that might be attributed to a 1.5 MJup planet orbiting at 1.8 AU from the host, but more data are required to determine the precise orbital parameters of this companion. The CoRoT space mission, launched on 27 December 2006, has been developed and is operated by the CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Program), Germany, and Spain. Some of the observations were made with the HARPS spectrograph at ESO La Silla Observatory (184.C-0639) and with the HIRES spectrograph at the Keck Telescope (N035Hr, N143Hr 260 and N095Hr). Partly based on observations obtained at ESO Paranal Observatory, Chile (086.C-0235(A) and B).Tables 2-4 and Fig. 12 are available in electronic form at http://www.aanda.org

  4. The driving mechanism of roAp stars : effects of global metallicity

    NASA Astrophysics Data System (ADS)

    Theado, S.; Dupret, M.-A.; Noels, A.

    2008-12-01

    We have investigated the influence of global metallicity on the excitation mechanism of roAp star pulsations. Our computations show that the opacity in the driving region of the roAp modes is strongly sensitive to the metal content but surprisingly the roAp theoretical instability strip is only weakly affected by metallicity changes.

  5. The driving mechanism of roAp stars : effects of local metallicity enhancement

    NASA Astrophysics Data System (ADS)

    Théado, S.; Dupret, M.-A.; Noels, A.

    2009-07-01

    We have investigated the influence of a local metallicity enhancement on the excitation mechanism of roAp star pulsations. Our computations show that such accumulations poorly affect the position of the theoretical roAp star instability strip although the opacity in the driving region of roAp modes is affected by metal accumulation.

  6. HERG1 Channel Agonists and Cardiac Arrhythmia

    PubMed Central

    Sanguinetti, Michael

    2014-01-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  7. HERG1 channel agonists and cardiac arrhythmia.

    PubMed

    Sanguinetti, Michael C

    2014-04-01

    Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel. PMID:24721650

  8. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  9. Melanocortin 1 Receptor Agonists Reduce Proteinuria

    PubMed Central

    Ebefors, Kerstin; Johansson, Martin E.; Stefánsson, Bergur; Granqvist, Anna; Arnadottir, Margret; Berg, Anna-Lena; Nyström, Jenny; Haraldsson, Börje

    2010-01-01

    Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. Recent reports suggest that treatment with adrenocorticotropic hormone (ACTH) reduces proteinuria, but the mechanism of action is unknown. Here, we identified gene expression of the melanocortin receptor MC1R in podocytes, glomerular endothelial cells, mesangial cells, and tubular epithelial cells. Podocytes expressed most MC1R protein, which colocalized with synaptopodin but not with an endothelial-specific lectin. We treated rats with passive Heymann nephritis (PHN) with MS05, a specific MC1R agonist, which significantly reduced proteinuria compared with untreated PHN rats (P < 0.01). Furthermore, treatment with MC1R agonists improved podocyte morphology and reduced oxidative stress. In summary, podocytes express MC1R, and MC1R agonism reduces proteinuria, improves glomerular morphology, and reduces oxidative stress in nephrotic rats with PHN. These data may explain the proteinuria-reducing effects of ACTH observed in patients with membranous nephropathy, and MC1R agonists may provide a new therapeutic option for these patients. PMID:20507942

  10. The Ro60 Autoantigen Binds Endogenous Retroelements and Regulates Inflammatory Gene Expression

    PubMed Central

    Hung, T.; Pratt, G.; Sundararaman, B.; Townsend, M. J.; Chaivorapol, C.; Bhangale, T.; Graham, R. R.; Ortmann, W.; Criswell, L. A.; Yeo, G.; Behrens, T. W.

    2015-01-01

    Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren’s syndrome. However, whether Ro60 and its associated RNAs contribute to disease pathogenesis is unclear. We catalogued the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated proinflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60 positive SLE immune complexes contained Alu RNAs, and Alu transcripts were upregulated in SLE whole blood samples compared to controls. These findings establish a link between the lupus autoantigen Ro60, Alu retroelements and type I interferon. PMID:26382853

  11. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression.

    PubMed

    Hung, T; Pratt, G A; Sundararaman, B; Townsend, M J; Chaivorapol, C; Bhangale, T; Graham, R R; Ortmann, W; Criswell, L A; Yeo, G W; Behrens, T W

    2015-10-23

    Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren's syndrome. However, it is unclear whether Ro60 and its associated RNAs contribute to disease pathogenesis. We catalogued the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated proinflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60-positive SLE immune complexes contained Alu RNAs, and Alu transcripts were up-regulated in SLE whole blood samples relative to controls. These findings establish a link among the lupus autoantigen Ro60, Alu retroelements, and type I interferon. PMID:26382853

  12. High performance RO membranes for desalination and wastewater reclamation and their operation results.

    PubMed

    Henmi, M; Fusaoka, Y; Tomioka, H; Kurihara, M

    2010-01-01

    Reverse osmosis (RO) membrane is one of the most powerful tools for solving the global water crisis, and is used in a variety of water treatment scenes such as drinking water purification, waste-water treatment, boiler feed water production, ultra pure water production for semiconductor industry, etc. The desired performance of RO membrane varies according to quality of feed water being treated, and Toray has been developing RO membranes with suitable characteristic for each operating condition. RO membranes for seawater desalination and wastewater reclamation are especially regarded as most promising targets. Recently, high boron removal and energy saving RO membrane for seawater desalination and low fouling RO membrane for wastewater reclamation have been developed. In this paper, the prospect of attaining these renovative RO membrane, and furthermore, job references will be discussed. PMID:21045342

  13. Different agonist- and antagonist-induced conformational changes in retinoic acid receptors analyzed by protease mapping.

    PubMed Central

    Keidel, S; LeMotte, P; Apfel, C

    1994-01-01

    The pleiotropic effects of retinoic acid on cell differentiation and proliferation are mediated by two subfamilies of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Recently the synthetic retinoid Ro 41-5253 was identified as a selective RAR alpha antagonist. As demonstrated by gel retardation assays, Ro 41-5253 and two related new RAR alpha antagonists do not influence RAR alpha/RXR alpha heterodimerization and DNA binding. In a limited trypsin digestion assay, complexation of RAR alpha with retinoic acid or several other agonistic retinoids altered the degradation of the receptor such that a 30-kDa proteolytic fragment became resistant to proteolysis. This suggests a ligand-induced conformational change, which may be necessary for the interaction of the DNA-bound RAR alpha/RXR alpha heterodimer with other transcription factors. Our results demonstrate that antagonists compete with agonists for binding to RAR alpha and may induce a different structural alteration, suggested by the tryptic resistance of a shorter 25-kDa protein fragment in the digestion assay. This RAR alpha conformation seems to allow RAR alpha/RXR alpha binding to DNA but not the subsequent transactivation of target genes. Protease mapping with C-terminally truncated receptors revealed that the proposed conformational changes mainly occur in the DE regions of RAR alpha. Complexation of RAR beta, RAR gamma, and RXR alpha, as well as the vitamin D3 receptor, with their natural ligands resulted in a similar resistance of fragments to proteolytic digestion. This could mean that ligand-induced conformational changes are a general feature in the hormonal activation of vitamin D3 and retinoid receptors. Images PMID:8264595

  14. CD45RO enriches for activated, highly mutated human germinal center B cells

    PubMed Central

    Jackson, Stephen M.; Harp, Natessa; Patel, Darshna; Zhang, Jeffrey; Willson, Savannah; Kim, Yoon J.; Clanton, Christian

    2007-01-01

    To date, there is no consensus regarding the influence of different CD45 isoforms during peripheral B-cell development. Examining correlations between surface CD45RO expression and various physiologic processes ongoing during the germinal center (GC) reaction, we hypothesized that GC B cells, like T cells, that up-regulate surface RO should progressively acquire phenotypes commonly associated with activated, differentiating lymphocytes. GC B cells (IgD−CD38+) were subdivided into 3 surface CD45RO fractions: RO−, RO+/−, and RO+. We show here that the average number of mutations per IgVH transcript increased in direct correlation with surface RO levels. Conjunctional use of RO and CD69 further delineated low/moderately and highly mutated fractions. Activation-induced cytidine deaminase (AID) mRNA was slightly reduced among RO+ GC B cells, suggesting that higher mutation averages are unlikely due to elevated somatic mutation activity. Instead, RO+ GC B cells were negative for Annexin V, comprised mostly (93%) of CD77− centrocytes, and were enriched for CD69+ cells. Collectively, RO+ GC B cells occupy what seems to be a specialized niche comprised mostly of centrocytes that may be in transition between activation states. These findings are among the first to sort GC B cells into populations enriched for live mutated cells solely using a single extracellular marker. PMID:17644737

  15. Calcium Binding by Ro 60 Multiple Antigenic Peptides on PVDF Membrane.

    PubMed

    Kurien, Biji T; Bachmann, Michael P

    2015-01-01

    Antibodies directed against ribonucleoprotein (RNP) particles are observed in systemic lupus erythematosus. Ro RNP particle is one such target. It is composed of a 60 kDa protein (Ro 60 or SS-A) that is non-covalently associated with at least one of the four short uridine-rich RNAs (the hY RNAs). Previously, we showed that multiple antigenic peptides (MAPs) made from the sequence of the Ro 60 autoantigen could be used, using double-immunodiffusion studies, enzyme-linked immunosorbant assay, affinity chromatography, and surface plasmon resonance, to show intramolecular and intermolecular protein-protein interaction within the Ro 60 RNP particle. We also observed that calcium is important in mediating this interaction. We hypothesized, therefore, that 60 kDa Ro is a calcium-binding protein. To investigate this, we electrophoresed 60 kDa Ro MAPs, transferred them to PVDF membrane, and assayed calcium binding using the Quin-2 system. Several Ro 60 MAPs were found to bind calcium using this assay, as well as bovine serum albumin, another calcium-binding protein. However, a MAP constructed from the Sm autoantigen did not bind to calcium. These data, along with our observation regarding the involvement of calcium in protein-protein interaction occurring between Ro 60 antigen and Ro 60 MAPs, makes us propose that Ro 60 antigen is a calcium-binding protein. PMID:26139264

  16. SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production

    SciTech Connect

    Jauharoh, Siti Nur Aisyah; Saegusa, Jun; Sugimoto, Takeshi; Ardianto, Bambang; Kasagi, Shimpei; Sugiyama, Daisuke; Kurimoto, Chiyo; Tokuno, Osamu; Nakamachi, Yuji; Kumagai, Shunichi; Kawano, Seiji

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Ro52{sup low} HeLa cells are resistant to apoptosis upon various stimulations. Black-Right-Pointing-Pointer Ro52 is upregulated by IFN-{alpha}, etoposide, or IFN-{gamma} and anti-Fas Ab. Black-Right-Pointing-Pointer Ro52-mediated apoptosis is independent of p53. Black-Right-Pointing-Pointer Ro52 selectively regulates Bcl-2 expression. -- Abstract: SS-A/Ro52 (Ro52), an autoantigen in systemic autoimmune diseases such as systemic lupus erythematosus and Sjoegren's syndrome, has E3 ligase activity to ubiquitinate proteins that protect against viral infection. To investigate Ro52's role during stress, we transiently knocked it down in HeLa cells by siRo52 transfection. We found that Ro52{sup low} HeLa cells were significantly more resistant to apoptosis than wild-type HeLa cells when stimulated by H{sub 2}O{sub 2}- or diamide-induced oxidative stress, IFN-{alpha}, IFN-{gamma} and anti-Fas antibody, etoposide, or {gamma}-irradiation. Furthermore, Ro52-mediated apoptosis was not influenced by p53 protein level in HeLa cells. Depleting Ro52 in HeLa cells caused Bcl-2, but not other Bcl-2 family molecules, to be upregulated. Taken together, our data showed that Ro52 is a universal proapoptotic molecule, and that its proapoptotic effect does not depend on p53, but is exerted through negative regulation of the anti-apoptotic protein Bcl-2. These findings shed light on a new physiological role for Ro52 that is important to intracellular immunity.

  17. Dopamine agonist: pathological gambling and hypersexuality.

    PubMed

    2008-10-01

    (1) Pathological gambling and increased sexual activity can occur in patients taking dopaminergic drugs. Detailed case reports and small case series mention serious familial and social consequences. The frequency is poorly documented; (2) Most affected patients are being treated for Parkinson's disease, but cases have been reported among patients prescribed a dopamine agonist for restless legs syndrome or pituitary adenoma; (3) Patients treated with this type of drug, and their relatives, should be informed of these risks so that they can watch for changes in behaviour. If such disorders occur, it may be necessary to reduce the dose or to withdraw the drug or replace it with another medication. PMID:19536937

  18. Assessing the agonist profiles of the prostacyclin analogues treprostinil and naxaprostene, particularly their DP₁ activity.

    PubMed

    Syed, Nawazish-i-Husain; Jones, Robert L

    2015-04-01

    In this study, the inhibitory profiles of the prostacyclin analogues treprostinil and naxaprostene on several isolated smooth muscle preparations have been investigated. Treprostinil was an agonist for prostanoid DP1, EP2 and IP receptors, but not EP4 receptors; its DP1 potency was only 3-4 times less than PGD2 itself. Naxaprostene was much more selective for IP receptors and tended towards partial agonism. Treprostinil is a 13,14-dihydro analogue and the role of conformation around C12-15 in controlling agonist specificity is debated; the synthesis of new analogues is proposed and possible clinical usage discussed. In terms of selective prostanoid antagonists employed, BW-A868C/MK-0524 (DP1), ACA-23 (EP2) and GW-627368 (EP4) were found fit for purpose. However, the IP antagonist RO-1138452 was compromised by α1 and α2-adrenoceptor-mediated contractile activity on rat tail artery and anti-muscarinic activity on mouse trachea. There is a need for IP receptor antagonists with better selectivity and higher affinity. PMID:25542069

  19. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  20. Mechanisms of agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Lin, Hong; Strange, Philip G

    2004-12-01

    In this study, we investigated the biochemical mechanisms of agonist action at the G protein-coupled D2 dopamine receptor expressed in Chinese hamster ovary cells. Stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding by full and partial agonists was determined at different concentrations of [35S]GTPgammaS (0.1 and 10 nM) and in the presence of different concentrations of GDP. At both concentrations of [35S]GTPgammaS, increasing GDP decreased the [35S]GTPgammaS binding observed with maximally stimulating concentrations of agonist, with partial agonists exhibiting greater sensitivity to the effects of GDP than full agonists. The relative efficacy of partial agonists was greater at the lower GDP concentrations. Concentration-response experiments were performed for a range of agonists at the two [35S]GTPgammaS concentrations and with different concentrations of GDP. At 0.1 nM [35S]GTPgammaS, the potency of both full and partial agonists was dependent on the GDP concentration in the assays. At 10 nM [35S]GTPgammaS, the potency of full agonists exhibited a greater dependence on the GDP concentration, whereas the potency of partial agonists was virtually independent of GDP. We concluded that at the lower [35S]GTPgammaS concentration, the rate-determining step in G protein activation is the binding of [35S]GTPgammaS to the G protein. At the higher [35S]GTPgammaS concentration, for full agonists, [35S]GTPgammaS binding remains the slowest step, whereas for partial agonists, another (GDP-independent) step, probably ternary complex breakdown, becomes rate-determining. PMID:15340043

  1. Ro15-4513 antagonizes depression of open-field horizontal activity by ethanol in rats.

    PubMed

    June, H L; Johnson, L T; Lewis, M J

    1989-01-01

    The imidazobenzodiazepine, Ro15-4513, has been shown to antagonize some of the behavioral effects of ethanol (ETOH). In rats having relatively little experience in the open field, the actions of ETOH (0.75 g/kg IP), Ro15-4513 (1.25 mg/kg and 2.5 mg/kg, IP), and Ro15-4513 in combination with ETOH were measured on horizontal activity. Rats receiving ETOH showed a significant depression in horizontal activity. Doses of Ro15-4513 given alone produced no significant differences in activity from baseline levels. Rats pretreated with Ro15-4513 prior to receiving ETOH, however, showed a significant attenuation of the ETOH induced depression of activity. These results indicate that Ro15-4513 is effective in attenuating the depressive effects of ETOH in the open field in rats having little experience in the apparatus. PMID:2765204

  2. Computational modeling toward understanding agonist binding on dopamine 3.

    PubMed

    Zhao, Yaxue; Lu, Xuefeng; Yang, Chao-Yie; Huang, Zhimin; Fu, Wei; Hou, Tingjun; Zhang, Jian

    2010-09-27

    The dopamine 3 (D3) receptor is a promising therapeutic target for the treatment of nervous system disorders, such as Parkinson's disease, and current research interests primarily focus on the discovery/design of potent D3 agonists. Herein, a well-designed computational protocol, which combines pharmacophore identification, homology modeling, molecular docking, and molecular dynamics (MD) simulations, was employed to understand the agonist binding on D3 aiming to provide insights into the development of novel potent D3 agonists. We (1) identified the chemical features required in effective D3 agonists by pharmacophore modeling based upon 18 known diverse D3 agonists; (2) constructed the three-dimensional (3D) structure of D3 based on homology modeling and the pharmacophore hypothesis; (3) identified the binding modes of the agonists to D3 by the correlation between the predicted binding free energies and the experimental values; and (4) investigated the induced fit of D3 upon agonist binding through MD simulations. The pharmacophore models of the D3 agonists and the 3D structure of D3 can be used for either ligand- or receptor-based drug design. Furthermore, the MD simulations further give the insight that the long and flexible EL2 acts as a "door" for agonist binding, and the "ionic lock" at the bottom of TM3 and TM6 is essential to transduce the activation signal. PMID:20695484

  3. Gas-Phase Ozonolysis of Cycloalkenes: Formation of Highly Oxidized RO2 Radicals and Their Reactions with NO, NO2, SO2, and Other RO2 Radicals.

    PubMed

    Berndt, Torsten; Richters, Stefanie; Kaethner, Ralf; Voigtländer, Jens; Stratmann, Frank; Sipilä, Mikko; Kulmala, Markku; Herrmann, Hartmut

    2015-10-15

    The gas-phase reaction of ozone with C5-C8 cycloalkenes has been investigated in a free-jet flow system at atmospheric pressure and a temperature of 297 ± 1 K. Highly oxidized RO2 radicals bearing at least 5 O atoms in the molecule and their subsequent reaction products were detected in most cases by means of nitrate-CI-APi-TOF mass spectrometry. Starting from a Criegee intermediate after splitting-off an OH-radical, the formation of these RO2 radicals can be explained via an autoxidation mechanism, meaning RO2 isomerization (ROO → QOOH) and subsequently O2 addition (QOOH + O2 → R'OO). Time-dependent RO2 radical measurements concerning the ozonolysis of cyclohexene indicate rate coefficients of the intramolecular H-shifts, ROO → QOOH, higher than 1 s(-1). The total molar yield of highly oxidized products (predominantly RO2 radicals) from C5-C8 cycloalkenes in air is 4.8-6.0% affected with a calibration uncertainty by a factor of about two. For the most abundant RO2 radical from cyclohexene ozonolysis, O,O-C6H7(OOH)2O2 ("O,O" stands for two O atoms arising from the ozone attack), the determination of the rate coefficients of the reaction with NO2, NO, and SO2 yielded (1.6 ± 0.5) × 10(-12), (3.4 ± 0.9) × 10(-11), and <10(-14) cm(3) molecule(-1) s(-1), respectively. The reaction of highly oxidized RO2 radicals with other peroxy radicals (R'O2) leads to detectable accretion products, RO2 + R'O2 → ROOR' + O2, which allows to acquire information on peroxy radicals not directly measurable with the nitrate ionization technique applied here. Additional experiments using acetate as the charger ion confirm conclusively the existence of highly oxidized RO2 radicals and closed-shell products. Other reaction products, detectable with this ionization technique, give a deeper insight in the reaction mechanism of cyclohexene ozonolysis. PMID:26392132

  4. RoBlock: a prototype autonomous manufacturing cell

    NASA Astrophysics Data System (ADS)

    Baekdal, Lars K.; Balslev, Ivar; Eriksen, Rene D.; Jensen, Soren P.; Jorgensen, Bo N.; Kirstein, Brian; Kristensen, Bent B.; Olsen, Martin M.; Perram, John W.; Petersen, Henrik G.; Petersen, Morten L.; Ruhoff, Peter T.; Skjolstrup, Carl E.; Sorensen, Anders S.; Wagenaar, Jeroen M.

    2000-10-01

    RoBlock is the first phase of an internally financed project at the Institute aimed at building a system in which two industrial robots suspended from a gantry, as shown below, cooperate to perform a task specified by an external user, in this case, assembling an unstructured collection of colored wooden blocks into a specified 3D pattern. The blocks are identified and localized using computer vision and grasped with a suction cup mechanism. Future phases of the project will involve other processes such as grasping and lifting, as well as other types of robot such as autonomous vehicles or variable geometry trusses. Innovative features of the control software system include: The use of an advanced trajectory planning system which ensures collision avoidance based on a generalization of the method of artificial potential fields, the use of a generic model-based controller which learns the values of parameters, including static and kinetic friction, of a detailed mechanical model of itself by comparing actual with planned movements, the use of fast, flexible, and robust pattern recognition and 3D-interpretation strategies, integration of trajectory planning and control with the sensor systems in a distributed Java application running on a network of PC's attached to the individual physical components. In designing this first stage, the aim was to build in the minimum complexity necessary to make the system non-trivially autonomous and to minimize the technological risks. The aims of this project, which is planned to be operational during 2000, are as follows: To provide a platform for carrying out experimental research in multi-agent systems and autonomous manufacturing systems, to test the interdisciplinary cooperation architecture of the Maersk Institute, in which researchers in the fields of applied mathematics (modeling the physical world), software engineering (modeling the system) and sensor/actuator technology (relating the virtual and real worlds) could

  5. Planetary transit candidates in the CoRoT LRa01 field

    NASA Astrophysics Data System (ADS)

    Carone, L.; Gandolfi, D.; Cabrera, J.; Hatzes, A. P.; Deeg, H. J.; Csizmadia, Sz.; Pätzold, M.; Weingrill, J.; Aigrain, S.; Alonso, R.; Alapini, A.; Almenara, J.-M.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Bruntt, H.; Carpano, S.; Cochran, W. D.; Deleuil, M.; Díaz, R. F.; Dreizler, S.; Dvorak, R.; Eislöffel, J.; Eigmüller, P.; Endl, M.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Gazzano, J.-C.; Gibson, N.; Gillon, M.; Gondoin, P.; Grziwa, S.; Günther, E. W.; Guillot, T.; Hartmann, M.; Havel, M.; Hébrard, G.; Jorda, L.; Kabath, P.; Léger, A.; Llebaria, A.; Lammer, H.; Lovis, C.; MacQueen, P. J.; Mayor, M.; Mazeh, T.; Moutou, C.; Nortmann, L.; Ofir, A.; Ollivier, M.; Parviainen, H.; Pepe, F.; Pont, F.; Queloz, D.; Rabus, M.; Rauer, H.; Régulo, C.; Renner, S.; de La Reza, R.; Rouan, D.; Santerne, A.; Samuel, B.; Schneider, J.; Shporer, A.; Stecklum, B.; Tal-Or, L.; Tingley, B.; Udry, S.; Wuchterl, G.

    2012-02-01

    Context. CoRoT is a pioneering space mission whose primary goals are stellar seismology and extrasolar planets search. Its surveys of large stellar fields generate numerous planetary candidates whose lightcurves have transit-like features. An extensive analytical and observational follow-up effort is undertaken to classify these candidates. Aims: We present the list of planetary transit candidates from the CoRoT LRa01 star field in the Monoceros constellation toward the Galactic anti-center direction. The CoRoT observations of LRa01 lasted from 24 October 2007 to 3 March 2008. Methods: We acquired and analyzed 7470 chromatic and 3938 monochromatic lightcurves. Instrumental noise and stellar variability were treated with several filtering tools by different teams from the CoRoT community. Different transit search algorithms were applied to the lightcurves. Results: Fifty-one stars were classified as planetary transit candidates in LRa01. Thirty-seven (i.e., 73% of all candidates) are "good" planetary candidates based on photometric analysis only. Thirty-two (i.e., 87% of the "good" candidates) have been followed-up. At the time of writing twenty-two cases were solved and five planets were discovered: three transiting hot-Jupiters (CoRoT-5b, CoRoT-12b, and CoRoT-21b), the first terrestrial transiting planet (CoRoT-7b), and another planet in the same system (CoRoT-7c, detected by radial velocity survey only). Evidence of another non-transiting planet in the CoRoT-7 system, namely CoRoT-7d, was recently found as well. The CoRoT space mission, launched on December 27, 2006, has been developed and is operated by CNES, with contributions of Austria, Belgium, Brazil, ESA (RSSD and Science Program), Germany and Spain.

  6. PRE-DISCOVERY OBSERVATIONS OF CoRoT-1b AND CoRoT-2b WITH THE BEST SURVEY

    SciTech Connect

    Rauer, H.; Erikson, A.; Kabath, P.; Hedelt, P.; Csizmadia, Sz.; Paris, P. v.; Renner, S.; Titz, R.; Voss, H.; Boer, M.; Tournois, G.; Carone, L.; Eigmueller, P.

    2010-01-15

    The Berlin Exoplanet Search Telescope (BEST) wide-angle telescope installed at the Observatoire de Haute-Provence and operated in remote control from Berlin by the Institut fuer Planetenforschung, DLR, has observed the CoRoT target fields prior to the mission. The resulting archive of stellar photometric light curves is used to search for deep transit events announced during CoRoT's alarm mode to aid in fast photometric confirmation of these events. The 'initial run' field of CoRoT (IRa01) was observed with BEST in 2006 November and December for 12 nights. The first 'long run' field (LRc01) was observed from 2005 June to September for 35 nights. After standard CCD data reduction, aperture photometry has been performed using the ISIS image subtraction method. About 30,000 light curves were obtained in each field. Transits of the first detected planets by the CoRoT mission, CoRoT-1b and CoRoT-2b, were found in archived data of the BEST survey and their light curves are presented here. Such detections provide useful information at the early stage of the organization of follow-up observations of satellite alarm-mode planet candidates. In addition, no period change was found over {approx}4 years between the first BEST observation and last available transit observations.

  7. Strategies for designing synthetic immune agonists.

    PubMed

    Wu, Tom Y-H

    2016-08-01

    Enhancing the immune system is a validated strategy to combat infectious disease, cancer and allergy. Nevertheless, the development of immune adjuvants has been hampered by safety concerns. Agents that can stimulate the immune system often bear structural similarities with pathogen-associated molecular patterns found in bacteria or viruses and are recognized by pattern recognition receptors (PRRs). Activation of these PRRs results in the immediate release of inflammatory cytokines, up-regulation of co-stimulatory molecules, and recruitment of innate immune cells. The distribution and duration of these early inflammatory events are crucial in the development of antigen-specific adaptive immunity in the forms of antibody and/or T cells capable of searching for and destroying the infectious pathogens or cancer cells. However, systemic activation of these PRRs is often poorly tolerated. Hence, different strategies have been employed to modify or deliver immune agonists in an attempt to control the early innate receptor activation through temporal or spatial restriction. These approaches include physicochemical manipulation, covalent conjugation, formulation and conditional activation/deactivation. This review will describe recent examples of discovery and optimization of synthetic immune agonists towards clinical application. PMID:27213842

  8. Proglumide exhibits delta opioid agonist properties.

    PubMed

    Rezvani, A; Stokes, K B; Rhoads, D L; Way, E L

    1987-01-01

    Recently, it was reported that proglumide, a cholecystokinin (CCK) antagonist, potentiates the analgetic effects of morphine and endogenous opioid peptides and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat. In order to provide additional insight into the mode of action of this agent, we assessed the effect of proglumide in the isolated guinea pig ileum and the mouse, rat and rabbit vas deferens. Furthermore, we studied the in vitro binding affinity of this substance to mouse brain synaptosomes. Our results show that proglumide inhibits, dose dependently, the electrically stimulated twitches in the mouse vas deferens and guinea pig ileum, but not in the rat or rabbit vas deferens. The inhibitory action of proglumide on the mouse vas deferens, but not on the guinea pig ileum, is antagonized by naloxone and by the selective delta-antagonist, ICI 174,864, in a competitive fashion. Other CCK antagonists were found to be devoid of such activity on the mouse vas deferens. In vitro binding studies showed that proglumide displaces D-ala-D-[leucine]5-enkephalin (DADLE), a delta agonist, but not ethylketocyclazocine (EKC), a preferentially selective kappa agonist. The effect of proglumide appeared to be elicited presynaptically since it did not alter the norepinephrine-induced contractions of the mouse vas deferens. Our results suggest that proglumide might exert its opiate-like effects by activation of delta-opioid receptors. PMID:3030338

  9. Chimpanzees Extract Social Information from Agonistic Screams

    PubMed Central

    Slocombe, Katie E.; Kaller, Tanja; Call, Josep; Zuberbühler, Klaus

    2010-01-01

    Chimpanzee (Pan troglodytes) agonistic screams are graded vocal signals that are produced in a context-specific manner. Screams given by aggressors and victims can be discriminated based on their acoustic structure but the mechanisms of listener comprehension of these calls are currently unknown. In this study, we show that chimpanzees extract social information from these vocal signals that, combined with their more general social knowledge, enables them to understand the nature of out-of-sight social interactions. In playback experiments, we broadcast congruent and incongruent sequences of agonistic calls and monitored the response of bystanders. Congruent sequences were in accordance with existing social dominance relations; incongruent ones violated them. Subjects looked significantly longer at incongruent sequences, despite them being acoustically less salient (fewer call types from fewer individuals) than congruent ones. We concluded that chimpanzees categorised an apparently simple acoustic signal into victim and aggressor screams and used pragmatics to form inferences about third-party interactions they could not see. PMID:20644722

  10. Transmembrane segment five serines of the D4 dopamine receptor uniquely influence the interactions of dopamine, norepinephrine, and Ro10-4548.

    PubMed

    Cummings, David F; Ericksen, Spencer S; Goetz, Angela; Schetz, John A

    2010-06-01

    Conserved serines of transmembrane segment (TM) five (TM5) are critical for the interactions of endogenous catecholamines with alpha(1)- and alpha(2)-adrenergic, beta(2)-adrenergic, and D1, D2, and D3 dopamine receptors. The unique high-affinity interaction of the D4 dopamine receptor subtype with both norepinephrine and dopamine, and the fact that TM5 serine interactions have never been studied for this receptor subtype, led us to investigate the interactions of ligands with D4 receptor TM5 serines. Serine-to-alanine mutations at positions 5.42 and 5.46 drastically decreased affinities of dopamine and norepinephrine for the D4 receptor. The D4-S5.43A receptor mutant had substantially reduced affinity for norepinephrine, but a modest loss of affinity for dopamine. In functional assays of cAMP accumulation, norephinephrine was unable to activate any of the mutant receptors, even though the agonist quinpirole displayed wild-type functional properties for all of them. Dopamine was unable to activate the S5.46A mutant and had reduced potency for the S5.43A mutant and reduced potency and efficacy for the S5.42A mutant. In contrast, Ro10-4548 [RAC-2'-2-hydroxy-3-4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl-propoxy-acetanilide], a catechol-like antagonist of the wild-type receptor unexpectedly functions as an agonist of the S5.43A mutant. Other noncatechol ligands had similar properties for mutant and wild-type receptors. This is the first example of a dopamine receptor point mutation selectively changing the receptor's interaction with a specific antagonist to that of an agonist, and together with other data, provides evidence, supported by molecular modeling, that catecholamine-type agonism is induced by different ligand-specific configurations of intermolecular H-bonds with the TM5 conserved serines. PMID:20215412

  11. VizieR Online Data Catalog: CoRoT observation log (N2-4.4) (CoRoT 2016)

    NASA Astrophysics Data System (ADS)

    COROT Team

    2014-03-01

    CoRoT, a space astronomy mission, has measured photometric micro-variability of stars from minutes to months (up to 150 days) with a high duty cycle (more than 90%). The mission was led by CNES in association with four French laboratories and 7 participating countries and agencies (Austria, Belgium, Brazil, Germany, Spain, and the ESA Science Programme). The satellite was composed of a PROTEUS platform (the 3rd in the series) and a unique instrument: a stellar rapid photometer. It was launched on December 27th 2006 by a Soyuz Rocket, from Bakonour. The mission has lasted almost 6 years (the nominal 3-year duration and a 3-year extension) and has observed more than 160 000 stars. It stopped sending data on November 2nd 2012. Two regions of the sky were accessible for long period of time: circles of 10 degrees centered on the equator around alpha=06:50 and alpha=18:50. They were called the CoRoT eyes: the "anticenter" and the "center eye" (as they are approximately in these directions). Each pointing covers 1.4x2.8 square degrees within one of those CoRoT eyes. The original scientific objectives were focussed on the study of stellar pulsations (asteroseismology) to probe the internal structure of stars, and the detection of small exoplanets through their "transit" in front of their host star, and the measurement of their size. This lead to introduce two modes of observations, working simultaneously: - The "bright star" mode dedicated to very precise seismology of a small sample of bright and closeby stars - The "faint star" mode, observing a very large number of stars at the same time, to detect transits, which are rare events, as they imply the alignment of the star, the planet and the observer. The large amount of data gathered in this mode turned out to be extremely fruitful for many topics of stellar physics. Beyond these two initial objectives, CoRoT data revealed stellar variability associated with various other phenomena: granulation, rotational modulation by

  12. VizieR Online Data Catalog: CoRoT observation log (N2-4.4) (CoRoT 2016)

    NASA Astrophysics Data System (ADS)

    COROT Team

    2014-03-01

    CoRoT, a space astronomy mission, has measured photometric micro-variability of stars from minutes to months (up to 150 days) with a high duty cycle (more than 90%). The mission was led by CNES in association with four French laboratories and 7 participating countries and agencies (Austria, Belgium, Brazil, Germany, Spain, and the ESA Science Programme). The satellite was composed of a PROTEUS platform (the 3rd in the series) and a unique instrument: a stellar rapid photometer. It was launched on December 27th 2006 by a Soyuz Rocket, from Bakonour. The mission has lasted almost 6 years (the nominal 3-year duration and a 3-year extension) and has observed more than 160 000 stars. It stopped sending data on November 2nd 2012. Two regions of the sky were accessible for long period of time: circles of 10 degrees centered on the equator around alpha=06:50 and alpha=18:50. They were called the CoRoT eyes: the "anticenter" and the "center eye" (as they are approximately in these directions). Each pointing covers 1.4x2.8 square degrees within one of those CoRoT eyes. The original scientific objectives were focussed on the study of stellar pulsations (asteroseismology) to probe the internal structure of stars, and the detection of small exoplanets through their "transit” in front of their host star, and the measurement of their size. This lead to introduce two modes of observations, working simultaneously: - The “bright star” mode dedicated to very precise seismology of a small sample of bright and closeby stars - The “faint star” mode, observing a very large number of stars at the same time, to detect transits, which are rare events, as they imply the alignment of the star, the planet and the observer. The large amount of data gathered in this mode turned out to be extremely fruitful for many topics of stellar physics. Beyond these two initial objectives, CoRoT data revealed stellar variability associated

  13. Regulation of Histone H4 Lys16 Acetylation by Predicted Alternative Secondary Structures in roX Noncoding RNAs▿ †

    PubMed Central

    Park, Seung-Won; Kuroda, Mitzi I.; Park, Yongkyu

    2008-01-01

    Despite differences in size and sequence, the two noncoding roX1 and roX2 RNAs are functionally redundant for dosage compensation of the Drosophila melanogaster male X chromosome. Consistent with functional conservation, we found that roX RNAs of distant Drosophila species could complement D. melanogaster roX mutants despite low homology. Deletion of a conserved predicted stem-loop structure in roX2, containing a short GUb (GUUNUACG box) in its 3′ stem, resulted in a defect in histone H4K16 acetylation on the X chromosome in spite of apparently normal localization of the MSL complex. Two copies of the GUb sequence, newly termed the “roX box,” were functionally redundant in roX2, as mutants in a single roX box had no phenotype, but double mutants showed reduced H4K16 acetylation. Interestingly, mutation of two of three roX boxes in the 3′ end of roX1 RNA also reduced H4K16 acetylation. Finally, fusion of roX1 sequences containing a roX box restored function to a roX2 deletion RNA lacking its cognate roX box. These results support a model in which the functional redundancy between roX1 and roX2 RNAs is based, at least in part, on short GUUNUACG sequences that regulate the activity of the MSL complex. PMID:18541664

  14. Regulation of histone H4 Lys16 acetylation by predicted alternative secondary structures in roX noncoding RNAs.

    PubMed

    Park, Seung-Won; Kuroda, Mitzi I; Park, Yongkyu

    2008-08-01

    Despite differences in size and sequence, the two noncoding roX1 and roX2 RNAs are functionally redundant for dosage compensation of the Drosophila melanogaster male X chromosome. Consistent with functional conservation, we found that roX RNAs of distant Drosophila species could complement D. melanogaster roX mutants despite low homology. Deletion of a conserved predicted stem-loop structure in roX2, containing a short GUb (GUUNUACG box) in its 3' stem, resulted in a defect in histone H4K16 acetylation on the X chromosome in spite of apparently normal localization of the MSL complex. Two copies of the GUb sequence, newly termed the "roX box," were functionally redundant in roX2, as mutants in a single roX box had no phenotype, but double mutants showed reduced H4K16 acetylation. Interestingly, mutation of two of three roX boxes in the 3' end of roX1 RNA also reduced H4K16 acetylation. Finally, fusion of roX1 sequences containing a roX box restored function to a roX2 deletion RNA lacking its cognate roX box. These results support a model in which the functional redundancy between roX1 and roX2 RNAs is based, at least in part, on short GUUNUACG sequences that regulate the activity of the MSL complex. PMID:18541664

  15. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  16. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  17. Cytotoxicity of Ro-07-0582; enhancement by hyperthermia and protection by cysteamine.

    PubMed Central

    Hall, E. J.; Astor, M.; Geard, C.; Biaglow, J.

    1977-01-01

    The selective cytotoxicity which Ro-07-0582 exhibits towards hypoxic cells is strongly temperature-dependent. This cytotoxicity is reduced by the radical scavenger cysteamine, suggesting that nitro radicals or nitroso intermediates are involved in cell killing by the drug. Chromosome aberrations are not induced by Ro-07-0582 even when the surviving fraction is reduced to 0-01. PMID:871368

  18. Estrogen receptor beta agonists in neurobehavioral investigations.

    PubMed

    Choleris, Elena; Clipperton, Amy E; Phan, Anna; Kavaliers, Martin

    2008-07-01

    Neurobehavioral investigations into the functions of estrogen receptor (ER)alpha and ERbeta have utilized 'knockout' mice, phytoestrogens and, more recently, ER-specific agonists. Feeding, sexual, aggressive and social behavior, anxiety, depression, drug abuse, pain perception, and learning (and associated synaptic plasticity) are affected by ERalpha and ERbeta in a manner that is dependent upon the specific behavior studied, gender and developmental stage. Overall, ERalpha and ERbeta appear to function together to foster sociosexual behavior while inhibiting behaviors that, if occurring at the time of behavioral estrous, may compete with reproduction (eg, feeding). Recently developed pharmacological tools have limited selectivity and availability to the research community at large, as they are not commercially available. The development of highly selective, commercially available ERbeta-specific antagonists would greatly benefit preclinical and applied research. PMID:18600582

  19. Non-Benzodiazepine Receptor Agonists for Insomnia.

    PubMed

    Becker, Philip M; Somiah, Manya

    2015-03-01

    Because of proven efficacy, reduced side effects, and less concern about addiction, non-benzodiazepine receptor agonists (non-BzRA) have become the most commonly prescribed hypnotic agents to treat onset and maintenance insomnia. First-line treatment is cognitive-behavioral therapy. When pharmacologic treatment is indicated, non-BzRA are first-line agents for the short-term and long-term management of transient and chronic insomnia related to adjustment, psychophysiologic, primary, and secondary causation. In this article, the benefits and risks of non-BzRA are reviewed, and the selection of a hypnotic agent is defined, based on efficacy, pharmacologic profile, and adverse events. PMID:26055674

  20. WARM SPITZER PHOTOMETRY OF THE TRANSITING EXOPLANETS CoRoT-1 AND CoRoT-2 AT SECONDARY ECLIPSE

    SciTech Connect

    Deming, Drake; Knutson, Heather; Agol, Eric; Cowan, Nicolas B.; Desert, Jean-Michel; Charbonneau, David; Burrows, Adam; Fortney, Jonathan J.; Laughlin, Gregory; Langton, Jonathan; Showman, Adam P.; Lewis, Nikole K.

    2011-01-10

    We measure secondary eclipses of the hot giant exoplanets CoRoT-1 at 3.6 and 4.5 {mu}m, and CoRoT-2 at 3.6 {mu}m, both using Warm Spitzer. We find that the Warm Spitzer mission is working very well for exoplanet science. For consistency of our analysis we also re-analyze archival cryogenic Spitzer data for secondary eclipses of CoRoT-2 at 4.5 and 8 {mu}m. We compare the total data for both planets, including optical eclipse measurements by the CoRoT mission, and ground-based eclipse measurements at 2 {mu}m, to existing models. Both planets exhibit stronger eclipses at 4.5 than at 3.6 {mu}m, which is often indicative of an atmospheric temperature inversion. The spectrum of CoRoT-1 is best reproduced by a 2460 K blackbody, due either to a high altitude layer that strongly absorbs stellar irradiance, or an isothermal region in the planetary atmosphere. The spectrum of CoRoT-2 is unusual because the 8 {mu}m contrast is anomalously low. Non-inverted atmospheres could potentially produce the CoRoT-2 spectrum if the planet exhibits line emission from CO at 4.5 {mu}m, caused by tidal-induced mass loss. However, the viability of that hypothesis is questionable because the emitting region cannot be more than about 30% larger than the planet's transit radius, based on the ingress and egress times at eclipse. An alternative possibility to account for the spectrum of CoRoT-2 is an additional opacity source that acts strongly at wavelengths less than 5 {mu}m, heating the upper atmosphere while allowing the deeper atmosphere seen at 8 {mu}m to remain cooler. We obtain a similar result as Gillon et al. for the phase of the secondary eclipse of CoRoT-2, implying an eccentric orbit with e cos({omega}) = -0.0030 {+-} 0.0004.

  1. Ro small cytoplasmic ribonucleoproteins are a subclass of La ribonucleoproteins: Further characterization of the Ro and La small ribonucleoproteins from uninfected mammalian cells

    SciTech Connect

    Hendrick, J.P.; Wolin, S.L.; Rinke, J.; Lerner, M.R.; Steitz, J.A.

    1981-12-01

    Small ribonucleic acid (RNA)-protein complexes precipitated by anti-Ro and anti-La antibodies from lupus patients have been examined with emphasis on their RNA components. In both ribonucleoprotein (RNP) classes, the numbers of different RNA molecules and their sequences vary between mouse and human cells. The complex mixtures of La RNAs include two previously sequenced 4.5S RNAs from mouse cells and 5S ribosomal RNA-like molecules from both mouse and human cells. All Ro and La RNAs possess 5'-triphosphates. Some La RNAs have internal modifications typical of transfer RNAs. The RoRNPs are quite stable and are localized by immunofluorescence in the cell cytoplasm, whereas the majority of the La RNPs turn over rapidly and reside in the nucleus. Despite these differences, reconstitution experiments show that the Ro particles carry the La as well as the Ro determinant. Studies using a nuclear transcription system demonstrate that most of the La RNAs are synthesized by RNA polymerase III. The possibility that the La protein(s) functions in the transcription or maturation of all RNA polymerase III transcripts is discussed.

  2. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  3. RO brine treatment and recovery by biological activated carbon and capacitive deionization process.

    PubMed

    Tao, Guihe; Viswanath, Bala; Kekre, Kiran; Lee, Lai Yoke; Ng, How Yong; Ong, Say Leong; Seah, Harry

    2011-01-01

    The generation of brine solutions from dense membrane (reverse osmosis, RO or nanofiltration, NF) water reclamation systems has been increasing worldwide, and the lack of cost effective disposal options is becoming a critical water resources management issue. In Singapore, NEWater is the product of a multiple barrier water reclamation process from secondary treated domestic effluent using MF/UF-RO and UV technologies. The RO brine (concentrates) accounts for more than 20% of the total flow treated. To increase the water recovery and treat the RO brine, a CDI based process with BAC as pretreatment was tested. The results show that ion concentrations in CDI product were low except SiO2 when compared with RO feed water. CDI product was passed through a RO and the RO permeate was of better quality including low SiO2 as compared to NEWater quality. It could be beneficial to use a dedicated RO operated at optimum conditions with better performance to recover the water. BAC was able to achieve 15-27% TOC removal of RO brine. CDI had been tested at a water recovery ranging from 71.6 to 92.3%. CDI based RO brine treatment could improve overall water recovery of NEWater production over 90%. It was found that calcium phosphate scaling and organic fouling was the major cause of CDI pressure increase. Ozone disinfection and sodium bisulfite dosing were able to reduce CDI fouling rate. For sustainable operation of CDI organic fouling control and effective organic fouling cleaning should be further studied. PMID:22053461

  4. Role of 5-HT2C Receptors in Effects of Monoamine Releasers on Intracranial Self-Stimulation in Rats

    PubMed Central

    Bauer, Clayton T.; Banks, Matthew L.; Blough, Bruce E.; Negus, S. Stevens

    2015-01-01

    Rationale Many monoamine releasers are abused by humans and produce abuse-related facilitation of intracranial self-stimulation (ICSS) in rats. Facilitation of ICSS in rats can be limited by monoamine releaser-induced serotonin (5-HT) release, but receptors that mediate 5-HT effects of monoamine releasers are unknown. Objectives Investigate whether 5-HT2C receptor activation is necessary for rate-decreasing effects produced in an ICSS procedure in rats by the 5-HT-selective monoamine releaser fenfluramine and the non-selective releasers napthylisopropylamine (PAL-287) and (+)-3,4-methylenedioxymethamphetamine ((+)-MDMA). Methods Adult male Sprague-Dawley rats with electrodes implanted in the medial forebrain bundle were trained to lever press for brain stimulation under a “frequency-rate” ICSS procedure. Effectiveness of the 5-HT2C antagonist SB 242,084 was evaluated to block rate-decreasing effects produced by (1) the 5-HT2C agonist Ro 60-0175, (2) the 5-HT-selective releaser fenfluramine, and (3) the mixed-action dopamine (DA)/norepinephrine (NE)/5-HT releasers PAL-287 (1.0-5.6 mg/kg), and (+)-MDMA (1.0-3.2 mg/kg). For comparison, effectiveness of SB 242,084 to alter rate-decreasing effects of the kappa opioid receptor agonist U69,593 and rate-increasing effects of the DA>5-HT releaser amphetamine were also examined. Results SB 242,084 pretreatment blocked rate-decreasing effects of Ro 60-0175 and fenfluramine, but not the rate-decreasing effects of U69,593 or the rate-increasing effects of amphetamine. SB 242,084 blunted the rate-decreasing effects and enhanced expression of rate-increasing effects of PAL-287 and (+)-MDMA. Conclusions These data suggest that 5-HT2C receptor activation contributes to rate-decreasing effects that are produced by selective and mixed-action 5-HT releasers in rats and that may oppose and limit the expression of abuse-related ICSS facilitation by these compounds. PMID:26041338

  5. Transiting exoplanets from the CoRoT space mission . VI. CoRoT-Exo-3b: the first secure inhabitant of the brown-dwarf desert

    NASA Astrophysics Data System (ADS)

    Deleuil, M.; Deeg, H. J.; Alonso, R.; Bouchy, F.; Rouan, D.; Auvergne, M.; Baglin, A.; Aigrain, S.; Almenara, J. M.; Barbieri, M.; Barge, P.; Bruntt, H.; Bordé, P.; Collier Cameron, A.; Csizmadia, Sz.; de La Reza, R.; Dvorak, R.; Erikson, A.; Fridlund, M.; Gandolfi, D.; Gillon, M.; Guenther, E.; Guillot, T.; Hatzes, A.; Hébrard, G.; Jorda, L.; Lammer, H.; Léger, A.; Llebaria, A.; Loeillet, B.; Mayor, M.; Mazeh, T.; Moutou, C.; Ollivier, M.; Pätzold, M.; Pont, F.; Queloz, D.; Rauer, H.; Schneider, J.; Shporer, A.; Wuchterl, G.; Zucker, S.

    2008-12-01

    Context: The CoRoT space mission routinely provides high-precision photometric measurements of thousands of stars that have been continuously observed for months. Aims: The discovery and characterization of the first very massive transiting planetary companion with a short orbital period is reported. Methods: A series of 34 transits was detected in the CoRoT light curve of an F3V star, observed from May to October 2007 for 152 days. The radius was accurately determined and the mass derived for this new transiting, thanks to the combined analysis of the light curve and complementary ground-based observations: high-precision radial-velocity measurements, on-off photometry, and high signal-to-noise spectroscopic observations. Results: CoRoT-Exo-3b has a radius of 1.01 ± 0.07 R_Jup and transits around its F3-type primary every 4.26 days in a synchronous orbit. Its mass of 21.66 ± 1.0 M_Jup, density of 26.4 ± 5.6 g cm-3, and surface gravity of logg = 4.72 clearly distinguish it from the regular close-in planet population, making it the most intriguing transiting substellar object discovered so far. Conclusions: With the current data, the nature of CoRoT-Exo-3b is ambiguous, as it could either be a low-mass brown-dwarf or a member of a new class of “superplanets”. Its discovery may help constrain the evolution of close-in planets and brown-dwarfs better. Finally, CoRoT-Exo-3b confirms the trend that massive transiting giant planets (M ≥ 4 M_Jup) are found preferentially around more massive stars than the Sun. The CoRoT space mission, launched on December 27th 2006, has been developed and is operating by CNES, with the contribution of Austria, Belgium, Brasil, ESA, Germany and Spain. The first CoRoT data will be available to the public in February 2009 from the CoRoT archive: http://idoc-corot.ias.u-psud.fr/ Table of the COROT photometry is only available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsweb

  6. Transiting exoplanets from the CoRoT space mission. XXV. CoRoT-27b: a massive and dense planet on a short-period orbit

    NASA Astrophysics Data System (ADS)

    Parviainen, H.; Gandolfi, D.; Deleuil, M.; Moutou, C.; Deeg, H. J.; Ferraz-Mello, S.; Samuel, B.; Csizmadia, Sz.; Pasternacki, T.; Wuchterl, G.; Havel, M.; Fridlund, M.; Angus, R.; Tingley, B.; Grziwa, S.; Korth, J.; Aigrain, S.; Almenara, J. M.; Alonso, R.; Baglin, A.; Barros, S. C. C.; Bordé, P.; Bouchy, F.; Cabrera, J.; Díaz, R. F.; Dvorak, R.; Erikson, A.; Guillot, T.; Hatzes, A.; Hébrard, G.; Mazeh, T.; Montagnier, G.; Ofir, A.; Ollivier, M.; Pätzold, M.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.

    2014-02-01

    Aims: We report the discovery of a massive and dense transiting planet CoRoT-27b on a 3.58-day orbit around a 4.2 Gyr-old G2 star. The planet candidate was identified from the CoRoT photometry, and was confirmed as a planet with ground-based spectroscopy. Methods: The confirmation of the planet candidate is based on radial velocity observations combined with imaging to rule out blends. The characterisation of the planet and its host star was carried out using a Bayesian approach where all the data (CoRoT photometry, radial velocities, and spectroscopic characterisation of the star) are used jointly. The Bayesian analysis included a study whether the assumption of white normally distributed noise holds for the CoRoT photometry and whether the use of a non-normal noise distribution offers advantages in parameter estimation and model selection. Results: CoRoT-27b has a mass of 10.39 ± 0.55MJup, a radius of 1.01 ± 0.04RJup, a mean density of 12.6-1.67+1.92g cm-3, and an effective temperature of 1500 ± 130 K. The planet orbits around its host star, a 4.2 Gyr-old G2-star with a mass M⋆ = 1.06M⊙ and a radius R⋆ = 1.05R⊙, on a 0.048 ± 0.007 AU orbit of 3.58 days. The radial velocity observations allow us to exclude highly eccentric orbits, namely, e < 0.065 with 99% confidence. Given its high mass and density, theoretical modelling of CoRoT-27b is demanding. We identify two solutions with heavy element mass fractions of 0.11 ± 0.08M⊕ and 0.07 ± 0.06M⊕, but even solutions void of heavy elements cannot be excluded. We carry out a secondary eclipse search from the CoRoT photometry using a method based on Bayesian model selection, but conclude that the noise level is too high to detect eclipses shallower than 9% of the transit depth. Using a non-normal noise model was shown not to affect the parameter estimation results, but led to significant improvement in the sensitivity of the model selection process. The CoRoT space mission, launched on December 27, 2006

  7. The high-energy environment in the super-Earth system CoRoT-7

    NASA Astrophysics Data System (ADS)

    Poppenhaeger, K.; Czesla, S.; Schröter, S.; Lalitha, S.; Kashyap, V.; Schmitt, J. H. M. M.

    2012-05-01

    High-energy irradiation of exoplanets has been identified to be a key influence on the stability of these planets' atmospheres. So far, irradiation-driven mass-loss has been observed only in two Hot Jupiters, and the observational data remain even more sparse in the super-Earth regime. We present an investigation of the high-energy emission in the CoRoT-7 system, which hosts the first known transiting super-Earth. To characterize the high-energy XUV radiation field into which the rocky planets CoRoT-7b and CoRoT-7c are immersed, we analyzed a 25 ks XMM-Newton observation of the host star. Our analysis yields the first clear (3.5σ) X-ray detection of CoRoT-7. We determine a coronal temperature of ≈ 3 MK and an X-ray luminosity of 3 × 1028 erg s-1. The level of XUV irradiation on CoRoT-7b amounts to ≈37 000 erg cm-2 s-1. Current theories for planetary evaporation can only provide an order-of-magnitude estimate for the planetary mass loss; assuming that CoRoT-7b has formed as a rocky planet, we estimate that CoRoT-7b evaporates at a rate of about 1.3 × 1011 g s-1 and has lost ≈4-10 earth masses in total.

  8. Experimental results from RO-PRO: a next generation system for low-energy desalination.

    PubMed

    Achilli, Andrea; Prante, Jeri L; Hancock, Nathan T; Maxwell, Eric B; Childress, Amy E

    2014-06-01

    A pilot system was designed and constructed to evaluate reverse osmosis (RO) energy reduction that can be achieved using pressure-retarded osmosis (PRO). The RO-PRO experimental system is the first known system to utilize energy from a volume of water transferred from atmospheric pressure to elevated pressure across a semipermeable membrane to prepressurize RO feedwater. In other words, the system demonstrated that pressure could be exchanged between PRO and RO subsystems. Additionally, the first experimental power density data for a RO-PRO system is now available. Average experimental power densities for the RO-PRO system ranged from 1.1 to 2.3 W/m2. This is higher than previous river-to-sea PRO pilot systems (1.5 W/m2) and closer to the goal of 5 W/m2 that would make PRO an economically feasible technology. Furthermore, isolated PRO system testing was performed to evaluate PRO element performance with higher cross-flow velocities and power densities exceeding 8 W/m2 were achieved with a 28 g/L NaCl draw solution. From this empirical data, inferences for future system performance can be drawn that indicate future RO-PRO systems may reduce the specific energy requirements for desalination by ∼1 kWh/m3. PMID:24798068

  9. Rapid field assessment of RO desalination of brackish agricultural drainage water.

    PubMed

    Thompson, John; Rahardianto, Anditya; Gu, Han; Uchymiak, Michal; Bartman, Alex; Hedrick, Marcos; Lara, David; Cooper, Jim; Faria, Jose; Christofides, Panagiotis D; Cohen, Yoram

    2013-05-15

    Rapid field evaluation of RO feed filtration requirements, selection of effective antiscalant type and dose, and estimation of suitable scale-free RO recovery level were demonstrated using a novel approach based on direct observation of mineral scaling and flux decline measurements, utilizing an automated Membrane Monitor (MeMo). The MeMo, operated in a stand-alone single-pass desalting mode, enabled rapid assessment of the adequacy of feed filtration by enabling direct observation of particulate deposition on the membrane surface. The diagnostic field study with RO feed water of high mineral scaling propensity revealed (via direct MeMo observation) that suspended particulates (even for feed water of turbidity <1 NTU) could serve as seeds for promoting surface crystal nucleation. With feed filtration optimized, a suitable maximum RO water recovery, with complete mineral scale suppression facilitated by an effective antiscalant dose, can be systematically and directly identified (via MeMo) in the field for a given feed water quality. Scale-free operating conditions, determined via standalone MeMo rapid diagnostic tests, were shown to be applicable to spiral-would RO system as validated via both flux decline measurements and ex-situ RO plant membrane scale monitoring. It was shown that the present approach is suitable for rapid field assessment of RO operability and it is particularly advantageous when evaluating water sources of composition that may vary both temporally and across the regions of interest. PMID:23538039

  10. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

  11. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pégorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  12. Risk versus benefit considerations for the beta(2)-agonists.

    PubMed

    Kelly, H William

    2006-09-01

    Short-acting beta(2)-agonists are the mainstay of therapy for acute bronchospasm associated with asthma and chronic obstructive pulmonary disease, whereas long-acting beta(2)-agonists are used in maintaining disease control in these respiratory disorders. This review describes and compares the pharmacology of the beta(2)-agonists and explains how these differences translate into differences in efficacy and beta(2)-adrenergic-mediated adverse effects. Questions commonly asked by clinicians regarding the efficacy and safety of short- and long-acting beta(2)-agonists include issues about cardiovascular effects, tolerance to their bronchodilator and bronchoprotective effects, blunting of albuterol response by long-acting beta(2)-agonists, potential masking of worsening asthma control, and the role of long-acting beta(2)-agonists as adjunctive therapy with inhaled corticosteroids in maintaining asthma control. Pharmacogenetics may play a role in determining which patients may be at risk for a reduced response to a beta(2)-agonist. The continued use of racemic albuterol, which contains a mixture of R-albuterol and S-albuterol, has been questioned because of data from preclinical and clinical studies suggesting that S-albuterol causes proinflammatory effects and may increase bronchial hyperreactivity. The preclinical and clinical effects of these two stereoisomers are reviewed. Data describing the efficacy and safety of levalbuterol (R-albuterol) and racemic albuterol are presented. PMID:16945063

  13. Dopamine agonist withdrawal syndrome: implications for patient care.

    PubMed

    Nirenberg, Melissa J

    2013-08-01

    Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID:23686524

  14. Expected Performance of the CoRoT Planet Search from Light Curve Beauty Contests

    NASA Astrophysics Data System (ADS)

    Moutou, C.; Aigrain, S.; Almenara, J.; Alonso, R.; Auvergne, M.; Barge, P.; Blouin, D.; Borde, P.; Cabrera, J.; Carone, L.; Cautain, R.; Deeg, H.; Erikson, A.; Fressin, F.; Guis, V.; Leger, A.; Guterman, P.; Irwin, M.; Kabath, P.; Lanza, A.; Maceroni, C.; Mazeh, T.; Ollivier, M.; Pont, F.; Paetzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Schneider, J.; Tamuz, O.; Voss, H.; Zucker, S.

    2007-07-01

    The CoRoT space mission, scheduled for launch in December 2006, has two primary science goals: asteroseismology and the detection of planetary transits, the latter being the subject of this contribution. Given its expected photometric performance and its 150 day observing window, CoRoT will detect planets with periods up to 75 days and radii down to 2 Earth radii. To prepare for the data analysis and evaluate the detection limits of the mission, a number of blind exercises to detect planets in simulated light curves have been carried out within the CoRoT exoplanet community, and their results to date are summarized here.

  15. Transiting exoplanets from the CoRoT space mission. XXIV. CoRoT-25b and CoRoT-26b: two low-density giant planets

    NASA Astrophysics Data System (ADS)

    Almenara, J. M.; Bouchy, F.; Gaulme, P.; Deleuil, M.; Havel, M.; Gandolfi, D.; Deeg, H. J.; Wuchterl, G.; Guillot, T.; Gardes, B.; Pasternacki, T.; Aigrain, S.; Alonso, R.; Auvergne, M.; Baglin, A.; Bonomo, A. S.; Bordé, P.; Cabrera, J.; Carpano, S.; Cochran, W. D.; Csizmadia, Sz.; Damiani, C.; Diaz, R. F.; Dvorak, R.; Endl, M.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Hébrard, G.; Gillon, M.; Guenther, E.; Hatzes, A.; Léger, A.; Lammer, H.; MacQueen, P. J.; Mazeh, T.; Moutou, C.; Ollivier, M.; Ofir, A.; Pätzold, M.; Parviainen, H.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Samuel, B.; Schneider, J.; Tal-Or, L.; Tingley, B.; Weingrill, J.

    2013-07-01

    We report the discovery of two transiting exoplanets, CoRoT-25b and CoRoT-26b, both of low density, one of which is in the Saturn mass-regime. For each star, ground-based complementary observations through optical photometry and radial velocity measurements secured the planetary nature of the transiting body and allowed us to fully characterize them. For CoRoT-25b we found a planetary mass of 0.27 ± 0.04 MJup, a radius of 1.08-0.10+0.3 RJup and hence a mean density of 0.15-0.06+0.15 g cm-3. The planet orbits an F9 main-sequence star in a 4.86-day period, that has a V magnitude of 15.0, solar metallicity, and an age of 4.5-2.0+1.8-Gyr. CoRoT-26b orbits a slightly evolved G5 star of 9.06 ± 1.5-Gyr age in a 4.20-day period that hassolar metallicity and a V magnitude of 15.8. With a mass of 0.52 ± 0.05 MJup, a radius of 1.26-0.07+0.13 RJup, and a mean density of 0.28-0.07+0.09 g cm-3, it belongs to the low-mass hot-Jupiter population. Planetary evolution models allowed us to estimate a core mass of a few tens of Earth mass for the two planets with heavy-element mass fractions of 0.52-0.15+0.08 and 0.26-0.08+0.05, respectively, assuming that a small fraction of the incoming flux is dissipated at the center of the planet. In addition, these models indicate that CoRoT-26b is anomalously large compared with what standard models could account for, indicating that dissipation from stellar heating could cause this size. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain. Partly based on observations obtained at the European Southern Observatory at Paranal and La Silla, Chile in programs 083.C-0690(A), 184.C-0639.

  16. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed

    Langmead, Christopher J; Christopoulos, Arthur

    2013-05-01

    The concept of 'super agonism' has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. PMID:23441648

  17. Transiting exoplanets from the CoRoT space mission. VIII. CoRoT-7b: the first super-Earth with measured radius

    NASA Astrophysics Data System (ADS)

    Léger, A.; Rouan, D.; Schneider, J.; Barge, P.; Fridlund, M.; Samuel, B.; Ollivier, M.; Guenther, E.; Deleuil, M.; Deeg, H. J.; Auvergne, M.; Alonso, R.; Aigrain, S.; Alapini, A.; Almenara, J. M.; Baglin, A.; Barbieri, M.; Bruntt, H.; Bordé, P.; Bouchy, F.; Cabrera, J.; Catala, C.; Carone, L.; Carpano, S.; Csizmadia, Sz.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Foing, B.; Fressin, F.; Gandolfi, D.; Gillon, M.; Gondoin, Ph.; Grasset, O.; Guillot, T.; Hatzes, A.; Hébrard, G.; Jorda, L.; Lammer, H.; Llebaria, A.; Loeillet, B.; Mayor, M.; Mazeh, T.; Moutou, C.; Pätzold, M.; Pont, F.; Queloz, D.; Rauer, H.; Renner, S.; Samadi, R.; Shporer, A.; Sotin, Ch.; Tingley, B.; Wuchterl, G.; Adda, M.; Agogu, P.; Appourchaux, T.; Ballans, H.; Baron, P.; Beaufort, T.; Bellenger, R.; Berlin, R.; Bernardi, P.; Blouin, D.; Baudin, F.; Bodin, P.; Boisnard, L.; Boit, L.; Bonneau, F.; Borzeix, S.; Briet, R.; Buey, J.-T.; Butler, B.; Cailleau, D.; Cautain, R.; Chabaud, P.-Y.; Chaintreuil, S.; Chiavassa, F.; Costes, V.; Cuna Parrho, V.; de Oliveira Fialho, F.; Decaudin, M.; Defise, J.-M.; Djalal, S.; Epstein, G.; Exil, G.-E.; Fauré, C.; Fenouillet, T.; Gaboriaud, A.; Gallic, A.; Gamet, P.; Gavalda, P.; Grolleau, E.; Gruneisen, R.; Gueguen, L.; Guis, V.; Guivarc'h, V.; Guterman, P.; Hallouard, D.; Hasiba, J.; Heuripeau, F.; Huntzinger, G.; Hustaix, H.; Imad, C.; Imbert, C.; Johlander, B.; Jouret, M.; Journoud, P.; Karioty, F.; Kerjean, L.; Lafaille, V.; Lafond, L.; Lam-Trong, T.; Landiech, P.; Lapeyrere, V.; Larqué, T.; Laudet, P.; Lautier, N.; Lecann, H.; Lefevre, L.; Leruyet, B.; Levacher, P.; Magnan, A.; Mazy, E.; Mertens, F.; Mesnager, J.-M.; Meunier, J.-C.; Michel, J.-P.; Monjoin, W.; Naudet, D.; Nguyen-Kim, K.; Orcesi, J.-L.; Ottacher, H.; Perez, R.; Peter, G.; Plasson, P.; Plesseria, J.-Y.; Pontet, B.; Pradines, A.; Quentin, C.; Reynaud, J.-L.; Rolland, G.; Rollenhagen, F.; Romagnan, R.; Russ, N.; Schmidt, R.; Schwartz, N.; Sebbag, I.; Sedes, G.; Smit, H.; Steller, M. B.; Sunter, W.; Surace, C.; Tello, M.; Tiphène, D.; Toulouse, P.; Ulmer, B.; Vandermarcq, O.; Vergnault, E.; Vuillemin, A.; Zanatta, P.

    2009-10-01

    Aims: We report the discovery of very shallow (Δ F/F ≈ 3.4× 10-4), periodic dips in the light curve of an active V = 11.7 G9V star observed by the CoRoT satellite, which we interpret as caused by a transiting companion. We describe the 3-colour CoRoT data and complementary ground-based observations that support the planetary nature of the companion. Methods: We used CoRoT colours information, good angular resolution ground-based photometric observations in- and out- of transit, adaptive optics imaging, near-infrared spectroscopy, and preliminary results from radial velocity measurements, to test the diluted eclipsing binary scenarios. The parameters of the host star were derived from optical spectra, which were then combined with the CoRoT light curve to derive parameters of the companion. Results: We examined all conceivable cases of false positives carefully, and all the tests support the planetary hypothesis. Blends with separation >0.40´´or triple systems are almost excluded with a 8 × 10-4 risk left. We conclude that, inasmuch we have been exhaustive, we have discovered a planetary companion, named CoRoT-7b, for which we derive a period of 0.853 59 ± 3 × 10-5 day and a radius of Rp = 1.68 ± 0.09 R_Earth. Analysis of preliminary radial velocity data yields an upper limit of 21 M_Earth for the companion mass, supporting the finding. Conclusions: CoRoT-7b is very likely the first Super-Earth with a measured radius. This object illustrates what will probably become a common situation with missions such as Kepler, namely the need to establish the planetary origin of transits in the absence of a firm radial velocity detection and mass measurement. The composition of CoRoT-7b remains loosely constrained without a precise mass. A very high surface temperature on its irradiated face, ≈1800-2600 K at the substellar point, and a very low one, ≈50 K, on its dark face assuming no atmosphere, have been derived. The CoRoT space mission, launched on 27

  18. Relamorelin: A Novel Gastrocolokinetic Synthetic Ghrelin Agonist

    PubMed Central

    Camilleri, Michael; Acosta, Andres

    2015-01-01

    Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately 6-fold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a pre-specified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders. PMID:25545036

  19. Quality of life in functional rhinoplasty: rhinoplasty outcomes evaluation German version (ROE-D).

    PubMed

    Bulut, Olcay Cem; Plinkert, Peter K; Wallner, Frank; Baumann, Ingo

    2016-09-01

    The aim of this study was to validate a German version of the rhinoplasty outcomes evaluation (ROE) questionnaire. A prospective study was conducted and a German translated ROE (ROE-D) questionnaire administered to 100 patients preoperatively, 6 and 12 months postoperatively. The translation was performed according to internationally accepted guidelines. To validate this instrument, we evaluated its reliability, validity and sensitivity. ROE-D was completed by 54 patients after 6 months and by 69 patients 1 year after functional rhinoplasty. Cronbach's α indicated good internal consistency. Reliability was tested with a split-half-reliability, showing significant correlation. Discrimination validity was demonstrated by a comparison with healthy controls. Sensitivity to change showed medium to large effects. ROE-D is a reliable, validated and sensitive German instrument for measuring health-related quality of life in patients after rhinoplasty. The ROE-D focuses mainly on the aesthetic aspects of the rhinoplasty surgery. PMID:26864439

  20. Micro-Electro-Mechanical-Systems-Based Micro-Ro-Boat Utilizing Steam as Propulsion Power

    NASA Astrophysics Data System (ADS)

    Choi, Ju Chan; Choi, Young Chan; Kyoo Lee, June; Kong, Seong Ho

    2012-06-01

    We report the design and fabrication of a micro-electro-mechanical-systems (MEMS)-based microactuator, that floats on the surface of water and is driven by steam. We named the actuator “micro-Ro-boat”, a compound word created from the words “robot” and “boat”. The MEMS-based micro-Ro-boat utilizes steam as the propulsion power, giving it a high speed and long lifetime. A hydrophobic surface has been utilized for the wing of the actuator to enhance the buoyancy. Instead of using gas or fuel, the proposed micro-Ro-boat utilizes steam form electrically heated water. The velocity of the micro-Ro-boat is in the range of 0.5-2 cm/s and the maximum loading capability for a device size of 10 ×10 mm2 is 0.4 g.

  1. Selecting agonists from single cells infected with combinatorial antibody libraries.

    PubMed

    Zhang, Hongkai; Yea, Kyungmoo; Xie, Jia; Ruiz, Diana; Wilson, Ian A; Lerner, Richard A

    2013-05-23

    We describe a system for direct selection of antibodies that are receptor agonists. Combinatorial antibody libraries in lentiviruses are used to infect eukaryotic cells that contain a fluorescent reporter system coupled to the receptor for which receptor agonist antibodies are sought. In this embodiment of the method, very large numbers of candidate antibodies expressing lentivirus and eukaryotic reporter cells are packaged together in a format where each is capable of replication, thereby forging a direct link between genotype and phenotype. Following infection, cells that fluoresce are sorted and the integrated genes encoding the agonist antibodies recovered. We validated the system by illustrating its ability to generate rapidly potent antibody agonists that are complete thrombopoietin phenocopies. The system should be generalizable to any pathway where its activation can be linked to production of a selectable phenotype. PMID:23706638

  2. Therapeutic Potential of 5-HT6 Receptor Agonists.

    PubMed

    Karila, Delphine; Freret, Thomas; Bouet, Valentine; Boulouard, Michel; Dallemagne, Patrick; Rochais, Christophe

    2015-10-22

    Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox. PMID:26099069

  3. Partial agonist therapy in schizophrenia: relevance to diminished criminal responsibility.

    PubMed

    Gavaudan, Gilles; Magalon, David; Cohen, Julien; Lançon, Christophe; Léonetti, Georges; Pélissier-Alicot, Anne-Laure

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. PMID:20579229

  4. Selective 5-HT2C agonists as potential antidepressants.

    PubMed

    Leysen, D C

    1999-02-01

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

  5. The influence of antiscalants on biofouling of RO membranes in seawater desalination.

    PubMed

    Sweity, Amer; Oren, Yoram; Ronen, Zeev; Herzberg, Moshe

    2013-06-15

    Antiscalants are surface active polyelectrolyte compounds commonly used in reverse osmosis (RO) desalination processes to avoid membrane scaling. In spite of the significant roles of antiscalants in preventing membrane scaling, they are prone to enhance biofilm growth on RO membranes by either altering membrane surface properties or by serving as nutritional source for microorganisms. In this study, the contribution of antiscalants to membrane biofouling in seawater desalination was investigated. The effects of two commonly used antiscalants, polyphosphonate- and polyacrylate-based, were tested. The effects of RO membrane (DOW-Filmtec SW30 HRLE-400) exposure to antiscalants on its physico-chemical properties were studied, including the consequent effects on initial deposition and growth of the sessile microorganisms on the RO membrane surface. The effects of antiscalants on membrane physico-chemical properties were investigated by filtration of seawater supplemented with the antiscalants through flat-sheet RO membrane and changes in surface zeta potential and hydrophobicity were delineated. Adsorption of antiscalants to polyamide surfaces simulating RO membrane's polyamide layer and their effects on the consequent bacterial adhesion was tested using a quartz crystal microbalance with dissipation monitoring technology (QCM-D) and direct fluorescent microscopy. A significant increase in biofilm formation rate on RO membranes surface was observed in the presence of both types of antiscalants. Polyacrylate-based antiscalant was shown to enhance initial cell attachment as observed with the QCM-D and a parallel plate flow cell, due to rendering the polyamide surface more hydrophobic. Polyphosphonate-based antiscalants also increased biofilm formation rate, most likely by serving as an additional source of phosphorous to the seawater microbial population. A thicker biofilm layer was formed on the RO membrane when the polyacrylate-based antiscalant was used. Following

  6. Agonist pharmacology of two Drosophila GABA receptor splice variants.

    PubMed Central

    Hosie, A. M.; Sattelle, D. B.

    1996-01-01

    1. The Drosophila melanogaster gamma-aminobutyric acid (GABA) receptor subunits, RDLac and DRC 17-1-2, form functional homo-oligomeric receptors when heterologously expressed in Xenopus laevis oocytes. The subunits differ in only 17 amino acids, principally in regions of the N-terminal domain which determine agonist pharmacology in vertebrate ionotropic neurotransmitter receptors. A range of conformationally restricted GABA analogues were tested on the two homo-oligomers and their agonists pharmacology compared with that of insect and vertebrate iontropic GABA receptors. 2. The actions of GABA, isoguvacine and isonipecotic acid on RDLac and DRC 17-1-2 homo-oligomers were compared, by use of two-electrode voltage-clamp. All three compounds were full agonists of both receptors, but were 4-6 fold less potent agonists of DRC 17-1-2 homo-oligomers than of RDLac. However, the relative potencies of these agonists on each receptor were very similar. 3. A more complete agonist profile was established for RDLac homo-oligomers. The most potent agonists of these receptors were GABA, muscimol and trans-aminocrotonic acid (TACA), which were approximately equipotent. RDLac homo-oligomers were fully activated by a range of GABA analogues, with the order of potency: GABA > ZAPA ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid) > isoguvacine > imidazole-4-acetic acid > or = isonipecotic acid > or = cis-aminocrotonic acid (CACA) > beta-alanine. 3-Aminopropane sulphonic acid (3-APS), a partial agonist of RDLac homo-oligomers, was the weakest agonist tested and 100 fold less potent than GABA. 4. SR95531, an antagonist of vertebrate GABAA receptors, competitively inhibited the GABA responses of RDLac homo-oligomers, which have previously been found to insensitive to bicuculline. However, its potency (IC50 500 microM) was much reduced when compared to GABAA receptors. 5. The agonist pharmacology of Drosophila RDLac homo-oligomers exhibits aspects of the characteristic pharmacology of

  7. CoRoT-7b: SUPER-EARTH OR SUPER-Io?

    SciTech Connect

    Barnes, Rory; Kaib, Nathan A.; Raymond, Sean N.; Greenberg, Richard; Jackson, Brian

    2010-02-01

    CoRoT-7b, a planet about 70% larger than the Earth orbiting a Sun-like star, is the first-discovered rocky exoplanet, and hence has been dubbed a 'super-Earth'. Some initial studies suggested that since the planet is so close to its host star, it receives enough insolation to partially melt its surface. However, these past studies failed to take into consideration the role that tides may play in this system. Even if the planet's eccentricity has always been zero, we show that tidal decay of the semimajor axis could have been large enough that the planet formed on a wider orbit which received less insolation. Moreover, CoRoT-7b could be tidally heated at a rate that dominates its geophysics and drives extreme volcanism. In this case, CoRoT-7b is a 'super-Io' that, like Jupiter's volcanic moon, is dominated by volcanism and rapid resurfacing. Such heating could occur with an eccentricity of just 10{sup -5}. This small value could be driven by CoRoT-7c if its own eccentricity is larger than {approx}10{sup -4}. CoRoT-7b may be the first of a class of planetary super-Ios likely to be revealed by the CoRoT and Kepler spacecraft.

  8. Planets and Stellar Activity: Hide and Seek in the CoRoT-7 system

    NASA Astrophysics Data System (ADS)

    Haywood, R. D.; Cameron, A. C.; Queloz, D.; Barros, S. C. C.; Deleuil, M.; Fares, R.; Gillon, M.; Hatzes, A.; Lanza, A. F.; Lovis, C.; Moutou, C.; Pepe, F.; Pollacco, D.; Santerne, A.; Ségransan, D.; Unruh, Y.

    2014-01-01

    Since the discovery of the transiting Super-Earth CoRoT-7b, several investigations have been made of the number and precise masses of planets present in the system, but they all yield different results, owing to the star's high level of activity. Radial velocity (RV) variations induced by stellar activity therefore need to be modelled and removed to allow a reliable detection of all planets in the system. We re-observed CoRoT-7 in January 2012 with both HARPS and the CoRoT satellite, so that we now have the benefit of simultaneous RV and photometric data. We fitted the off-transit variations in the CoRoT lightcurve using a harmonic decomposition similar to that implemented in Queloz et al. (2009). This fit was then used to model the stellar RV contribution, according to the methods described by Aigrain et al. (2011). This model was incorporated into a Monte Carlo Markov Chain in order to make a precise determination of the orbits of CoRoT-7b and CoRoT-7c. We also assess the evidence for the presence of one or two additional planetary companions.

  9. CoRoT-7b: Super-Earth or Super-Io?

    NASA Astrophysics Data System (ADS)

    Barnes, Rory; Raymond, Sean N.; Greenberg, Richard; Jackson, Brian; Kaib, Nathan A.

    2010-02-01

    CoRoT-7b, a planet about 70% larger than the Earth orbiting a Sun-like star, is the first-discovered rocky exoplanet, and hence has been dubbed a "super-Earth." Some initial studies suggested that since the planet is so close to its host star, it receives enough insolation to partially melt its surface. However, these past studies failed to take into consideration the role that tides may play in this system. Even if the planet's eccentricity has always been zero, we show that tidal decay of the semimajor axis could have been large enough that the planet formed on a wider orbit which received less insolation. Moreover, CoRoT-7b could be tidally heated at a rate that dominates its geophysics and drives extreme volcanism. In this case, CoRoT-7b is a "super-Io" that, like Jupiter's volcanic moon, is dominated by volcanism and rapid resurfacing. Such heating could occur with an eccentricity of just 10-5. This small value could be driven by CoRoT-7c if its own eccentricity is larger than ~10-4. CoRoT-7b may be the first of a class of planetary super-Ios likely to be revealed by the CoRoT and Kepler spacecraft.

  10. Sleep attacks in patients taking dopamine agonists: review

    PubMed Central

    Homann, Carl Nikolaus; Wenzel, Karoline; Suppan, Klaudia; Ivanic, Gerd; Kriechbaum, Norbert; Crevenna, Richard; Ott, Erwin

    2002-01-01

    Objectives To assess the evidence for the existence and prevalence of sleep attacks in patients taking dopamine agonists for Parkinson's disease, the type of drugs implicated, and strategies for prevention and treatment. Design Review of publications between July 1999 and May 2001 in which sleep attacks or narcoleptic-like attacks were discussed in patients with Parkinson's disease. Results 124 patients with sleep events were found in 20 publications. Overall, 6.6% of patients taking dopamine agonists who attended movement disorder centres had sleep events. Men were over-represented. Sleep events occurred at both high and low doses of the drugs, with different durations of treatment (0-20 years), and with or without preceding signs of tiredness. Sleep attacks are a class effect, having been found in patients taking the following dopamine agonists: levodopa (monotherapy in 8 patients), ergot agonists (apomorphine in 2 patients, bromocriptine in 13, cabergoline in 1, lisuride or piribedil in 23, pergolide in 5,) and non-ergot agonists (pramipexole in 32, ropinirole in 38). Reports suggest two distinct types of events: those of sudden onset without warning and those of slow onset with prodrome drowsiness. Conclusion Insufficient data are available to provide effective guidelines for prevention and treatment of sleep events in patients taking dopamine agonists for Parkinson's disease. Prospective population based studies are needed to provide this information. What is already known on this topicCar crashes in patients with Parkinson's disease have been associated with sleep attacks caused by the dopamine agonists pramipexole and ropiniroleWhether sleep attacks exist, their connection with certain agonists, prevention or treatment, and the justification of legal actions are controversialWhat this study addsSleep attacks as a phenomenon distinct from normal somnolence really do existThey are a class effect of all dopamine drugsEffective prevention and treatment

  11. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  12. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25326839

  13. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25437461

  14. PPAR dual agonists: are they opening Pandora's Box?

    PubMed

    Balakumar, Pitchai; Rose, Madhankumar; Ganti, Subrahmanya S; Krishan, Pawan; Singh, Manjeet

    2007-08-01

    Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in

  15. Mechanisms of inverse agonist action at D2 dopamine receptors.

    PubMed

    Roberts, David J; Strange, Philip G

    2005-05-01

    Mechanisms of inverse agonist action at the D2(short) dopamine receptor have been examined. Discrimination of G-protein-coupled and -uncoupled forms of the receptor by inverse agonists was examined in competition ligand-binding studies versus the agonist [3H]NPA at a concentration labelling both G-protein-coupled and -uncoupled receptors. Competition of inverse agonists versus [3H]NPA gave data that were fitted best by a two-binding site model in the absence of GTP but by a one-binding site model in the presence of GTP. K(i) values were derived from the competition data for binding of the inverse agonists to G-protein-uncoupled and -coupled receptors. K(coupled) and K(uncoupled) were statistically different for the set of compounds tested (ANOVA) but the individual values were different in a post hoc test only for (+)-butaclamol. These observations were supported by simulations of these competition experiments according to the extended ternary complex model. Inverse agonist efficacy of the ligands was assessed from their ability to reduce agonist-independent [35S]GTP gamma S binding to varying degrees in concentration-response curves. Inverse agonism by (+)-butaclamol and spiperone occurred at higher potency when GDP was added to assays, whereas the potency of (-)-sulpiride was unaffected. These data show that some inverse agonists ((+)-butaclamol, spiperone) achieve inverse agonism by stabilising the uncoupled form of the receptor at the expense of the coupled form. For other compounds tested, we were unable to define the mechanism. PMID:15735658

  16. Transiting exoplanets from the CoRoT space mission. XXVII. CoRoT-28b, a planet orbiting an evolved star, and CoRoT-29b, a planet showing an asymmetric transit

    NASA Astrophysics Data System (ADS)

    Cabrera, J.; Csizmadia, Sz.; Montagnier, G.; Fridlund, M.; Ammler-von Eiff, M.; Chaintreuil, S.; Damiani, C.; Deleuil, M.; Ferraz-Mello, S.; Ferrigno, A.; Gandolfi, D.; Guillot, T.; Guenther, E. W.; Hatzes, A.; Hébrard, G.; Klagyivik, P.; Parviainen, H.; Pasternacki, Th.; Pätzold, M.; Sebastian, D.; Tadeu dos Santos, M.; Wuchterl, G.; Aigrain, S.; Alonso, R.; Almenara, J.-M.; Armstrong, J. D.; Auvergne, M.; Baglin, A.; Barge, P.; Barros, S. C. C.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Carpano, S.; Chaffey, C.; Deeg, H. J.; Díaz, R. F.; Dvorak, R.; Erikson, A.; Grziwa, S.; Korth, J.; Lammer, H.; Lindsay, C.; Mazeh, T.; Moutou, C.; Ofir, A.; Ollivier, M.; Pallé, E.; Rauer, H.; Rouan, D.; Samuel, B.; Santerne, A.; Schneider, J.

    2015-07-01

    Context. We present the discovery of two transiting extrasolar planets by the satellite CoRoT. Aims: We aim at a characterization of the planetary bulk parameters, which allow us to further investigate the formation and evolution of the planetary systems and the main properties of the host stars. Methods: We used the transit light curve to characterize the planetary parameters relative to the stellar parameters. The analysis of HARPS spectra established the planetary nature of the detections, providing their masses. Further photometric and spectroscopic ground-based observations provided stellar parameters (log g, Teff, v sin i) to characterize the host stars. Our model takes the geometry of the transit to constrain the stellar density into account, which when linked to stellar evolutionary models, determines the bulk parameters of the star. Because of the asymmetric shape of the light curve of one of the planets, we had to include the possibility in our model that the stellar surface was not strictly spherical. Results: We present the planetary parameters of CoRoT-28b, a Jupiter-sized planet (mass 0.484 ± 0.087 MJup; radius 0.955 ± 0.066 RJup) orbiting an evolved star with an orbital period of 5.208 51 ± 0.000 38 days, and CoRoT-29b, another Jupiter-sized planet (mass 0.85 ± 0.20 MJup; radius 0.90 ± 0.16 RJup) orbiting an oblate star with an orbital period of 2.850 570 ± 0.000 006 days. The reason behind the asymmetry of the transit shape is not understood at this point. Conclusions: These two new planetary systems have very interesting properties and deserve further study, particularly in the case of the star CoRoT-29. The CoRoT space mission, launched on December 27th 2006, was developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany, and Spain. Based on observations obtained with the Nordic Optical Telescope, operated on the island of La Palma jointly by Denmark, Finland, Iceland

  17. Differential effects of AMPK agonists on cell growth and metabolism

    PubMed Central

    Vincent, Emma E.; Coelho, Paula P.; Blagih, Julianna; Griss, Takla; Viollet, Benoit; Jones, Russell G.

    2016-01-01

    As a sensor of cellular energy status, the AMP-activated protein kinase (AMPK) is believed to act in opposition to the metabolic phenotypes favored by proliferating tumor cells. Consequently, compounds known to activate AMPK have been proposed as cancer therapeutics. However, the extent to which the anti-neoplastic properties of these agonists are mediated by AMPK is unclear. Here we examined the AMPK-dependence of six commonly used AMPK agonists (metformin, phenformin, AICAR, 2DG, salicylate and A-769662) and their influence on cellular processes often deregulated in tumor cells. We demonstrate that the majority of these agonists display AMPK-independent effects on cell proliferation and metabolism with only the synthetic activator, A-769662, exerting AMPK-dependent effects on these processes. We find that A-769662 promotes an AMPK-dependent increase in mitochondrial spare respiratory capacity (SRC). Finally, contrary to the view of AMPK activity being tumor suppressive, we find A-769662 confers a selective proliferative advantage to tumor cells growing under nutrient deprivation. Our results indicate that many of the anti-growth properties of these agonists cannot be attributed to AMPK activity in cells, and thus any observed effects using these agonists should be confirmed using AMPK-deficient cells. Ultimately, our data urge caution, not only regarding the type of AMPK agonist proposed for cancer treatment, but also the context in which they are used. PMID:25241895

  18. Perception of specific trigeminal chemosensory agonists

    PubMed Central

    Frasnelli, J; Albrecht, J; Bryant, B; Lundström, JN

    2011-01-01

    The intranasal trigeminal system is a third chemical sense in addition to olfaction and gustation. As opposed to smell and taste, we still lack knowledge on the relationship between receptor binding and perception for the trigeminal system. We therefore investigated the sensitivity of the intranasal trigeminal system towards agonists of the trigeminal receptors TRPM8 and TRPA1 by assessing subjects’ ability to identify which nostril has been stimulated in a monorhinal stimulation design. We summed the number of correct identifications resulting in a lateralization score. Stimuli were menthol (activating TRPM8 receptors), eucalyptol (TRPM8), mustard oil (TRPA1) and two mixtures thereof (menthol/eucalyptol and menthol/mustard oil). In addition, we examined the relationship between intensity and lateralization scores and investigated whether intensity evaluation and lateralization scores of the mixtures show additive effects. All stimuli were correctly lateralized significantly above chance. Across subjects the lateralization scores for single compounds activating the same receptor showed a stronger correlation than stimuli activating different receptors. Although single compounds were isointense, the mixture of menthol and eucalyptol (activating only TRPM8) was perceived as weaker and was lateralized less accurately than the mixture of menthol and mustard oil (activating both TRPM8 and TRPA1) suggesting suppression effects in the former mixture. In conclusion, sensitivity of different subpopulations of trigeminal sensory neurons seems to be related, but only to a certain degree. The large coherence in sensitivity between various intranasal trigeminal stimuli suggests that measuring sensitivity to one single trigeminal chemical stimulus may be sufficient to generally assess the trigeminal system’s chemosensitivity. Further, for stimuli activating the same receptor a mixture suppression effect appears to occur similar to that observed in the other chemosensory

  19. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3′-OH of the 2′-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  20. Implications of Plasma Protein Binding for Pharmacokinetics and Pharmacodynamics of the γ-Secretase Inhibitor RO4929097

    PubMed Central

    Wu, Jianmei; LoRusso, Patricia M.; Matherly, Larry H.; Li, Jing

    2013-01-01

    Purpose Understanding of plasma protein binding will provide mechanistic insights into drug interactions or unusual pharmacokinetic properties. This study investigated RO4929097 binding in plasma and its implications for the pharmacokinetics and pharmacodynamics of this compound. Experimental Design RO4929097 binding to plasma proteins was determined using a validated equilibrium dialysis method. Pharmacokinetics of total and unbound RO4929097 was evaluated in eight patients with breast cancer receiving RO4929097 alone and in combination with the Hedgehog inhibitor GDC-0449. The impact of protein binding on RO4929097 pharmacodynamics was assessed using an in vitro Notch cellular assay. Results RO4929097 was extensively bound in human plasma, with the total binding constant of 1.0 × 106 and 1.8 × 104 L/mol for α1-acid glycoprotein (AAG) and albumin, respectively. GDC-0449 competitively inhibited RO4929097 binding to AAG. In patients, RO4929097 fraction unbound (Fu) exhibited large intra- and interindividual variability; GDC-0449 increased RO4929097 Fu by an average of 3.7-fold. Concomitant GDC-0449 significantly decreased total (but not unbound) RO4929097 exposure. RO4929097 Fu was strongly correlated with the total drug exposure. Binding to AAG abrogated RO4929097 in vitro Notch-inhibitory activity. Conclusions RO4929097 is highly bound in human plasma with high affinity to AAG. Changes in plasma protein binding caused by concomitant drug (e.g., GDC-0449) or disease states (e.g., ↑AAG level in cancer) can alter total (but not unbound) RO4929097 exposure. Unbound RO4929097 is pharmacologically active. Monitoring of unbound RO4929097 plasma concentration is recommended to avoid misleading conclusions on the basis of the total drug levels. PMID:22351688

  1. Transiting exoplanets from the CoRoT space mission. XVIII. CoRoT-18b: a massive hot Jupiter on a prograde, nearly aligned orbit

    NASA Astrophysics Data System (ADS)

    Hébrard, G.; Evans, T. M.; Alonso, R.; Fridlund, M.; Ofir, A.; Aigrain, S.; Guillot, T.; Almenara, J. M.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Cabrera, J.; Carone, L.; Carpano, S.; Cavarroc, C.; Csizmadia, Sz.; Deeg, H. J.; Deleuil, M.; Díaz, R. F.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Gandolfi, D.; Gibson, N.; Gillon, M.; Guenther, E.; Hatzes, A.; Havel, M.; Jorda, L.; Lammer, H.; Léger, A.; Llebaria, A.; Mazeh, T.; Moutou, C.; Ollivier, M.; Parviainen, H.; Pätzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Tingley, B.; Wuchterl, G.

    2011-09-01

    We report the detection of CoRoT-18b, a massive hot Jupiter transiting in front of its host star with a period of 1.9000693 ± 0.0000028 days. This planet was discovered thanks to photometric data secured with the CoRoT satellite combined with spectroscopic and photometric ground-based follow-up observations. The planet has a mass Mp = 3.47 ± 0.38 MJup, a radius Rp = 1.31 ± 0.18 RJup, and a density ρp = 2.2 ± 0.8 g cm-3. It orbits a G9V star with a mass M⋆ = 0.95 ± 0.15 M⊙, a radius R⋆ = 1.00 ± 0.13 R⊙, and arotation period Prot = 5.4 ± 0.4 days. The age of the system remains uncertain, with stellar evolution models pointing either to a few tens Ma or several Ga, while gyrochronology and lithium abundance point towards ages of a few hundred Ma. This mismatch potentially points to a problem in our understanding of the evolution of young stars, with possibly significant implications for stellar physics and the interpretation of inferred sizes of exoplanets around young stars. We detected the Rossiter-McLaughlin anomaly in the CoRoT-18 system thanks to the spectroscopic observation of a transit. We measured the obliquity ψ = 20° ± 20° (sky-projected value λ = -10° ± 20°), indicating that the planet orbits in the same way as the star is rotating and that this prograde orbit is nearly aligned with the stellar equator. The CoRoT space mission, launched on 2006 December 27, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain.Table 2 is available in electronic form at http://www.aanda.org

  2. Transiting exoplanets from the CoRoT space mission. XXIII. CoRoT-21b: a doomed large Jupiter around a faint subgiant star

    NASA Astrophysics Data System (ADS)

    Pätzold, M.; Endl, M.; Csizmadia, Sz.; Gandolfi, D.; Jorda, L.; Grziwa, S.; Carone, L.; Pasternacki, T.; Aigrain, S.; Almenara, J. M.; Alonso, R.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Cabrera, J.; Cavarroc, C.; Cochran, W. B.; Deleuil, M.; Deeg, H. J.; Díaz, R.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Gillon, M.; Guillot, T.; Hatzes, A.; Hébrard, G.; Léger, A.; Llebaria, A.; Lammer, H.; MacQueen, P. J.; Mazeh, T.; Moutou, C.; Ofir, A.; Ollivier, M.; Parviainen, H.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Tingley, B.; Weingrill, J.; Wuchterl, G.

    2012-09-01

    CoRoT-21, a F8IV star of magnitude V = 16 mag, was observed by the space telescope CoRoT during the Long Run 01 (LRa01) in the first winter field (constellation Monoceros) from October 2007 to March 2008. Transits were discovered during the light curve processing. Radial velocity follow-up observations, however, were performed mainly by the 10-m Keck telescope in January 2010. The companion CoRoT-21b is a Jupiter-like planet of 2.26 ± 0.33 Jupiter masses and 1.30 ± 0.14 Jupiter radii in an circular orbit of semi-major axis 0.0417 ± 0.0011 AU and an orbital period of 2.72474 ± 0.00014 days. The planetary bulk density is (1.36 ± 0.48) × 103 kg m-3, very similar to the bulk density of Jupiter, and follows an M1/3 - R relation like Jupiter. The F8IV star is a sub-giant star of 1.29 ± 0.09 solar masses and 1.95 ± 0.2 solar radii. The star and the planet exchange extremetidal forces that will lead to orbital decay and extreme spin-up of the stellar rotation within 800 Myr if the stellar dissipation is Q∗/k2∗ ≤ 107. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain.

  3. Transiting exoplanets from the CoRoT space mission. XX. CoRoT-20b: A very high density, high eccentricity transiting giant planet

    NASA Astrophysics Data System (ADS)

    Deleuil, M.; Bonomo, A. S.; Ferraz-Mello, S.; Erikson, A.; Bouchy, F.; Havel, M.; Aigrain, S.; Almenara, J.-M.; Alonso, R.; Auvergne, M.; Baglin, A.; Barge, P.; Bordé, P.; Bruntt, H.; Cabrera, J.; Carpano, S.; Cavarroc, C.; Csizmadia, Sz.; Damiani, C.; Deeg, H. J.; Dvorak, R.; Fridlund, M.; Hébrard, G.; Gandolfi, D.; Gillon, M.; Guenther, E.; Guillot, T.; Hatzes, A.; Jorda, L.; Léger, A.; Lammer, H.; Mazeh, T.; Moutou, C.; Ollivier, M.; Ofir, A.; Parviainen, H.; Queloz, D.; Rauer, H.; Rodríguez, A.; Rouan, D.; Santerne, A.; Schneider, J.; Tal-Or, L.; Tingley, B.; Weingrill, J.; Wuchterl, G.

    2012-02-01

    We report the discovery by the CoRoT space mission of a new giant planet, CoRoT-20b. The planet has a mass of 4.24 ± 0.23 MJup and a radius of 0.84 ± 0.04 RJup. With a mean density of 8.87 ± 1.10 g cm-3, it is among the most compact planets known so far. Evolutionary models for the planet suggest a mass of heavy elements of the order of 800 M⊕ if embedded in a central core, requiring a revision either of the planet formation models or both planet evolution and structure models. We note however that smaller amounts of heavy elements are expected by more realistic models in which they are mixed throughout the envelope. The planet orbits a G-type star with an orbital period of 9.24 days and an eccentricity of 0.56.The star's projected rotational velocity is vsini = 4.5 ± 1.0 km s-1, corresponding to a spin period of 11.5 ± 3.1 days if its axis of rotation is perpendicular to the orbital plane. In the framework of Darwinian theories and neglecting stellar magnetic breaking, we calculate the tidal evolution of the system and show that CoRoT-20b is presently one of the very few Darwin-stable planets that is evolving toward a triple synchronous state with equality of the orbital, planetary and stellar spin periods. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany, and Spain.

  4. Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist

    PubMed Central

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    BACKGROUND AND PURPOSE The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg−1), unmasked etorphine (3 mg·kg−1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg−1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg−1) and diazepam (1 mg·kg−1). CONCLUSIONS AND IMPLICATIONS Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles

  5. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard

    2012-01-01

    Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6 weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further

  6. Agonists and antagonists for P2 receptors

    PubMed Central

    Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman

    2015-01-01

    Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

  7. Data Analysis Provenance: Use Case for Exoplanet Search in CoRoT Database

    NASA Astrophysics Data System (ADS)

    de Souza, L.; Salete Marcon Gomes Vaz, M.; Emílio, M.; Ferreira da Rocha, J. C.; Janot Pacheco, E.; Carlos Boufleur, R.

    2012-09-01

    CoRoT (COnvection Rotation and Planetary Transits) is a mission led by the French national space agency CNES, in collaboration with Austria, Spain, Germany, Belgium and Brazil. The mission priority is dedicated to exoplanet search and stellar seismology. CoRoT light curves database became public after one year of their delivery to the CoRoT Co-Is, following the CoRoT data policy. The CoRoT archive contains thousands of light curves in FITS format. Several exoplanet search algorithms require detrend algorithms to remove both stellar and instrumental signal, improving the chance to detect a transit. Different detrend and transit detection algorithms can be applied to the same database. Tracking the origin of the information and how the data was derived in each level in the data analysis process is essential to allow sharing, reuse, reprocessing and further analysis. This work aims at applying a formalized and codified knowledge model by means of domain ontology. It allows to enrich the data analysis with semantic and standardization. It holds the provenance information in the database for a posteriori recovers by humans or software agents.

  8. Abnormal clinical pharmacokinetics of the developmental radiosensitizers pimonidazole (Ro 03-8799) and etanidazole (SR 2508)

    SciTech Connect

    Maughan, T.S.; Newman, H.F.; Bleehen, N.M.; Ward, R.; Workman, P. )

    1990-05-01

    The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) are under evaluation as single agents (Phase III) and in combination (Phase I). Ro 03-8799 produces an acute, transient central nervous system syndrome, whereas SR 2508 causes cumulative, peripheral neurotoxicity; both effects are dose-limiting. Pharmacokinetic studies have shown the importance of area under the plasma drug concentration versus time curve (AUC) in predicting the risk of peripheral neuropathy. Most patients have very similar pharmacokinetic parameters. This study reports 2/25 patients receiving 0.75 g/m2 Ro 03-8799 plus 2.0 g/m2 SR 2508 who showed significant discrepancies in drug handling. One patient exhibited a markedly elevated AUC and prolonged t1/2 beta for SR 2508 and this was associated with an unusually rapid onset of peripheral neuropathy. A second patient showed normal handling of SR 2508 but prolonged values for both t1/2 alpha and t1/2 beta for Ro 03-8799 and unusually low levels of its N-oxide metabolite. In addition a low peak Ro 03-8799 concentration combined with a very high volume of distribution was found in this patient, leading to a normal AUC value and toxicity profile. Both patients exhibited a relatively low creatinine clearance. The mechanisms which may underlie these findings are discussed, and the importance of pharmacokinetic monitoring in the use of these agents is emphasized.

  9. Revisiting the transits of CoRoT-7b at a lower activity level

    NASA Astrophysics Data System (ADS)

    Barros, S. C. C.; Almenara, J. M.; Deleuil, M.; Diaz, R. F.; Csizmadia, Sz.; Cabrera, J.; Chaintreuil, S.; Collier Cameron, A.; Hatzes, A.; Haywood, R.; Lanza, A. F.; Aigrain, S.; Alonso, R.; Bordé, P.; Bouchy, F.; Deeg, H. J.; Erikson, A.; Fridlund, M.; Grziwa, S.; Gandolfi, D.; Guillot, T.; Guenther, E.; Leger, A.; Moutou, C.; Ollivier, M.; Pasternacki, T.; Pätzold, M.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Wuchterl, G.

    2014-09-01

    The first super-Earth with measured radius discovered was CoRoT-7b and it has opened the new field of rocky exoplanet characterisation. To better understand this interesting system, new observations were taken with the CoRoT satellite. During this run 90 new transits were obtained in the imagette mode. These were analysed together with the previous 151 transits obtained in the discovery run and HARPS radial velocity observations to derive accurate system parameters. A difference is found in the posterior probability distribution of the transit parameters between the previous CoRoT run (LRa01) and the new run (LRa06). We propose that this is due to an extra noise component in the previous CoRoT run suspected of being transit spot occultation events. These lead to the mean transit shape becoming V-shaped. We show that the extra noise component is dominant at low stellar flux levels and reject these transits in the final analysis. We obtained a planetary radius, Rp = 1.585 ± 0.064 R⊕ , in agreement with previous estimates. Combining the planetary radius with the new mass estimates results in a planetary density of 1.19 ± 0.27 ρ⊕ which is consistent with a rocky composition. The CoRoT-7 system remains an excellent test bed for the effects of activity in the derivation of planetary parameters in the shallow transit regime.

  10. Honokiol: A non-adipogenic PPARγ agonist from nature☆

    PubMed Central

    Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.

    2013-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators. Methods We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. Results The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. PMID:23811337

  11. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  12. Radiation therapy generates platelet-activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.

    2016-01-01

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  13. Radiation therapy generates platelet-activating factor agonists.

    PubMed

    Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan; Murphy, Robert C; Konger, Raymond L; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F; Travers, Jeffrey B

    2016-04-12

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  14. Research and development of Ro-boat: an autonomous river cleaning robot

    NASA Astrophysics Data System (ADS)

    Sinha, Aakash; Bhardwaj, Prashant; Vaibhav, Bipul; Mohommad, Noor

    2013-12-01

    Ro-Boat is an autonomous river cleaning intelligent robot incorporating mechanical design and computer vision algorithm to achieve autonomous river cleaning and provide a sustainable environment. Ro-boat is designed in a modular fashion with design details such as mechanical structural design, hydrodynamic design and vibrational analysis. It is incorporated with a stable mechanical system with air and water propulsion, robotic arms and solar energy source and it is proceed to become autonomous by using computer vision. Both "HSV Color Space" and "SURF" are proposed to use for measurements in Kalman Filter resulting in extremely robust pollutant tracking. The system has been tested with successful results in the Yamuna River in New Delhi. We foresee that a system of Ro-boats working autonomously 24x7 can clean a major river in a city on about six months time, which is unmatched by alternative methods of river cleaning.

  15. Identification of the Ro and La antigens in the endoribonuclease VII--ribonucleoprotein complex.

    PubMed Central

    Bachmann, M; Mayet, W J; Schröder, H C; Pfeifer, K; Meyer zum Büschenfelde, K H; Müller, W E

    1987-01-01

    45 S RNP (ribonucleoprotein) particles from calf thymus or L5178y mouse lymphoma cells contain the poly(A)-modulated and oligo(U)-binding endoribonuclease VII [Bachmann, Zahn & Müller (1983) J. Biol. Chem. 258, 7033-7040]. From these particles a 4.5 S RNA was isolated that possesses an oligo(U) sequence. By using monospecific and non-cross-reacting antibodies directed against the La or Ro antigen, both proteins were identified in the endoribonuclease VII-RNP complex after phosphorylation in vitro. In a second approach, endoribonuclease VII activity was identified in immunoaffinity-purified Ro RNPs after preparative isoelectric focusing. Therefore we conclude that the 4.5 S RNA belongs to the Ro RNAs. The results indicate a possible function of endoribonuclease VII in activating stored mRNAs. Images Fig. 1. Fig. 3. PMID:2440423

  16. PAPR reduction based on improved Nyquist pulse shaping technology in OFDM-RoF systems

    NASA Astrophysics Data System (ADS)

    Liu, Jian-fei; Li, Ning; Lu, Jia; Zeng, Xiang-ye; Li, Jie; Wang, Meng-jun

    2013-01-01

    High peak-to-average power ratio (PAPR) is the main disadvantage in orthogonal frequency-division multiplexing (OFDM) communication systems, which also exists in OFDM-radio over fiber (RoF) systems. In this paper, we firstly analyze the impact of high PAPR on a 40 GHz OFDM-RoF system, and then describe the theory of Nyquist pulse shaping technology for reducing PAPR. To suppress PAPR further, an improved Nyquist pulse shaping technology is proposed, in which the distribution of original-data amplitude is changed by properly selecting the time-limited waveforms of the different subcarriers. We firstly apply the improved Nyquist pulse shaping technology to an OFDM-RoF system. The simulation results show that PAPR is effectively reduced by more than 2 dB with the bit error rate (BER) declining by about 0.125%.

  17. Removal of bisphenol A (BPA) from water by various nanofiltration (NF) and reverse osmosis (RO) membranes.

    PubMed

    Yüksel, Suna; Kabay, Nalan; Yüksel, Mithat

    2013-12-15

    The removal of an endocrine disrupting compound, bisphenol A (BPA), from model solutions by selected nanofiltration (NF) and reverse osmosis (RO) membranes was studied. The commercially available membranes NF 90, NF 270, XLE BWRO, BW 30 (Dow FilmTech), CE BWRO and AD SWRO (GE Osmonics) were used to compare their performances for BPA removal. The water permeability coefficients, rejection of BPA and permeate flux values were calculated for all membranes used. No significant changes in their BPA removal were observed for all tight polyamide based NF and RO membranes tested except for loose NF 270 membrane. The polyamide based membranes exhibited much better performance than cellulose acetate membrane for BPA removal. Almost a complete rejection (≥ 98%) for BPA was obtained with three polyamide based RO membranes (BW 30, XLE BWRO and AD SWRO). But cellulose acetate based CE BWRO membrane offered a low and variable (10-40%) rejection for BPA. PMID:23731784

  18. Validation of the smallest CoRoT candidates using PASTIS

    NASA Astrophysics Data System (ADS)

    Díaz, R. F.; Almenara, J. M.; Santerne, A.; Moutou, C.; Lethuillier, A.; Deleuil, M.; Bouchy, F.; Hébrard, G.; Montagnier, G.

    2013-09-01

    The majority of the smallest transiting planet candidates detected by CoRoT could not be directly confirmed by a dynamical measurement of their mass. This is due mainly to the faintness of the typical stars observed by CoRoT and to the small reflex motion induced by low-mass planets on their host stars. These candidates have traditionally being labeled as "unresolved", and virtually forgotten in the hope that the new generation of ultra-precise spectrographs installed in large telescopes would permit their confirmation. A way out of this problem is to statistically validate these candidates. In this talk, I will present PASTIS, the validation tool developed in Marseille that is being used to study the CoRoT unresolved candidates.

  19. Planets and stellar activity: hide and seek in the CoRoT-7 system

    NASA Astrophysics Data System (ADS)

    Haywood, R. D.; Collier Cameron, A.; Queloz, D.; Barros, S. C. C.; Deleuil, M.; Fares, R.; Gillon, M.; Lanza, A. F.; Lovis, C.; Moutou, C.; Pepe, F.; Pollacco, D.; Santerne, A.; Ségransan, D.; Unruh, Y. C.

    2014-09-01

    Since the discovery of the transiting super-Earth CoRoT-7b, several investigations have yielded different results for the number and masses of planets present in the system, mainly owing to the star's high level of activity. We re-observed CoRoT-7 in 2012 January with both HARPS and CoRoT, so that we now have the benefit of simultaneous radial-velocity and photometric data. This allows us to use the off-transit variations in the star's light curve to estimate the radial-velocity variations induced by the suppression of convective blueshift and the flux blocked by starspots. To account for activity-related effects in the radial velocities which do not have a photometric signature, we also include an additional activity term in the radial-velocity model, which we treat as a Gaussian process with the same covariance properties (and hence the same frequency structure) as the light curve. Our model was incorporated into a Monte Carlo Markov Chain in order to make a precise determination of the orbits of CoRoT-7b and CoRoT-7c. We measure the masses of planets b and c to be 4.73 ± 0.95 and 13.56 ± 1.08 M⊕, respectively. The density of CoRoT-7b is (6.61 ± 1.72)(Rp/1.58 R⊕)-3 g cm-3, which is compatible with a rocky composition. We search for evidence of an additional planet d, identified by previous authors with a period close to 9 d. We are not able to confirm the existence of a planet with this orbital period, which is close to the second harmonic of the stellar rotation at ˜7.9 d. Using Bayesian model selection, we find that a model with two planets plus activity-induced variations is most favoured.

  20. Planetary transit candidates in the CoRoT-SRc01 field

    NASA Astrophysics Data System (ADS)

    Erikson, A.; Santerne, A.; Renner, S.; Barge, P.; Aigrain, S.; Alapini, A.; Almenara, J.-M.; Alonso, R.; Auvergne, M.; Baglin, A.; Benz, W.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Bruntt, H.; Cabrera, J.; Carone, L.; Carpano, S.; Csizmadia, Sz.; Deleuil, M.; Deeg, H. J.; Díaz, R. F.; Dvorak, R.; Ferraz-Mello, S.; Fridlund, M.; Gandolfi, D.; Gazzano, J.-C.; Gillon, M.; Guenther, E. W.; Guillot, T.; Hatzes, A.; Hébrard, G.; Jorda, L.; Lammer, H.; Léger, A.; Llebaria, A.; Mayor, M.; Mazeh, T.; Moutou, C.; Ollivier, M.; Ofir, A.; Pätzold, M.; Pepe, F.; Pont, F.; Queloz, D.; Rabus, M.; Rauer, H.; Régulo, C.; Rouan, D.; Samuel, B.; Schneider, J.; Shporer, A.; Tingley, B.; Udry, S.; Wuchterl, G.

    2012-03-01

    Context. The space mission CoRoT is devoted to the analysis of stellar variability and the photometric detection of extrasolar planets. Aims: We present the list of planetary transit candidates detected in the first short run observed by CoRoT that targeted SRc01, towards the Galactic center in the direction of Aquila, which lasted from April to May 2007. Methods: Among the acquired data, we analyzed those for 1269 sources in the chromatic bands and 5705 in the monochromatic band. Instrumental noise and the stellar variability were treated with several detrending tools, to which several transit-search algorithms were subsequently applied. Results: Fifty-one sources were classified as planetary transit candidates and 26 were followed up with ground-based observations. Until now, no planet has been detected in the CoRoT data from the SRc01 field. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with contributions from Austria, Belgium, Brazil, ESA, Germany, and Spain. The CoRoT data are available to the community from the CoRoT archive: http://idoc-corot.ias.u-psud.frBased in part on observations made with the 1.93-m telescope at Observatoire de Haute Provence (CNRS), France (SOPHIE Program 08A.PNP.MOUT).Based in part on observations made with the ESO-3.60-m telescope at La Silla Observatory (ESO), Chile (HARPS Program ESO - 081.C-0388) and with the ESO-VLT telescope at Paranal Observatory (ESO), Chile (FLAMES Program ESO - 081.C-0413).

  1. The legacy of CoRoT and Kepler on the physics of stellar evolution

    NASA Astrophysics Data System (ADS)

    Chaplin, William

    2015-08-01

    It is a golden era for stellar astrophysics studies, driven by new satellite observations of unprecedented quality and scope. In this talk I will review advances in our understanding that have followed from asteroseismic studies with CoRoT and Kepler data, not only for stellar evolution theory but also in respect of the legacy for exoplanet and Galactic stellar population studies. I will also highlight the huge amount of work that remains to be performed to fully exploit the CoRoT and Kepler databases, and look to ongoing studies with K2, and the future promise of the NASA TESS and ESA PLATO Missions.

  2. Multiple star systems observed with CoRoT and Kepler

    NASA Astrophysics Data System (ADS)

    Southworth, John

    2015-09-01

    The CoRoT and Kepler satellites were the first space platforms designed to perform high-precision photometry for a large number of stars. Multiple systems display a wide variety of photometric variability, making them natural benefactors of these missions. I review the work arising from CoRoT and Kepler observations of multiple systems, with particular emphasis on eclipsing binaries containing giant stars, pulsators, triple eclipses and/or low-mass stars. Many more results remain untapped in the data archives of these missions, and the future holds the promise of K2, TESS and PLATO.

  3. How to separate the low amplitude delta Scuti variation in CoRoT data unambigousely?

    NASA Astrophysics Data System (ADS)

    Benko, Jozsef M.; Paparo, Margit

    2015-08-01

    Rich regular frequency patterns were found in the Fourier spectra of low-amplitude Delta Scuti stars observed by CoRoT satellite. The CoRoT observations are, however, influenced by the disturbing effect of the SAA. The effect is marginal for high amplitude variable stars but it could be dangerous in the case of low amplitude variables, especially if the frequency range of the intrinsic variation overlaps the instrumental frequencies. Systematic tests were carried out both on synthetic and real data. Our aim was to determine a limit amplitude above which we were sure that the frequency pattern belonged to the stars.

  4. AST/RO: Lessons from a Decade of Sub-mm Astronomy at the South Pole

    NASA Astrophysics Data System (ADS)

    Tothill, N. F. H.

    AST/RO spent over a decade at the South Pole, observing submillimetre-wave emission from the interstellar medium. We outline some of the lessons learned and experience gained that may be relevant to future Antarctic projects. Small submillimetre-wave telescopes, on the excellent sites provided by the Antarctic plateau, have very strong large-area mapping capabilities, together with the potential for ground-based THz observations. Highlighted technical aspects include AST/RO's lack of icing problems and availability of warm space.

  5. Supra-physiological efficacy at GPCRs: superstition or super agonists?

    PubMed Central

    Langmead, Christopher J; Christopoulos, Arthur

    2013-01-01

    The concept of ‘super agonism’ has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on this phenomenon and indicate that super agonists may be more than superstition. Linked Article This article is a commentary on Schrage et al., pp. 357–370 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12003 PMID:23441648

  6. Principles of agonist recognition in Cys-loop receptors

    PubMed Central

    Lynagh, Timothy; Pless, Stephan A.

    2014-01-01

    Cys-loop receptors are ligand-gated ion channels that are activated by a structurally diverse array of neurotransmitters, including acetylcholine, serotonin, glycine, and GABA. After the term “chemoreceptor” emerged over 100 years ago, there was some wait until affinity labeling, molecular cloning, functional studies, and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically diverse as glycine and serotonin has been subject to intense research over the last three decades. This review outlines the functional diversity and current structural understanding of agonist-binding sites, including those of invertebrate Cys-loop receptors. Together, this provides a framework to understand the atomic determinants involved in how these valuable therapeutic targets recognize and bind their ligands. PMID:24795655

  7. Alpha-2 agonists as pain therapy in horses.

    PubMed

    Valverde, Alexander

    2010-12-01

    Alpha-2 agonists, such as xylazine, clonidine, romifidine, detomidine, medetomidine, and dexmedetomidine, are potent analgesic drugs that also induce physiologic and behavioral changes, such as hypertension, bradycardia, atrioventricular block, excessive sedation and ataxia, all of which can potentially limit their systemic use as analgesics in some clinical cases. The use of medetomidine and dexmetomidine has been introduced for equine anesthesia/analgesia, and although not approved in this species, their increased specificity for alpha-2 receptors may offer some potential advantages over the traditional alpha-2 agonists. Similarly, other routes of administration and benefits of alpha-2 agonists are recognized in the human and laboratory animal literature, which may prove useful in the equine patient if validated in the near future. This review presents this relevant information. PMID:21056297

  8. Transiting exoplanets from the CoRoT space mission . XIX. CoRoT-23b: a dense hot Jupiter on an eccentric orbit

    NASA Astrophysics Data System (ADS)

    Rouan, D.; Parviainen, H.; Moutou, C.; Deleuil, M.; Fridlund, M.; Ofir, A.; Havel, M.; Aigrain, S.; Alonso, R.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Cabrera, J.; Cavarroc, C.; Csizmadia, Sz.; Deeg, H. J.; Diaz, R. F.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Gandolfi, D.; Gillon, M.; Guillot, T.; Hatzes, A.; Hébrard, G.; Jorda, L.; Léger, A.; Llebaria, A.; Lammer, H.; Lovis, C.; Mazeh, T.; Ollivier, M.; Pätzold, M.; Queloz, D.; Rauer, H.; Samuel, B.; Santerne, A.; Schneider, J.; Tingley, B.; Wuchterl, G.

    2012-01-01

    We report the detection of CoRoT-23b, a hot Jupiter transiting in front of its host star with a period of 3.6314 ± 0.0001 days. This planet was discovered thanks to photometric data secured with the CoRoT satellite, combined with spectroscopic radial velocity (RV) measurements. A photometric search for possible background eclipsing binaries conducted at CFHT and OGS concluded with a very low risk of false positives. The usual techniques of combining RV and transit data simultaneously were used to derive stellar and planetary parameters. The planet has a mass of Mp = 2.8 ± 0.3 MJup, a radius of Rpl= 1.05 ± 0.13RJup, a density of ≈ 3 g cm-3. RV data also clearly reveal a nonzero eccentricity of e = 0.16 ± 0.02. The planet orbits a mature G0 main sequence star of V = 15.5 mag, with a mass M⋆ = 1.14 ± 0.08 M⊙, a radius R ⋆ = 1. 61 ± 0.18 R⊙ and quasi-solarabundances. The age of the system is evaluated to be 7 Gyr, not far from the transition to subgiant, in agreement with the rather large stellar radius. The two features of a significant eccentricity of the orbit and of a fairly high density are fairly uncommon for a hot Jupiter. The high density is, however, consistent with a model of contraction of a planet at this mass, given the age of the system. On the other hand, at such an age, circularization is expected to be completed. In fact, we show that for this planetary mass and orbital distance, any initial eccentricity should not totally vanish after 7 Gyr, as long as the tidal quality factor Qp is more than a few 105, a value that is the lower bound of the usually expected range. Even if CoRoT-23b features a density and an eccentricity that are atypical of a hot Jupiter, it is thus not an enigmatic object. The CoRoT space mission, launched on 27 December 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA, Germany, and Spain. First CoRoT data are available to the public from the CoRoT archive: http

  9. Transiting exoplanets from the CoRoT space mission. XVII. The hot Jupiter CoRoT-17b: a very old planet

    NASA Astrophysics Data System (ADS)

    Csizmadia, Sz.; Moutou, C.; Deleuil, M.; Cabrera, J.; Fridlund, M.; Gandolfi, D.; Aigrain, S.; Alonso, R.; Almenara, J.-M.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Bruntt, H.; Carone, L.; Carpano, S.; Cavarroc, C.; Cochran, W.; Deeg, H. J.; Díaz, R. F.; Dvorak, R.; Endl, M.; Erikson, A.; Ferraz-Mello, S.; Fruth, Th.; Gazzano, J.-C.; Gillon, M.; Guenther, E. W.; Guillot, T.; Hatzes, A.; Havel, M.; Hébrard, G.; Jehin, E.; Jorda, L.; Léger, A.; Llebaria, A.; Lammer, H.; Lovis, C.; MacQueen, P. J.; Mazeh, T.; Ollivier, M.; Pätzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Santerne, A.; Schneider, J.; Tingley, B.; Titz-Weider, R.; Wuchterl, G.

    2011-07-01

    We report on the discovery of a hot Jupiter-type exoplanet, CoRoT-17b, detected by the CoRoT satellite. It has a mass of 2.43 ± 0.30 MJup and a radius of 1.02 ± 0.07 RJup, while its mean density is 2.82 ± 0.38 g/cm3. CoRoT-17b is in a circular orbit with a period of 3.7681 ± 0.0003 days. The host star is an old (10.7 ± 1.0 Gyr) main-sequence star, which makes it an intriguing object for planetary evolution studies. The planet's internal composition is not well constrained and can range from pure H/He to one that can contain ~380 earth masses of heavier elements. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain. Part of the observations were obtained at the Canada-France-Hawaii Telescope (CFHT) which is operated by the National Research Council of Canada, the Institut National des Sciences de l'Univers of the Centre National de la Recherche Scientifique of France, and the University of Hawaii. Based on observations made with HARPS spectrograph on the 3.6-m European Organisation for Astronomical Research in the Southern Hemisphere telescope at La Silla Observatory, Chile (ESO program 184.C-0639). Based on observations made with the IAC80 telescope operated on the island of Tenerife by the Instituto de Astrofísica de Canarias in the Spanish Observatorio del Teide. Part of the data presented herein were obtained at the W.M. Keck Observatory, which is operated as a scientific partnership among the California Institute of Technology, the University of California and the National Aeronautics and Space Administration. The Observatory was made possible by the generous financial support of the W.M. Keck Foundation.

  10. Agonist treatment in opioid use: advances and controversy.

    PubMed

    Viswanath, Biju; Chand, Prabhat; Benegal, Vivek; Murthy, Pratima

    2012-06-01

    Opioid dependence is a chronic relapsing condition which requires comprehensive care; pharmacological agents form the mainstay of its long term treatment. The two most popular approaches are the harm reduction method using agonists and the complete abstinence method using antagonists. Currently, particularly from the harm minimization perspective and the low feasibility of an abstinence based approach, there is an increasing trend toward agonist treatment. The use of buprenorphine has gained popularity in view of its safety profile and the availability of the buprenorphine-naloxone combination has made it popular as a take-home treatment. This review outlines the pharmacological advances and controversies in this area. PMID:22813654

  11. Insect Nicotinic Receptor Agonists as Flea Adulticides in Small Animals

    PubMed Central

    Vo, Dai Tan; Hsu, Walter H.; Martin, Richard J.

    2013-01-01

    Fleas are significant ectoparasites of small animals. They can be a severe irritant to animals and serve as a vector for a number of infectious diseases. In this article, we discuss the pharmacological characteristics of four insect nicotinic acetylcholine receptor (nAChR) agonists used as fleacides in dogs and cats, which include three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) and spinosad. Insect nAChR agonists are one of the most important new classes of insecticides, which are used to control sucking insects both on plants and on companion animals. These new compounds provide a new approach for practitioners to safely and effectively eliminate fleas. PMID:20646191

  12. Piperidine derivatives as nonprostanoid IP receptor agonists 2.

    PubMed

    Hayashi, Ryoji; Ito, Hiroaki; Ishigaki, Takeshi; Morita, Yasuhiro; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-06-15

    We searched for a strong and selective nonprostanoid IP agonist bearing piperidine and benzanilide moieties. Through optimization of substituents on the benzanilide moiety, the crucial part of the agonist, 43 (2-((1-(2-(N-(4-tolyl)benzo[d][1,3]dioxole-5-carboxamido)ethyl)piperidin-4-yl)oxy)acetic acid monohydrate monohydrochloride) was discovered and exhibited strong platelet aggregation inhibition (IC50=21nM) and 100-fold selectivity for IP receptor over other PG receptors. The systemic exposure level and bioavailability after oral administration of 43 were also good in dog. PMID:27133594

  13. Increasing RO efficiency by chemical-free ion-exchange and Donnan dialysis: Principles and practical implications.

    PubMed

    Vanoppen, Marjolein; Stoffels, Griet; Demuytere, Célestin; Bleyaert, Wouter; Verliefde, Arne R D

    2015-09-01

    Ion-exchange (IEX) and Donnan dialysis (DD) are techniques which can selectively remove cations, limiting scaling in reverse osmosis (RO). If the RO concentrate could be recycled for regeneration of these pre-treatment techniques, RO recovery could be largely increased without the need for chemical addition or additional technologies. In this study, two different RO feed streams (treated industrial waste water and simple tap water) were tested in the envisioned IEX-RO and DD-RO hybrids including RO concentrate recycling. The efficiency of multivalent cation removal depends mainly on the ratio of monovalent to multivalent cations in the feed stream, influencing the ion-exchange efficiency in both IEX and DD. Since the mono-to-multivalent ratio was very high in the waste water, the RO recovery could potentially be increased to 92%. For the tap water, these high RO recoveries could only be reached by adding additional NaCl, because of the low initial monovalent to multivalent ratio in the feed. In both cases, the IEX-RO hybrid proved to be most cost-efficient, due to the high current cost of the membranes used in DD. The membrane cost would have to decrease from ±300 €/m² to 10-30 €/m² - comparable to current reverse osmosis membranes - to achieve a comparable cost. In conclusion, the recycling of RO concentrate to regenerate ion exchange pre-treatment techniques for RO is an interesting option to increase RO recovery without addition of chemicals, but only at high monovalent/multivalent cation-ratios in the feed stream. PMID:25996753

  14. Pyrrolo- and Pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

    PubMed Central

    Kumar, V.; Clark, M.J.; Traynor, J.R.; Lewis, J.W.; Husbands, S.M.

    2014-01-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  15. Pyrrolo- and pyridomorphinans: non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists.

    PubMed

    Kumar, V; Clark, M J; Traynor, J R; Lewis, J W; Husbands, S M

    2014-08-01

    Opioid ligands have found use in a number of therapeutic areas, including for the treatment of pain and opiate addiction (using agonists) and alcohol addiction (using antagonists such as naltrexone and nalmefene). The reaction of imines, derived from the opioid ligands oxymorphone and naltrexone, with Michael acceptors leads to pyridomorphinans with structures similar to known pyrrolo- and indolomorphinans. One of the synthesized compounds, 5e, derived from oxymorphone had substantial agonist activity at delta opioid receptors but not at mu and/or kappa opioid receptors and in that sense profiled as a selective delta opioid receptor agonist. The pyridomorphinans derived from naltrexone and naloxone were all found to be non-selective potent antagonists and as such could have utility as treatments for alcohol abuse. PMID:24973818

  16. Draft Genome Sequence of the Xylella fastidiosa CoDiRO Strain.

    PubMed

    Giampetruzzi, Annalisa; Chiumenti, Michela; Saponari, Maria; Donvito, Giacinto; Italiano, Alessandro; Loconsole, Giuliana; Boscia, Donato; Cariddi, Corrado; Martelli, Giovanni Paolo; Saldarelli, Pasquale

    2015-01-01

    We determined the draft genome sequence of the Xylella fastidiosa CoDiRO strain, which has been isolated from olive plants in southern Italy (Apulia). It is associated with olive quick decline syndrome (OQDS) and characterized by extensive scorching and desiccation of leaves and twigs. PMID:25676759

  17. Jean Vigo's "Zéro De Conduite" and the Spaces of Revolt

    ERIC Educational Resources Information Center

    Vanobbergen, Bruno; Grosvenor, Ian; Simon, Frank

    2014-01-01

    In this article we will contribute to the contemporary theoretical debate about film by considering, from a history-of-education perspective, the film "Zéro de conduite" by Jean Vigo (1905--1934). This film is classified under the umbrella of "poetic realism": a product of "cinéma de gauche" and an avant-gardist,…

  18. Highly Oxidized RO2 Radicals and Consecutive Products from the Ozonolysis of Three Sesquiterpenes.

    PubMed

    Richters, Stefanie; Herrmann, Hartmut; Berndt, Torsten

    2016-03-01

    The formation of highly oxidized multifunctional organic compounds (HOMs) from the ozonolysis of three sesquiterpenes, α-cedrene, β-caryophyllene, and α-humulene, was investigated for the first time. Sesquiterpenes contribute 2.4% to the global carbon emission of biogenic volatile organic compounds (BVOCs) and can be responsible for up to 70% of the regional BVOC emissions. HOMs were detected with chemical ionization-atmospheric pressure interface-time-of-flight mass spectrometry and nitrate and acetate ionization. Acetate ions were more sensitive toward highly oxidized RO2 radicals containing a single hydroperoxide moiety. Under the chosen reaction conditions, product formation was dominated by highly oxidized RO2 radicals which react with NO, NO2, HO2, and other RO2 radicals under atmospheric conditions. The ozonolysis of sesquiterpenes resulted in molar HOM yields of 0.6% for α-cedrene (acetate), 1.8% for β-caryophyllene (acetate), and 1.4% for α-humulene (nitrate) afflicted with an uncertainty factor of 2. Molar yields of highly oxidized RO2 radicals were identical with HOM yields measuring the corresponding closed-shell products. HOM formation from ozonolysis of α-cedrene was explained by an autoxidation mechanism initiated by ozone attack at the double bond similar to that found in the ozonolysis of cyclohexene and limonene. PMID:26830670

  19. Proposal of adaptive wireless cell configuration for RoF-DAS over WDM-PON system

    NASA Astrophysics Data System (ADS)

    Iwakuni, Tatsuhiko; Miyamoto, Kenji; Higashino, Takeshi; Tsukamoto, Katsutoshi; Komaki, Shozo; Tashiro, Takayoshi; Fukada, Youichi; Kani, Jun-ichi; Yoshimoto, Naoto; Iwatsuki, Katsumi

    2013-01-01

    Radio on fiber (RoF) - distributed antenna system (DAS) over wavelength division multiplexing - passive optical network (WDM-PON) with multiple - input multiple - output (MIMO) has been proposed as a next generation radio access network (RAN). This system employs optical time division multiplexing (OTDM) over one WDM channel to multiplex and transmit various types of wireless interfaces such as 3.9G, Wireless LAN and WiMAX. A combination of star and bus topologies has employed to cover a wider service area. The optical transmission loss is caused notably at remote base stations (RBSs) quipped on a WDM bus link. The loss is relatively small, but at the RBS far from the center station (CS), the RBS suffers the large accumulated loss, so the reduction of cell size provides the increasing of the number of RBSs, causes the degradation of the SNR of RoF link. This paper addresses this trade-off problem, and considers the application to the actual service area by the channel capacity investigation of RoF-DAS over WDM-PON with computer simulation. Then, this paper focuses on the flexibility of RoF-DAS over WDM-PON, considers the adaptive wireless cell configuration according to population fluctuations of day and night, or densely populated areas and sparsely populated areas, respectively.

  20. HD 12098 a new far-northern roAp star

    NASA Astrophysics Data System (ADS)

    Girish, V.; Joshi, S.; Seetha, S.; Ashoka, B. N.; Martinez, P.; Chaubey, U. S.; Gupta, S. K.; Kurtz, D. W.; Sagar, R.

    2001-09-01

    The rapidly oscillating Ap (roAp) stars are cool, magnetic, chemically peculiar stars which pulsate in non-radial p-modes in the period range 4-16 min and have Johnson B amplitudes less than 8 mmag. "The NainiTal-Cape survey" to search for and study new roAp stars in the northern hemisphere was initiated in 1998 in collaboration between ISAC & UPSO from India and SAAO & UCT from South Africa. HD12098 is the first roAp star discovered in this survey and also the first far northern hemisphere roAp star. During the initial observations the star showed modulation in the pulsation amplitude indicating the multi-periodicity of pulsations. The multi-periodicity may be either due to the excitation of different modes or due to the rotation of the star. In order to resolve these frequencies HD12098 was observed extensively in October 2000. The preliminary results of these observations are presented here.

  1. Bidirectional hybrid PM-based RoF and VCSEL-based VLLC system.

    PubMed

    Li, Chung-Yi; Lu, Hai-Han; Chang, Ching-Hung; Lin, Chun-Yu; Wu, Po-Yi; Zheng, Jun-Ren; Lin, Chia-Rung

    2014-06-30

    A bidirectional hybrid phase modulation (PM)-based radio-over-fiber (RoF) and vertical cavity surface emitting laser (VCSEL)-based visible laser light communication (VLLC) systems employing injection-locked VCSEL-based PM-to-intensity modulation (IM) converters and optical interleavers (ILs) is proposed and demonstrated. To be the first one of using injection-locked VCSEL-based PM-to-IM converters and optical ILs in such bidirectional hybrid RoF and VLLC systems, the downstream light is successfully phase-remodulated with RoF signal for up-link transmission. Through a serious investigation in systems, bit error rate (BER) and eye diagram perform brilliantly over a 40-km single-mode fiber (SMF) transport and a 12-m free-space transmission. Such a bidirectional hybrid RoF and VLLC system would be very attractive for the integration of fiber backbone and in-door networks to provide broadband integrated services, including Internet and telecommunication services. PMID:24977870

  2. RoMPS concept review automatic control of space robot, volume 2

    NASA Technical Reports Server (NTRS)

    Dobbs, M. E.

    1991-01-01

    Topics related to robot operated materials processing in space (RoMPS) are presented in view graph form and include: (1) system concept; (2) Hitchhiker Interface Requirements; (3) robot axis control concepts; (4) Autonomous Experiment Management System; (5) Zymate Robot Controller; (6) Southwest SC-4 Computer; (7) oven control housekeeping data; and (8) power distribution.

  3. Spectral characterization and differential rotation study of active CoRoT stars

    NASA Astrophysics Data System (ADS)

    Nagel, E.; Czesla, S.; Schmitt, J. H. M. M.

    2016-05-01

    The CoRoT space telescope observed nearly 160 000 light curves. Among the most outstanding is that of the young, active planet host star CoRoT-2A. In addition to deep planetary transits, the light curve of CoRoT-2A shows strong rotational variability and a superimposed beating pattern. To study the stars that produce such an intriguing pattern of photometric variability, we identified a sample of eight stars with rotation periods between 0.8 and 11 days and photometric variability amplitudes of up to 7.5%, showing a similar CoRoT light curve. We also obtained high-resolution follow-up spectroscopy with TNG/SARG and carried out a spectral analysis with SME and MOOG. We find that the color dependence of the light curves is consistent with rotational modulation due to starspots and that latitudinal differential rotation provides a viable explanation for the light curves, although starspot evolution is also expected to play an important role. Our MOOG and SME spectral analyses provide consistent results, showing that the targets are dwarf stars with spectral types between F and mid-K. Detectable Li i absorption in four of the targets confirms a low age of 100-400 Myr also deduced from gyrochronology. Our study indicates that the photometric beating phenomenon is likely attributable to differential rotation in fast-rotating stars with outer convection zones.

  4. Possible role of anti-SSA/Ro antibodies in the pathogenesis of pulmonary hypertension

    PubMed Central

    Guerreso, Kelsey; Conner, Edward Alexander

    2016-01-01

    Introduction There are many different causes of pulmonary hypertension and the pathogenesis of the disease is still being elucidated. Although they are not the most common, autoimmunity and inflammation have been identified as possible causes. No one autoantibody has been identified as the definite cause of pulmonary hypertension. We present a rare association of anti-SSA/Ro antibodies and isolated pulmonary hypertension. Case presentation A 53 year old African American female presented with abdominal pain, nausea, weight loss, dyspnea and fatigue. Upon further exam she was found to have high titers of antinuclear antibodies and anti-SSA/Ro antibodies. This antibody profile would typically be suggestive of Sjögren's Syndrome, which is characterized by dry eyes and poor salivary gland function. However, since this patient did not have any symptoms consistent with the disease a diagnosis of Sjögren's Syndrome could not be made. A combination of laboratory, imaging and diagnostic studies were done that revealed a final diagnosis of pulmonary hypertension. Conclusion It is known that pulmonary hypertension has association with autoimmune diseases, however no clear markers yet exist. Anti-SSA/Ro antibodies have been rarely described in cases of pulmonary disease, and less so in pulmonary hypertension. This case describes a unique association between isolated pulmonary hypertension and anti-SSA/Ro antibody, thereby illustrating the need to investigate this autoantibody and others in the pathogenesis of autoimmune pulmonary hypertension.

  5. Uncovering the planets and stellar activity of CoRoT-7 using only radial velocities

    NASA Astrophysics Data System (ADS)

    Faria, J. P.; Haywood, R. D.; Brewer, B. J.; Figueira, P.; Oshagh, M.; Santerne, A.; Santos, N. C.

    2016-04-01

    Stellar activity can induce signals in the radial velocities of stars, complicating the detection of orbiting low-mass planets. We present a method to determine the number of planetary signals present in radial-velocity datasets of active stars, using only radial-velocity observations. Instead of considering separate fits with different number of planets, we use a birth-death Markov chain Monte Carlo algorithm to infer the posterior distribution for the number of planets in a single run. In a natural way, the marginal distributions for the orbital parameters of all planets are also inferred. This method is applied to HARPS data of CoRoT-7. We confidently recover the orbits of both CoRoT-7b and CoRoT-7c although the data show evidence for the presence of additional signals. All data and software presented in this article are available online at http://https://github.com/j-faria/exoBD-CoRoT7

  6. A New Method for Detecting and Monitoring Atmospheric Natural Hazards with GPS RO

    NASA Astrophysics Data System (ADS)

    Biondi, R.; Steiner, A. K.; Rieckh, T. M.; Kirchengast, G.

    2014-12-01

    Global Positioning System (GPS) Radio Occultation (RO) allows measurements in any meteorological condition, with global coverage, high vertical resolution, and high accuracy. With more than 13 years of data availability, RO also became a fundamental tool for studying climate change. We present here the application of RO for detecting and monitoring tropical cyclones (TCs), deep convective systems (CSs) and volcanic ash clouds (ACs).Deep CSs and TCs play a fundamental role in atmospheric circulation producing vertical transport, redistributing water vapor and trace gases, changing the thermal structure of the Upper Troposphere and Lower Stratosphere (UTLS) and affecting climate through overshooting into the stratosphere. Explosive volcanic eruptions produce large ACs dangerous for the aviation and they can impact climate when the ash is injected into the UTLS.The detection of cloud top height, the determination of cloud extent, the discrimination of ACs from CSs clouds and the detection of overshooting are main challenges for atmospheric natural hazards study. We created a reference atmosphere with a resolution of 5° in latitude and longitude, sampled on a 1° x 1° grid, and a vertical sampling of 100 m. We then compared RO profiles acquired during TCs, CSs and ACs to the reference atmosphere and computed anomaly profiles.CSs, TCs and the ACs leave a clear signature in the atmosphere which can be detected by RO. Using RO temperature and bending angle profiles we gain insight into the vertical thermal structure and developed a new method for detecting the cloud top altitude with high accuracy.We have characterized the TCs by ocean basins and intensities, showing that they have a different thermal structure and reach to different altitudes according to the basin. We provide statistics on overshooting frequency, achieving results consistent with patterns found in the literature and demonstrating that RO is well suited for this kind of study. We have analyzed the

  7. The 52 000 MW Ro/SS-A autoantigen in Sjögren's syndrome/systemic lupus erythematosus (Ro52) is an interferon-gamma inducible tripartite motif protein associated with membrane proximal structures.

    PubMed

    Rhodes, Davd A; Ihrke, Gudrun; Reinicke, Anna T; Malcherek, Georg; Towey, Michael; Isenberg, David A; Trowsdale, John

    2002-06-01

    The 52 000 MW Ro/SS-A (Ro52) protein is a major target of autoantibodies in autoimmune conditions such as systemic lupus erythematosus and Sjögren's syndrome. Recent genomic and bioinformatic studies have shown that Ro52 belongs to a large family of related RING/Bbox/coiled-coil (RBCC) tripartite motif proteins sharing overall domain structure and 40-50% identity at the amino acid level. Ro52 also has a B30.2 domain at the C-terminus. Using the human genome draft sequence, the genomic organization of the Ro52 gene on human chromosome 11p15.5 has been deduced and related to the protein domain structure. We show that the steady-state levels of Ro52 mRNA are normally very low but are induced by cell activation with interferon-gamma. In transient transfection of HeLa cells, epitope-tagged Ro52 protein was localized to unidentified membrane proximal rod-like structures. Using in vitro coupled transcription/translation followed by immunoprecipitation, the autoimmune response to Ro52 protein was investigated and two distinct interactions were resolved. The Ro52 C-terminal B30.2 domain interacts with human immunoglobulin independently of antibody specificities. Sera derived from patients with Sjögren's syndrome and systemic lupus erythematosus, in addition, contained specific autoantibodies directed towards the rest of the Ro52 molecule. The majority of these autoimmune sera also immunoprecipitated the Ro52-related molecule RNF15. A possible role for Ro52 protein in alterations of plasma membranes during cellular activation or apoptosis is discussed. PMID:12047754

  8. PTEN regulates sensitivity of melanoma cells to RO4929097, the γ-secretase inhibitor.

    PubMed

    Nair, Jayasree S; Sheikh, Tahir; Ho, Alan L; Schwartz, Gary K

    2013-04-01

    De-regulated expression of components of the Notch signaling pathway is observed in malignant melanoma. This pathway is activated by catalytic cleavage of the Notch receptor by γ-secretase. Phase-I trials with RO4929097, a potent gamma secretase inhibitor (GSI), and other agents of this class have demonstrated clinical activity in patients with melanoma. An understanding of the mechanisms for de novo sensitivity and resistance to this class of drugs would be critical for future drug development. We treated a panel of Phosphatase and Tensin Homolog (PTEN)-null, -mutant and -wild-type human melanoma cell lines with RO4929097 and evaluated the efficacy alone and in combination with chemotherapy. Although cleaved Notch-1 formation was observed in all the cell lines, RO4929097-induced senescence or apoptosis was achieved only in PTEN-wild-type cell lines in which gamma-secretase inhibition with an induction of PTEN expression and decreased AKT/PKB (protein kinase B) phosphorylation in addition to transcriptional suppression at the Hairy and enhancer of split-1 (HES1) gene promoter. Overexpression of wild-type PTEN in PTEN-null and -mutant cell lines, and studies with isogenic breast cell lines that differ only in PTEN status, confirmed the importance of PTEN expression for conferring tumor cell susceptibility to RO4929097. Furthermore, in PTEN-expressing rapidly accelerated fibrosarcoma 1 (B-RAF)-mutant melanoma cells, RO4929097 enhanced the effect of temozolomide both in vitro and in vivo. These results indicate that tumor cell susceptibility to a GSI, whether alone or in combination with chemotherapy, are reliant upon reducing AKT phosphorylation and hence GSI in combination with chemotherapy may be useful as a new therapeutic approach in treating PTEN-wild-type melanoma. PMID:23564767

  9. Quantum Calculation of Inelastic CO Collisions with H. III. Rate Coefficients for Ro-vibrational Transitions

    NASA Astrophysics Data System (ADS)

    Song, L.; Balakrishnan, N.; Walker, K. M.; Stancil, P. C.; Thi, W. F.; Kamp, I.; van der Avoird, A.; Groenenboom, G. C.

    2015-11-01

    We present calculated rate coefficients for ro-vibrational transitions of CO in collisions with H atoms for a gas temperature range of 10 K ≤ T ≤ 3000 K, based on the recent three-dimensional ab initio H-CO interaction potential of Song et al. Rate coefficients for ro-vibrational v=1,j=0-30\\to v\\prime =0,j\\prime transitions were obtained from scattering cross sections previously computed with the close-coupling (CC) method by Song et al. Combining these with the rate coefficients for vibrational v=1-5\\to v\\prime \\lt v quenching obtained with the infinite-order sudden approximation, we propose a new extrapolation scheme that yields the rate coefficients for ro-vibrational v=2-5,j=0-30\\to v\\prime ,j\\prime de-excitation. Cross sections and rate coefficients for ro-vibrational v=2,j=0-30\\to v\\prime =1,j\\prime transitions calculated with the CC method confirm the effectiveness of this extrapolation scheme. Our calculated and extrapolated rates are very different from those that have been adopted in the modeling of many astrophysical environments. The current work provides the most comprehensive and accurate set of ro-vibrational de-excitation rate coefficients for the astrophysical modeling of the H-CO collision system. The application of the previously available and new data sets in astrophysical slab models shows that the line fluxes typically change by 20%-70% in high temperature environments (800 K) with an H/H2 ratio of 1; larger changes occur for lower temperatures.

  10. Colloidal interactions and fouling of NF and RO membranes: a review.

    PubMed

    Tang, Chuyang Y; Chong, T H; Fane, Anthony G

    2011-05-11

    Colloids are fine particles whose characteristic size falls within the rough size range of 1-1000 nm. In pressure-driven membrane systems, these fine particles have a strong tendency to foul the membranes, causing a significant loss in water permeability and often a deteriorated product water quality. There have been a large number of systematic studies on colloidal fouling of reverse osmosis (RO) and nanofiltration (NF) membranes in the last three decades, and the understanding of colloidal fouling has been significantly advanced. The current paper reviews the mechanisms and factors controlling colloidal fouling of both RO and NF membranes. Major colloidal foulants (including both rigid inorganic colloids and organic macromolecules) and their properties are summarized. The deposition of such colloidal particles on an RO or NF membrane forms a cake layer, which can adversely affect the membrane flux due to 1) the cake layer hydraulic resistance and/or 2) the cake-enhanced osmotic pressure. The effects of feedwater compositions, membrane properties, and hydrodynamic conditions are discussed in detail for inorganic colloids, natural organic matter, polysaccharides, and proteins. In general, these effects can be readily explained by considering the mass transfer near the membrane surface and the colloid-membrane (or colloid-colloid) interaction. The critical flux and limiting flux concepts, originally developed for colloidal fouling of porous membranes, are also applicable to RO and NF membranes. For small colloids (diameter≪100 nm), the limiting flux can result from two different mechanisms: 1) the diffusion-solubility (gel formation) controlled mechanism and 2) the surface interaction controlled mechanism. The former mechanism probably dominates for concentrated solutions, while the latter mechanism may be more important for dilute solutions. Future research needs on RO and NF colloidal fouling are also identified in the current paper. PMID:21094487

  11. Investigation of the mechanisms of neuroprotection mediated by Ro5-4864 in brain injury.

    PubMed

    Palzur, Eilam; Sharon, Aviram; Shehadeh, Mona; Soustiel, Jean Francois

    2016-08-01

    Increasing evidence has established the involvement of the 18-kDa translocator protein (TSPO) in the process of mitochondrial membrane permeabilization and subsequent apoptosis through modulation of the mitochondrial permeability transition pore. Recent studies have shown that treatment with Ro5-4864, a TSPO ligand, resulted in a neuroprotective effect in traumatic brain injury. Yet, the nature of this effect remained uncertain as mature neurons are considered to be lacking the TSPO protein. In order to investigate the mechanism of Ro5-4864-mediated neuroprotection, the neuro-inflammatory and neurosteroid response to cortical injury was tested in sham-operated, vehicle, cyclosporine A (CsA) and Ro5-4864-treated rats. As anticipated, the levels of interleukin 1β and tumor necrosis factor α, as well as the astrocyte and microglia cellular density in the injured area were all decreased by CsA in comparison with the vehicle group. By contrast, no visible effect could be observed in Ro5-4864-treated animals. None of the groups showed any significant difference with any other in respect with the expression of brain-derived neurotrophic factor. Double immunofluorescence staining with NeuN and TSPO confirmed the absence of TSPO in native neurons though showed clear evidence of co-localization of TSPO in the cytoplasm of NeuN-stained injured neurons. Altogether, this study shows that the neuronal protection mediated by Ro5-4864 in brain injury cannot be solely attributed to an indirect effect of the ligand on glial TSPO but may also represent the consequence of the modulation of upregulated TSPO in injured neurons. This observation may be of importance for future pharmacological research in neurotrauma. PMID:27223627

  12. BEER analysis of Kepler and CoRoT light curves. III. Spectroscopic confirmation of seventy new beaming binaries discovered in CoRoT light curves

    NASA Astrophysics Data System (ADS)

    Tal-Or, L.; Faigler, S.; Mazeh, T.

    2015-08-01

    Context. The BEER algorithm searches stellar light curves for the BEaming, Ellipsoidal, and Reflection photometric modulations that are caused by a short-period companion. These three effects are typically of very low amplitude and can mainly be detected in light curves from space-based photometers. Unlike eclipsing binaries, these effects are not limited to edge-on inclinations. Aims: Applying the algorithm to wide-field photometric surveys such as CoRoT and Kepler offers an opportunity to better understand the statistical properties of short-period binaries. It also widens the window for detecting intrinsically rare systems, such as short-period brown-dwarf and massive-planetary companions to main-sequence stars. Methods: Applying the search to the first five long-run center CoRoT fields, we identified 481 non-eclipsing candidates with periodic flux amplitudes of 0.5-87 mmag. Optimizing the Anglo-Australian-Telescope pointing coordinates and the AAOmega fiber-allocations with dedicated softwares, we acquired six spectra for 231 candidates and seven spectra for another 50 candidates in a seven-night campaign. Analysis of the red-arm AAOmega spectra, which covered the range of 8342-8842 Å, yielded a radial-velocity precision of ~1 km s-1. Spectra containing lines of more than one star were analyzed with the two-dimensional correlation algorithm TODCOR. Results: The measured radial velocities confirmed the binarity of seventy of the BEER candidates - 45 single-line binaries, 18 double-line binaries, and 7 diluted binaries. We show that red giants introduce a major source of false candidates and demonstrate a way to improve BEER's performance in extracting higher fidelity samples from future searches of CoRoT light curves. The periods of the confirmed binaries span a range of 0.3-10 days and show a rise in the number of binaries per ΔlogP toward longer periods. The estimated mass ratios of the double-line binaries and the mass ratios assigned to the single

  13. Synthetic RORγt Agonists Enhance Protective Immunity.

    PubMed

    Chang, Mi Ra; Dharmarajan, Venkatasubramanian; Doebelin, Christelle; Garcia-Ordonez, Ruben D; Novick, Scott J; Kuruvilla, Dana S; Kamenecka, Theodore M; Griffin, Patrick R

    2016-04-15

    The T cell specific RORγ isoform RORγt has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and TC17 cells, cells that have demonstrated antitumor efficacy. RORγt controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of RORγt have been shown to increase the basal activity of RORγt enhancing TH17 cell proliferation. Here, we show that activation of RORγt using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, a mechanism that should enhance antitumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of RORγt should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment; thus such a molecule would provide a unique approach for the treatment of cancer. PMID:26785144

  14. Amphetamine- type reinforcement by dopaminergic agonists in the rat.

    PubMed

    Yokel, R A; Wise, R A

    1978-07-19

    Intravenous self-administration of d-amphetamine (0.25 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil. The dopaminergic agonists appear to suppress amphetamine intake in the same way as do 'free' amphetamine injections, by extending drug satiation in a given interresponse period. Clonidine, an alpha noradrenergic agonist, did not have similar effects. Apomorphine and piribedil did not increase 14C-amphetamine levels in rat brains, nor did they retard disappearance of 14C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism. Rats responding for amphetamine continued to respond for apomorphine or peribedil when the latter drugs were substituted for the former. Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil. The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine. These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties. PMID:98800

  15. Alkaloid delta agonist BW373U86 increases hypoxic tolerance.

    PubMed

    Bofetiado, D M; Mayfield, K P; D'Alecy, L G

    1996-06-01

    Activation of delta opioid receptors increases survival time during acute, lethal hypoxia in mice. delta Agonists therefore present a promising avenue for therapeutic application to reduce the morbidity and mortality associated with clinical hypoxia in settings such as drowning, head injury apnea, and complicated childbirths. However, most delta agonists now available are peptides, and may have limited clinical utility. In the present study, we evaluate the neuroprotective ability of an alkaloid delta agonist, BW373U86. Alkaloid compounds, due to increased stability and increased systemic distribution, may be more favorable for clinical use. We found that BW373U86, like the peptide delta agonist, DPDPE ([D-Pen2, D-Pen5]-enkephalin), increases survival time of mice during lethal hypoxia. The mechanism of neuroprotection induced by delta receptor activation appears to involve decreasing body temperature. Further, using selective opioid receptor antagonists, it appears that BW373U86 exerts these neuroprotective effects by acting at delta-opioid receptors. PMID:8638797

  16. The Agonistic Approach: Reframing Resistance in Qualitative Research

    ERIC Educational Resources Information Center

    Vitus, Kathrine

    2008-01-01

    The agonistic approach--aimed at embracing opposing perspectives as part of a qualitative research process and acknowledging that process as fundamentally political--sheds light on both the construction of and the resistance to research identities. This approach involves reflexively embedding interview situations into the ethnographic context as a…

  17. [Alpha-2 adrenoreceptor agonists in anaesthesia and intensive care medicine].

    PubMed

    Mavropoulos, G; Minguet, G; Brichant, J F

    2014-02-01

    Alpha-2 adrenoreceptor agonists have long been used in the treatment of arterial hypertension. However, in that indication they have progressively been replaced by antihypertensive drugs with a more interesting therapeutic profile. Nonetheless, pharmacological activation of alpha-2 adrenoreceptors leads to a variety of clinical effects that are of major interest for anaesthesia and intensive care practice. Indeed, the sedative and analgesic properties of alpha-2 adrenoreceptor agonists allow a reduction of hypnotic and opioid needs during general anaesthesia. In addition, they induce a down-regulation of the level of consciousness comparable to that of natural slow-wave sleep during post-anaesthesia and intensive care unit stay. These drugs may also prevent some deleterious effects of the sympathetic discharge in response to surgical stress. Furthermore, alpha-2 adrenoreceptor agonists are potent adjuncts for locoregional anaesthesia. In this article, we will summarize the most frequent applications of alpha-2 adrenoreceptor agonists in anaesthesia and intensive care medicine. We will focus on the clinical data available for the two most representative molecules of this pharmacological class: clonidine and dexmedetomidine. PMID:24683831

  18. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents. PMID:27194194

  19. Physician perceptions of GLP-1 receptor agonists in the UK.

    PubMed

    Matza, Louis S; Curtis, Sarah E; Jordan, Jessica B; Adetunji, Omolara; Martin, Sherry A; Boye, Kristina S

    2016-05-01

    Objectives Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetes for almost a decade, and new treatments in this class have recently been introduced. The purpose of this study was to examine perceptions of GLP-1 receptor agonists among physicians who treat patients with type 2 diabetes in the UK. Methods A total of 670 physicians (226 diabetes specialists; 444 general practice [GP] physicians) completed a survey in 2014. Results Almost all physicians had prescribed GLP-1 receptor agonists (95.4% total sample; 99.1% specialists; 93.5% GP), most frequently to patients whose glucose levels are not adequately controlled with oral medications (85.9% of physicians) and obese/overweight patients (83.7%). Physicians' most common reasons for prescribing a GLP-1 receptor agonist were: associated with weight loss (65.8%), good efficacy (55.7%), less hypoglycemia risk than insulin (55.2%), not associated with weight gain (34.5%), and better efficacy than oral medications (32.7%). Factors that most commonly cause hesitation when prescribing this class were: not considered first line therapy according to guidelines (56.9%), injectable administration (44.6%), cost (36.7%), gastrointestinal side effects (33.4%), and risk of pancreatitis (26.7%). Almost all specialists (99.1%) believed they had sufficient knowledge to prescribe a GLP-1 receptor agonist, compared with 76.1% of GPs. Conclusions Results highlight the widespread use of GLP-1 receptor agonists for treatment of type 2 diabetes in the UK. However, almost a quarter of GPs reported that they do not have enough knowledge to prescribe GLP-1s, suggesting a need for increased dissemination of information to targeted groups of physicians. Study limitations were that the generalizability of the clinician sample is unknown; survey questions required clinicians to select answers from multiple response options rather than generating the responses themselves; and responses to this survey conducted

  20. Activation of endplate nicotinic acetylcholine receptors by agonists.

    PubMed

    Auerbach, Anthony

    2015-10-15

    The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ∼300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by αY190) that behaves similarly at all sites and a coupled pair (led by γW55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of α(1) and one each of β, δ, and either γ (fetal) or ϵ (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at αδ and either αγ or αϵ subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C→O opening rate constant and C↔O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly

  1. Linc-RoR promotes c-Myc expression through hnRNP I and AUF1.

    PubMed

    Huang, Jianguo; Zhang, Ali; Ho, Tsui-Ting; Zhang, Ziqiang; Zhou, Nanjiang; Ding, Xianfeng; Zhang, Xu; Xu, Min; Mo, Yin-Yuan

    2016-04-20

    Linc-RoR was originally identified to be a regulator for induced pluripotent stem cells in humans and it has also been implicated in tumorigenesis. However, the underlying mechanism of Linc-RoR-mediated gene expression in cancer is poorly understood. The present study demonstrates that Linc-RoR plays an oncogenic role in part through regulation of c-Myc expression. Linc-RoR knockout (KO) suppresses cell proliferation and tumor growth. In particular, Linc-RoR KO causes a significant decrease in c-Myc whereas re-expression of Linc-RoR in the KO cells restores the level of c-Myc. Mechanistically, Linc-RoR interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) I and AU-rich element RNA-binding protein 1 (AUF1), respectively, with an opposite consequence to their interaction with c-Myc mRNA. While Linc-RoR is required for hnRNP I to bind to c-Myc mRNA, interaction of Linc-RoR with AUF1 inhibits AUF1 to bind to c-Myc mRNA. As a result, Linc-RoR may contribute to the increased stability of c-Myc mRNA. Although hnRNP I and AUF1 can interact with many RNA species and regulate their functions, with involvement of Linc-RoR they would be able to selectively regulate mRNA stability of specific genes such as c-Myc. Together, these results support a role for Linc-RoR in c-Myc expression in part by specifically enhancing its mRNA stability, leading to cell proliferation and tumorigenesis. PMID:26656491

  2. VizieR Online Data Catalog: Fourier analysis of HD 49330 CoRoT light curve (Huat+, 2009)

    NASA Astrophysics Data System (ADS)

    Huat, A.-L.; Hubert, A.-M.; Baudin, F.; Floquet, M.; Neiner, C.; Fremat, Y.; Gutierrez-Soto, J.; Andrade, L.; de Batz, B.; Diago, P. D.; Emilio, M.; Espinosa, F. Lara; Fabregat, J.; Janot-Pacheco, E.; Leroy, B.; Martayan, C.; Semaan, T.; Suso, J.; Auvergne, M.; Catala, C.; Michel, E.; Samadi, R.

    2009-09-01

    This work analyses the high precision photometric light curve obtained for the CoRoT target HD49330 (B0.5 IVe) which was observed during 136.886 days with a sample of 32s. During the CoRoT run the star underwent an outburst often observed in hot Be star. The CoRoT light curve was analysed using Fourier methods and non-linear least square fitting. (5 data files).

  3. VizieR Online Data Catalog: Algorithm for correcting CoRoT raw light curves (Mislis+, 2010)

    NASA Astrophysics Data System (ADS)

    Mislis, D.; Schmitt, J. H. M. M.; Carone, L.; Guenther, E. W.; Patzold, M.

    2010-10-01

    Requirements : gfortran (or g77, ifort) compiler Input Files : The input files sould be raw CoRoT txt files (http://idoc-corot.ias.u-psud.fr/index.jsp) with names CoRoT*.txt Run the cda by typing C>: ./cda.csh (code and data sould be in the same directory) Output files : CDA creates one ascii output file with name - CoRoT*.R.cor for R filter (2 data files).

  4. Linc-RoR promotes c-Myc expression through hnRNP I and AUF1

    PubMed Central

    Huang, Jianguo; Zhang, Ali; Ho, Tsui-Ting; Zhang, Ziqiang; Zhou, Nanjiang; Ding, Xianfeng; Zhang, Xu; Xu, Min; Mo, Yin-Yuan

    2016-01-01

    Linc-RoR was originally identified to be a regulator for induced pluripotent stem cells in humans and it has also been implicated in tumorigenesis. However, the underlying mechanism of Linc-RoR-mediated gene expression in cancer is poorly understood. The present study demonstrates that Linc-RoR plays an oncogenic role in part through regulation of c-Myc expression. Linc-RoR knockout (KO) suppresses cell proliferation and tumor growth. In particular, Linc-RoR KO causes a significant decrease in c-Myc whereas re-expression of Linc-RoR in the KO cells restores the level of c-Myc. Mechanistically, Linc-RoR interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) I and AU-rich element RNA-binding protein 1 (AUF1), respectively, with an opposite consequence to their interaction with c-Myc mRNA. While Linc-RoR is required for hnRNP I to bind to c-Myc mRNA, interaction of Linc-RoR with AUF1 inhibits AUF1 to bind to c-Myc mRNA. As a result, Linc-RoR may contribute to the increased stability of c-Myc mRNA. Although hnRNP I and AUF1 can interact with many RNA species and regulate their functions, with involvement of Linc-RoR they would be able to selectively regulate mRNA stability of specific genes such as c-Myc. Together, these results support a role for Linc-RoR in c-Myc expression in part by specifically enhancing its mRNA stability, leading to cell proliferation and tumorigenesis. PMID:26656491

  5. Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists.

    PubMed

    Yang, Ting; Liu, Qian; Cheng, Yaobang; Cai, Wei; Ma, Yingli; Yang, Liuqing; Wu, Qianqian; Orband-Miller, Lisa A; Zhou, Ling; Xiang, Zhijun; Huxdorf, Melanie; Zhang, Wei; Zhang, Jing; Xiang, Jia-Ning; Leung, Stewart; Qiu, Yang; Zhong, Zhong; Elliott, John D; Lin, Xichen; Wang, Yonghui

    2014-01-01

    A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists. PMID:24900774

  6. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    PubMed

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  7. Sex differences in opioid antinociception: kappa and 'mixed action' agonists.

    PubMed

    Craft, R M; Bernal, S A

    2001-08-01

    A number of investigators have shown that male animals are more sensitive than females to the antinociceptive effects of mu-opioid agonists. The present study was conducted to examine sex differences in opioid antinociception in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu-receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine, (-)-bremazocine, (-)-pentazocine, butorphanol and nalbuphine on the 50 or 54 degrees C hotplate and warm water tail withdrawal assays; spontaneous locomotor activity was measured 32-52 min post-injection in the same rats. On the hotplate assay, only butorphanol (54 degrees C) and nalbuphine (50 degrees C) were significantly more potent in males than females. On the tail withdrawal assay, all agonists were significantly more potent or efficacious in males than females at one or both temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses to drug (50 degrees C experiment). These results suggest that (1) sex differences in antinociceptive effects of opioids are not mu-receptor-dependent, as they may occur with opioids known to have significant kappa-receptor-mediated activity; (2) the mechanisms underlying sex differences in kappa-opioid antinociception may be primarily spinal rather than supraspinal; (3) sex differences in antinociceptive effects of opioid agonists are not secondary to sex differences in their sedative effects. PMID:11418226

  8. Noise properties of the CoRoT data. A planet-finding perspective

    NASA Astrophysics Data System (ADS)

    Aigrain, S.; Pont, F.; Fressin, F.; Alapini, A.; Alonso, R.; Auvergne, M.; Barbieri, M.; Barge, P.; Bordé, P.; Bouchy, F.; Deeg, H.; de La Reza, R.; Deleuil, M.; Dvorak, R.; Erikson, A.; Fridlund, M.; Gondoin, P.; Guterman, P.; Jorda, L.; Lammer, H.; Léger, A.; Llebaria, A.; Magain, P.; Mazeh, T.; Moutou, C.; Ollivier, M.; Pätzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Schneider, J.; Wuchter, G.; Zucker, S.

    2009-10-01

    In this short paper, we study the photometric precision of stellar light curves obtained by the CoRoT satellite in its planet-finding channel, with a particular emphasis on the time scales characteristic of planetary transits. Together with other articles in the same issue of this journal, it forms an attempt to provide the building blocks for a statistical interpretation of the CoRoT planet and eclipsing binary catch to date. After pre-processing the light curves so as to minimise long-term variations and outliers, we measure the scatter of the light curves in the first three CoRoT runs lasting more than 1 month, using an iterative non-linear filter to isolate signal on the time scales of interest. The behaviour of the noise on 2 h time scales is described well by a power-law with index 0.25 in R-magnitude, ranging from 0.1 mmag at R=11.5 to 1 mmag at R=16, which is close to the pre-launch specification, though still a factor 2-3 above the photon noise due to residual jitter noise and hot pixel events. There is evidence of slight degradation in the performance over time. We find clear evidence of enhanced variability on hour time scales (at the level of 0.5 mmag) in stars identified as likely giants from their R magnitude and B-V colour, which represent approximately 60 and 20% of the observed population in the directions of Aquila and Monoceros, respectively. On the other hand, median correlated noise levels over 2 h for dwarf stars are extremely low, reaching 0.05 mmag at the bright end. The CoRoT space mission, launched on December 27, 2006, has been developed and is operated by the CNES, with the contribution of Austria, Belgium, Brazil, ESA, Germany, and Spain. CoRoT data become publicly available one year after release to the Co-Is of the mission from the CoRoT archive: http://idoc-corot.ias.u-psud.fr/.

  9. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore

    SciTech Connect

    Washburn, David G.; Hoang, Tram H.; Campobasso, Nino; Smallwood, Angela; Parks, Derek J.; Webb, Christine L.; Frank, Kelly A.; Nord, Melanie; Duraiswami, Chaya; Evans, Christopher; Jaye, Michael; Thompson, Scott K.

    2009-03-27

    A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXR{alpha} will be disclosed.

  10. Glucagon-Like Peptide-1 Receptor Agonists: Beta-Cell Protection or Exhaustion?

    PubMed

    van Raalte, Daniël H; Verchere, C Bruce

    2016-07-01

    Glucagon-like peptide (GLP)-1 receptor agonists enhance insulin secretion and may improve pancreatic islet cell function. However, GLP-1 receptor (GLP-1R) agonist treatment may have more complex, and sometimes deleterious, effects on beta cells. We discuss the concepts of beta cell protection versus exhaustion for different GLP-1R agonists based on recent data. PMID:27160799

  11. CoRoT light curves of Blazhko RR Lyrae stars. Evidence of a strong correlation between phase and amplitude modulations of CoRoT ID 0105288363

    NASA Astrophysics Data System (ADS)

    Chadid, M.; Perini, C.; Bono, G.; Auvergne, M.; Baglin, A.; Weiss, W. W.; Deboscher, J.

    2011-03-01

    Context. The CoRoT - Convection Rotation and planetary Transits - space mission provides a unique opportunity to monitor RR Lyrae stars with excellent time-sampling, unprecedented photometric precision, and a long time base of 150 days. Aims: The pulsation characteristics of RR Lyrae stars rely on robust physics, but we still lack a firm quantitative understanding of the physical mechanisms driving the Blazhko modulation and the long-term changes in their pulsation behavior. We use the high-precision space data of an unknown RR Lyrae star CoRoT ID 0105288363 observed during a second long run centered on the Galaxy - LRc02 -, to improve our understanding of the pulsation properties of RR Lyrae stars. Methods: The CoRoT data were corrected using a jump and trend filtering code. We applied different period-finding techniques including Period04, MuFrAn, PDM, and SigSpec. Amplitude and phase modulation were investigated using an analytical function method as well as traditional O-C diagrams. Results: For the first time, we detect significant cycle-to-cycle changes in the Blazhko modulation, which appear to be analogous to those predicted by Stothers - owing to the suppression of turbulent convection - to explain this phenomenon. We discuss the clear correlations between the phase and the amplitude of the bump, and the skewness and acuteness of the light curve during different Blazhko cycles. We find that these quantities are strongly anticorrelated with the fundamental pulsation period. This provides a strong support to the slow convective cycle model suggested by Stothers. We also detect a long-term modulation period in the maximum brightness spectrum. A more extended coverage of the long-term modulation is required to constrain its period. Seventh-order side peaks of the pulsation multiplet structure are also visible with the left-side peak amplitudes being higher than those of the right. This has never previously been detected. Future theoretical investigations are

  12. Stellar parameters for stars of the CoRoT exoplanet field

    NASA Astrophysics Data System (ADS)

    Cortés, C.; Maciel, S. C.; Vieira, S.; Ferreira Lopes, C. E.; Leão, I. C.; de Oliveira, G. P.; Correia, C.; Canto Martins, B. L.; Catelan, M.; De Medeiros, J. R.

    2015-09-01

    Context. Spectroscopic observations represent a fundamental step in the physical characterization of stars and, in particular, in the precise location of stars in the HR diagram. Rotation is also a key parameter, impacting stellar properties and evolution, which modulates the interior and manifests itself on the surface of stars. To date, the lack of analysis based on large samples has prevented our understanding of the real impact of stellar parameters and rotation on the stellar evolution as well as on the behavior of surface abundances. The space missions, CoRoT and Kepler, are providing us with rotation periods for thousands of stars, thus enabling a robust assessment of the behavior of rotation for different populations and evolutionary stages. For these reasons, the follow-up programs are fundamental to increasing the returns of these space missions. An analysis that combines spectroscopic data and rotation/modulation periods obtained from these space missions provides the basis for establishing the evolutionary behavior of the angular momentum of solar-like stars at different evolutionary stages, and the relation of rotation with other relevant physical and chemical parameters. Aims: To support the computation and evolutionary interpretation of periods associated with the rotational modulation, oscillations, and variability of stars located in the CoRoT fields, we are conducting a spectroscopic survey for stars located in the fields already observed by the satellite. These observations allow us to compute physical and chemical parameters for our stellar sample. Methods: Using spectroscopic observations obtained with UVES/VLT and Hydra/Blanco, and based on standard analysis techniques, we computed physical and chemical parameters (Teff, log (g), [Fe/H], vmic, vrad, vsin (i), and A(Li)) for a large sample of CoRoT targets. Results: We provide physical and chemical parameters for a sample comprised of 138 CoRoT targets. Our analysis shows the stars in our

  13. Isolated anti-Ro/SSA thrombocytopenia: a rare feature of neonatal lupus

    PubMed Central

    Ayadi, Imene Dahmane; Hamida, Emira Ben; Boukhris, Mohamed Riadh; Bezzine, Ahlem; Chaouachi, Sihem; Marrakchi, Zahra

    2015-01-01

    We report a rare case of isolated thrombocytopenia related to anti-Ro/SSA antibodies. The mother was followed for unlabeled familial thrombocytopenia. The mother had positive anti-Ro/SSA antibodies. She was asymptomatic without skin lesions or other criteria neither of systemic lupus erythematosus nor other connective tissue disease. Pregnancy was uneventful. The postnatal examination was normal. On the first day of life, blood cells count showed thrombocytopenia at 40 x 109/L. Within the second day of life, platelet level dropped to 20 x 109/L. The management of thrombocytopenia included platelet transfusion and human immunoglobulin infusion. On the fifth day of life, there has been a drop in platelet count to 10 x 109/L requiring renewed platelet transfusion and human immunoglobulin infusion. On the 10th of life platelets rate was stable around 60 x 109/L. The infant had no evidence of cardiac, dermatologic or hepatobilary involvement initially or throughout follow up. PMID:26977221

  14. Thematic trip: "Save Roşia MontanÄă"

    NASA Astrophysics Data System (ADS)

    Eugenia, Marcu

    2015-04-01

    The name Roşia Montană, situated in Transylvania, became well known after a Romanian-Canadian company, Roşia Montană Gold Company (RMGC), obtained the concession license on exploitation for gold and silver minerals in the Roşia Montană area. The project consists of opening the largest surface gold mines in Europe using cyanide, which will include four open pits and a processing plant for gold and silver in The Roşia Valley and a tailings facility with an area of 367 hectares in the Corna Valley. One of the main fears is related to a possible ecological accident like the one in Baia Mare in 2000, when a tailing facility dam break led to cyanide pollution of Tisa and Danube rivers that resulted in the death of 1,200 tons of fish and contamination of water resources for 2 million people. This thematic trip is important for the scientific preparation of students and an opportunity to educate them in the spirit of environmental protection. The training and education of students will require assimilation and understanding, actively and consciously, using the knowledge acquired during the compulsory curriculum and training skills. REASON: The continuous degradation of the environment is a major crisis due to human intervention in nature, and the proposed Roşia Montană mining project will continue this trend. The company proposes to extract gold from mines by using the gold separation technique using cyanide, a process that involves destroying a total area of 16 km² which includes 5 mountains, 7 churches, 11 cemeteries and the ruins of Alburnus Maior Citadel, as well as creating pollution that would last for hundreds of years. The extraction of gold from low-grade ores using cyanide processes was estimated to result in a worldwide emission of 45,300 tons of hydrogen cyanide. Environmental education for a healthy life has children as target group, because they are the trustees and beneficiaries of tomorrow's natural resources and can influence the attitudes of

  15. VizieR Online Data Catalog: CoRoT 105906206 frequencies analysis (da Silva+, 2014)

    NASA Astrophysics Data System (ADS)

    da Silva, R.; Maceroni, C.; Gandolfi, D.; Lehmann, H.; Hatzes, A. P.

    2014-03-01

    The file frequenc.dat contains the table with 220 frequencies, amplitudes, and phases, together with their uncertainties, derived for the light curve of CoRoT 105906206 with pulsations only (after subtracting the best binary model). The uncertainties are the formal values computed using equations (4), (10), and (11) of Montgomery & O'Donoghue (1999DSSN...13...28M). (1 data file).

  16. Raman investigation of ro-vibrational modes of interstitial H2 in Si

    NASA Astrophysics Data System (ADS)

    Koch, S. G.; Lavrov, E. V.; Weber, J.

    2012-08-01

    A Raman scattering study of ro-vibrational transitions Q(J) of the interstitial H2 in Si is presented. It is shown that the Q(2) mode of para hydrogen is coupled to the TAX phonon of Si. The mode appears in the spectra at temperatures above 200 K. The results presented also suggest that the Q(3) transition of ortho hydrogen is resonantly coupled to the OΓ phonon.

  17. European landscape in astrobiology, results of the AstRoMap consultation

    NASA Astrophysics Data System (ADS)

    Horneck, Gerda; Rettberg, Petra; Walter, Nicolas; Gomez, Felipe

    2015-05-01

    Astrobiology is a multidisciplinary field of research, which encompasses scientists ranging from cosmology, astronomy, planetary sciences, physics, chemistry, geology, paleontology to biology. In order to map the existing astrobiological expertise in Europe a comprehensive community consultation has been performed within the AstRoMap (Astrobiology Road Mapping) project that is supported by the European Commission FP7 framework. From this information a data base of scientists (European and beyond) interested in astrobiology and planetary exploration (see:

  18. Antiscalant removal in accelerated desupersaturation of RO concentrate via chemically-enhanced seeded precipitation (CESP).

    PubMed

    McCool, Brian C; Rahardianto, Anditya; Cohen, Yoram

    2012-09-01

    An experimental study was carried out to demonstrate and quantify the feasibility of antiscalant (AS) removal from brackish water RO concentrate of high gypsum scaling propensity via lime treatment prior to seeded gypsum precipitation. Based on studies with model solutions, it was shown that sufficient AS removal (up to ∼90%) from RO concentrate is feasible via a lime treatment step (at a dose significantly lower than that required for conventional lime softening) to enable effective subsequent seeded gypsum precipitation. This two-step chemically-enhanced seeded precipitation (CESP) treatment of primary RO concentrate is suitable as an intermediate concentrate demineralization (ICD) stage for high recovery desalting employing secondary RO desalination. Analysis of gypsum precipitation and lime treatment kinetic data suggests that, after adequate CaCO(3) precipitation has been induced for effective AS scavenging, CaSO(4) desupersaturation can be achieved via seeded gypsum precipitation without retardation due to seed poisoning by AS. Also, the lime dose required to prevent seed poisoning during subsequent gypsum desupersaturation via seeded gypsum precipitation can be adequately assessed with a precipitation kinetics model that considers AS seed poisoning based on a Langmuir adsorption isotherm. The degree of AS removal after lime treatment increased linearly with the logarithm of the single lime dose additions. Staged lime dosing (i.e., multiple lime additions), however, removed a higher degree of AS relative to an equivalent single lime dose addition since a higher driving force for CaCO(3) precipitation could be maintained over the course of the lime treatment period. PMID:22673342

  19. 77 FR 47275 - Airworthiness Directives; HPH s. r.o. Sailplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-08

    ...We are adopting a new airworthiness directive (AD) for all HPH s. r.o. Models 304C, 304CZ, and 304CZ-17 sailplanes. This AD results from mandatory continuing airworthiness information (MCAI) issued by an aviation authority of another country to identify and correct an unsafe condition on an aviation product. The MCAI describes the unsafe condition as the lack of a drain hole in the elevator......

  20. Learning to Improve E-mail Classification with numéro interactive

    NASA Astrophysics Data System (ADS)

    Jones, Dean M.

    This paper describes some of the ways in which we use artificial intelligence technologies in numéro interactive, a Customer Interaction Management system. In particular, we focus on the classification of e-mail messages into one of multiple business categories. We describe different features that are extracted from e-mail messages to help in this classification, and the improvement in the overall classification accuracy that results from the use of each kind of feature.

  1. Multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole)

    SciTech Connect

    Bleehen, N.M.; Newman, H.F.; Maughan, T.S.; Workman, P.

    1989-04-01

    The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

  2. THE FUTURE OF THE SUN: AN EVOLVED SOLAR TWIN REVEALED BY CoRoT

    SciTech Connect

    Do Nascimento, J.-D. Jr.; Da Costa, J. S.; Castro, M.; Takeda, Y.; Melendez, J.

    2013-07-10

    The question of whether the Sun is peculiar within the class of solar-type stars has been the subject of active investigation over the past three decades. Although several solar twins have been found with stellar parameters similar to those of the Sun (albeit in a range of Li abundances and with somewhat different compositions), their rotation periods are unknown, except for 18 Sco, which is younger than the Sun and with a rotation period shorter than solar. It is difficult to obtain rotation periods for stars of solar age from ground-based observations, as a low-activity level implies a shallow rotational modulation of their light curves. CoRoT has provided space-based long time series from which the rotation periods of solar twins as old as the Sun could be estimated. Based on high-signal-to-noise, high-resolution spectroscopic observations gathered at the Subaru Telescope, we show that the star CoRoT ID 102684698 is a somewhat evolved solar twin with a low Li abundance. Its rotation period is 29 {+-} 5 days, compatible with its age (6.7 Gyr) and low lithium content, A{sub Li} {approx}< 0.85 dex. Interestingly, our CoRoT solar twin seems to have enhanced abundances of the refractory elements with respect to the Sun, a typical characteristic of most nearby twins. With a magnitude V {approx_equal} 14.1, ID 102684698 is the first solar twin revealed by CoRoT, the farthest field solar twin so far known, and the only solar twin older than the Sun for which a rotation period has been determined.

  3. The Transit Detection Algorithm DST and its application to CoRoT and Kepler data

    NASA Astrophysics Data System (ADS)

    Cabrera, J.; Rauer, H.; Erikson, A.; Csizmadia, S.

    2011-10-01

    Transit detection algorithms are mathematical tools used to detect the presence of planets in the photometric data of transit surveys. Space missions are exploring the parameter space of transit surveys towards small planets where classical algorithms do not perform optimally, either due to the low signal to noise ratio of the signal or to its non-periodic characteristics. We present an algorithm addressing these challenges and its performance in an application to CoRoT and Kepler data.

  4. A theoretical perspective on the ultra-compact systems of CoRoT and Kepler

    NASA Astrophysics Data System (ADS)

    Wuchterl, G.

    2011-10-01

    CoRoT and Kepler discovered closely spaced short period planetary systems. We investigate into the physics of these systems by combining an approach that was developed for the CoRoT mission to determine the distributions of planetary masses and radii based on a minimum number of basic physical principles with the classical approach of Hill-exclusion volumes to estimate dynamical stability. We discuss to what extent the discovered systems can be understood as a random draw from the theoretical mass and/or radius distributions with Hill-exclusion stability as a constraint. We point to the bi-modality of the theoretical planetary mass-function as a key factor in shaping the architecture of the presently known systems. Given the first-time availability of new high-resolution epoch-of observation theoretical radius distributions for the entire present period sensitivity of CoRoT and Keplerreleases, we take the opportunity to confront the various radius anomalies — 'styrofoam' planets, inflated Jupiters and Neptunes — to our statistical approach.

  5. Quantum scattering calculations for ro-vibrational de-excitation of CO by hydrogen atoms

    SciTech Connect

    Song, Lei; Avoird, Ad van der; Karman, Tijs; Groenenboom, Gerrit C.; Balakrishnan, N.

    2015-05-28

    We present quantum-mechanical scattering calculations for ro-vibrational relaxation of carbon monoxide (CO) in collision with hydrogen atoms. Collisional cross sections of CO ro-vibrational transitions from v = 1, j = 0 − 30 to v′ = 0, j′ are calculated using the close coupling method for collision energies between 0.1 and 15 000 cm{sup −1} based on the three-dimensional potential energy surface of Song et al. [J. Phys. Chem. A 117, 7571 (2013)]. Cross sections of transitions from v = 1, j ≥ 3 to v′ = 0, j′ are reported for the first time at this level of theory. Also calculations by the more approximate coupled states and infinite order sudden (IOS) methods are performed in order to test the applicability of these methods to H–CO ro-vibrational inelastic scattering. Vibrational de-excitation rate coefficients of CO (v = 1) are presented for the temperature range from 100 K to 3000 K and are compared with the available experimental and theoretical data. All of these results and additional rate coefficients reported in a forthcoming paper are important for including the effects of H–CO collisions in astrophysical models.

  6. Special cascade LMS equalization scheme suitable for 60-GHz RoF transmission system.

    PubMed

    Liu, Siming; Shen, Guansheng; Kou, Yanbin; Tian, Huiping

    2016-05-16

    We design a specific cascade least mean square (LMS) equalizer and to the best of our knowledge, it is the first time this kind of equalizer has been employed for 60-GHz millimeter-wave (mm-wave) radio over fiber (RoF) system. The proposed cascade LMS equalizer consists of two sub-equalizers which are designated for optical and wireless channel compensations, respectively. We control the linear and nonlinear factors originated from optical link and wireless link separately. The cascade equalization scheme can keep the nonlinear distortions of the RoF system in a low degree. We theoretically and experimentally investigate the parameters of the two sub-equalizers to reach their best performances. The experiment results show that the cascade equalization scheme has a faster convergence speed. It needs a training sequence with a length of 10000 to reach its stable status, which is only half as long as the traditional LMS equalizer needs. With the utility of a proposed equalizer, the 60-GHz RoF system can successfully transmit 5-Gbps BPSK signal over 10-km fiber and 1.2-m wireless link under forward error correction (FEC) limit 10-3. An improvement of 4dBm and 1dBm in power sensitivity at BER 10-3 over traditional LMS equalizer can be observed when the signals are transmitted through Back-to-Back (BTB) and 10-km fiber 1.2-m wireless links, respectively. PMID:27409882

  7. THE CoRoT DISCOVERY OF A UNIQUE TRIPLE-MODE CEPHEID IN THE GALAXY

    SciTech Connect

    Poretti, E.; Baglin, A.; Weiss, W. W.

    2014-11-10

    The exploitation of the CoRoT treasure of stars observed in the exoplanetary field allowed the detection of a unusual triple-mode Cepheid in the Milky Way, CoRoT 0223989566. The two modes with the largest amplitudes and a period ratio of 0.80 are identified with the first (P {sub 1} = 1.29 days) and second (P {sub 2} = 1.03 days) radial overtones. The third period, which has the smallest amplitude but is able to produce combination terms with the other two, is the longest one (P {sub 3} = 1.89 days). The ratio of 0.68 between the first-overtone period and the third period is the unusual feature. Its identification with the fundamental radial or a nonradial mode is discussed with respect to similar cases in the Magellanic Clouds. In both cases, the period triplet and the respective ratios make the star unique in our Galaxy. The distance derived from the period-luminosity relation and the galactic coordinates put CoRoT 0223989566 in the metal-rich environment of the ''outer arm'' of the Milky Way.

  8. RoCoMAR: Robots' Controllable Mobility Aided Routing and Relay Architecture for Mobile Sensor Networks

    PubMed Central

    Van Le, Duc; Oh, Hoon; Yoon, Seokhoon

    2013-01-01

    In a practical deployment, mobile sensor network (MSN) suffers from a low performance due to high node mobility, time-varying wireless channel properties, and obstacles between communicating nodes. In order to tackle the problem of low network performance and provide a desired end-to-end data transfer quality, in this paper we propose a novel ad hoc routing and relaying architecture, namely RoCoMAR (Robots' Controllable Mobility Aided Routing) that uses robotic nodes' controllable mobility. RoCoMAR repeatedly performs link reinforcement process with the objective of maximizing the network throughput, in which the link with the lowest quality on the path is identified and replaced with high quality links by placing a robotic node as a relay at an optimal position. The robotic node resigns as a relay if the objective is achieved or no more gain can be obtained with a new relay. Once placed as a relay, the robotic node performs adaptive link maintenance by adjusting its position according to the movements of regular nodes. The simulation results show that RoCoMAR outperforms existing ad hoc routing protocols for MSN in terms of network throughput and end-to-end delay. PMID:23881134

  9. Water Quality of Hills Water, Supply Water and RO Water Machine at Ulu Yam Selangor

    NASA Astrophysics Data System (ADS)

    Ngadiman, N.; ‘I Bahari, N.; Kaamin, M.; Hamid, N. B.; Mokhtar, M.; Sahat, S.

    2016-07-01

    The rapid development resulted in the deterioration of the quality of drinking water in Malaysia. Recognizing the importance of water quality, new alternatives for drinking water such as mineral water processing from reverse osmosis (RO) machine become more popular. Hence, the demand for mineral water, natural spring water or water from the hills or mountains rose lately. More consumers believed the quality of these spring water better than other source of drinking water. However, the quality of all the drinking water sources is to meet the required quality standard. Therefore, this paper aims to measure the quality of the waters from hills, from RO machine and the water supply in Ulu Yam, Selangor Batang Kali, Malaysia. The water quality was determined based on following parameters: ammoniacal nitrogen (NH3), iron (Fe), turbidity (NTU) and pH. The results show that the water from hills has better quality compared to water supply and water from RO machine. The value of NH3 ranged from 0.03 mg/L- 0.67 mg/L; Fe was from 0.03mg/L - 0.12 mg/L, turbidity at 0.42 NTU - 0.88 NTU and pH is at 6.60 - 0.71. Based on the studied parameters, all three types of water are fit for drinking and have met the required national drinking water quality standard.

  10. Quantum scattering calculations for ro-vibrational de-excitation of CO by hydrogen atoms

    NASA Astrophysics Data System (ADS)

    Song, Lei; Balakrishnan, N.; van der Avoird, Ad; Karman, Tijs; Groenenboom, Gerrit C.

    2015-05-01

    We present quantum-mechanical scattering calculations for ro-vibrational relaxation of carbon monoxide (CO) in collision with hydrogen atoms. Collisional cross sections of CO ro-vibrational transitions from v = 1, j = 0 - 30 to v' = 0, j' are calculated using the close coupling method for collision energies between 0.1 and 15 000 cm-1 based on the three-dimensional potential energy surface of Song et al. [J. Phys. Chem. A 117, 7571 (2013)]. Cross sections of transitions from v = 1, j ≥ 3 to v' = 0, j' are reported for the first time at this level of theory. Also calculations by the more approximate coupled states and infinite order sudden (IOS) methods are performed in order to test the applicability of these methods to H-CO ro-vibrational inelastic scattering. Vibrational de-excitation rate coefficients of CO (v = 1) are presented for the temperature range from 100 K to 3000 K and are compared with the available experimental and theoretical data. All of these results and additional rate coefficients reported in a forthcoming paper are important for including the effects of H-CO collisions in astrophysical models.

  11. [Phase II study of recombinant leukocyte A interferon (Ro 22-8181) in hematological malignancies].

    PubMed

    1985-04-01

    A Phase II study of recombinant leukocyte A interferon (rIFN-alpha A, Ro 22-8181) was performed in 121 patients with hematological malignancies at 33 institutions from July, 1982 to May, 1984. Patients received Ro 22-8181 by intramuscular injection daily for more than 4 weeks. Daily doses were escalated from 3 X 10(6) to 6X, 9X, 18X, 36X and 50X 10(6) units every 3-7 days. Among 70 evaluable cases, complete or partial responses were observed in 15 patients (21.4%). One complete and 10 partial responses (22.4%) were noted in 49 cases of multiple myeloma, 2 partial remissions (18.2%) in 11 cases of malignant lymphoma and 2 partial remissions (25.0%) in 8 cases of leukemia. Side effects included fever (57.0%), anorexia (34.2%), nausea-vomiting (22.8%), malaise (19.0%), leukopenia (44.3%), thrombocytopenia (45.6%) and increase of GOT or GPT (26.6% or 22.8%). They were all not serious and disappeared quickly after the discontinuation of Ro 22-8181. PMID:3885864

  12. The CoRoT Discovery of a Unique Triple-mode Cepheid in the Galaxy

    NASA Astrophysics Data System (ADS)

    Poretti, E.; Baglin, A.; Weiss, W. W.

    2014-11-01

    The exploitation of the CoRoT treasure of stars observed in the exoplanetary field allowed the detection of a unusual triple-mode Cepheid in the Milky Way, CoRoT 0223989566. The two modes with the largest amplitudes and a period ratio of 0.80 are identified with the first (P 1 = 1.29 days) and second (P 2 = 1.03 days) radial overtones. The third period, which has the smallest amplitude but is able to produce combination terms with the other two, is the longest one (P 3 = 1.89 days). The ratio of 0.68 between the first-overtone period and the third period is the unusual feature. Its identification with the fundamental radial or a nonradial mode is discussed with respect to similar cases in the Magellanic Clouds. In both cases, the period triplet and the respective ratios make the star unique in our Galaxy. The distance derived from the period-luminosity relation and the galactic coordinates put CoRoT 0223989566 in the metal-rich environment of the "outer arm" of the Milky Way.

  13. Radiative accuracy assessment of CrIS upper level channels using COSMIC RO data

    NASA Astrophysics Data System (ADS)

    Qi, C.; Weng, F.; Han, Y.; Lin, L.; Chen, Y.; Wang, L.

    2012-12-01

    The Cross-track Infrared Sounder(CrIS) onboard Suomi National Polar-orbiting Partnership(NPP) satellite is designed to provide high vertical resolution information on the atmosphere's three-dimensional structure of temperature and water vapor. There are much work has been done to verify the observation accuracy of CrIS since its launch date of Oct. 28, 2011, such as SNO cross comparison with other hyper-spectral infrared instruments and forward simulation comparison using radiative transfer model based on numerical prediction background profiles. Radio occultation technique can provide profiles of the Earth's ionosphere and neutral atmosphere with high accuracy, high vertical resolution and global coverage. It has advantages of all-weather capability, low expense, long-term stability etc. Assessing CrIS radiative calibration accuracy was conducted by comparison between observation and Line-by-line simulation using COSMIC RO data. The main process technique include : (a) COSMIC RO data downloading and collocation with CrIS measurements through weighting function (wf) peak altitude dependent collocation method; (b) High spectral resolution of Line-by-line radiance simulation using collocated COSMIC RO profiles ; (c) Generation of CrIS channel radiance by FFT transform method; (d): Bias analysis . This absolute calibration accuracy assessing method verified a 0.3K around bias error of CrIS measurements.

  14. Constraints on the exosphere of CoRoT-7b

    NASA Astrophysics Data System (ADS)

    Guenther, E. W.; Cabrera, J.; Erikson, A.; Fridlund, M.; Lammer, H.; Mura, A.; Rauer, H.; Schneider, J.; Tulej, M.; von Paris, Ph.; Wurz, P.

    2011-01-01

    Context. The small radius and high density of CoRoT-7b implies that this transiting planet belongs to a different species than all transiting planets previously found. Current models suggest that this is the first transiting rocky planet found outside the solar system. Given that the planet orbits a solar-like star at a distance of only 4.5 R*, it is expected that material released from its surface may then form an exosphere. Aims: We constrain the properties of the exosphere by observing the planet in- and out-of-transit. Detecting the exosphere of CoRoT-7b would for the first time allow us to study the material originating in the surface of a rocky extrasolar planet. We scan the entire optical spectrum for any lines originating from the planet, focusing particularly on spectral lines such as those detected in Mercury and Io in our solar system. Methods: Since lines originating in the exosphere are expected to be narrow, we observed CoRoT-7b at high resolution with UVES on the VLT. By subtracting the two spectra from each other, we search for emission and absorption lines originating in the exosphere of CoRoT-7b. Results: In the first step, we focus on Ca I, Ca II, and Na, because these lines have been detected in Mercury. Since the signal-to-noise ratio (S/N) of the spectra is as high as 300, we derive firm upper limits for the flux-range between 1.6 × 10-18 and 3.2 × 10-18 W m-2. For CaO, we find an upper limit of 10-17 W m-2. We also search for emission lines originating in the plasma torus fed by volcanic activity and derive upper limits for these lines. In the whole spectrum we finally try to identify other lines originating in the planet. Conclusions: Except for CaO, the upper limits derived correspond to 2-6 × 10-6 L*, demonstrating the capability of UVES to detect very weak lines. Our observations certainly exclude the extreme interpretations of data for CoRoT-7b, such as an exosphere that emits 2000 times as brightly as Mercury. Based on observations

  15. Distribution of refractory and volatile elements in CoRoT exoplanet host stars

    NASA Astrophysics Data System (ADS)

    Chavero, C.; de La Reza, R.; Domingos, R. C.; Drake, N. A.; Pereira, C. B.; Winter, O. C.

    2010-07-01

    The relative distribution of abundances of refractory, intermediate, and volatile elements in stars with planets can be an important tool for investigating the internal migration of a giant planet. This migration can lead to the accretion of planetesimals and the selective enrichment of the star with these elements. We report on a spectroscopic determination of the atmospheric parameters and chemical abundances of the parent stars in transiting planets CoRoT-2b and CoRoT-4b. Adding data for CoRoT-3 and CoRoT-5 from the literature, we find a flat distribution of the relative abundances as a function of their condensation temperatures. For CoRoT-2, the relatively high lithium abundance and intensity of its Li i resonance line permit us to propose an age of 120 Myr, making this star one of the youngest stars with planets to date. We introduce a new methodology to investigate a relation between the abundances of these stars and the internal migration of their planets. By simulating the internal migration of a planet in a disk formed only by planetesimals, we are able, for the first time, to separate the stellar fractions of refractory, intermediate, and volatile rich planetesimals accreting onto the central star. Intermediate and volatile element fractions enriching the star are similar and much larger than those of pure refractory ones. This result is opposite to what has been considered in the literature for the accreting self-enrichment processes of stars with planets. We also show that these results are highly dependent on the model adopted for the disk distribution regions in terms of refractory, intermediate, and also volatile elements and other parameters considered. We note however, that this self-enrichment mechanism is only efficient during the first 20-30 Myr or later in the lifetime of the disk when the surface convection layers of the central star for the first time attain its minimum size configuration. Based on observations made with the 2.2 m telescope

  16. Study of HD 169392A observed by CoRoT and HARPS

    NASA Astrophysics Data System (ADS)

    Mathur, S.; Bruntt, H.; Catala, C.; Benomar, O.; Davies, G. R.; García, R. A.; Salabert, D.; Ballot, J.; Mosser, B.; Régulo, C.; Chaplin, W. J.; Elsworth, Y.; Handberg, R.; Hekker, S.; Mantegazza, L.; Michel, E.; Poretti, E.; Rainer, M.; Roxburgh, I. W.; Samadi, R.; Stȩślicki, M.; Uytterhoeven, K.; Verner, G. A.; Auvergne, M.; Baglin, A.; Barceló Forteza, S.; Baudin, F.; Roca Cortés, T.

    2013-01-01

    Context. The results obtained by asteroseismology with data from space missions such as CoRoT and Kepler are providing new insights into stellar evolution. After five years of observations, CoRoT is continuing to provide high-quality data and we here present an analysis of the CoRoT observations of the double star HD 169392, complemented by ground-based spectroscopic observations. Aims: This work aims at characterising the fundamental parameters of the two stars, their chemical composition, the acoustic-mode global parameters including their individual frequencies, and their dynamics. Methods: We analysed HARPS observations of the two stars to derive their chemical compositions. Several methods were used and compared to determine the global properties of stars' acoustic modes and their individual frequencies from the photometric data of CoRoT. Results: The new spectroscopic observations and archival astrometric values suggest that HD 169392 is a weakly bound wide binary system. We obtained spectroscopic parameters for both components which suggest that they originate from the same interstellar cloud. However, only the signature of oscillation modes of HD 169392 A was measured; the signal-to-noise ratio of the modes in HD 169392B is too low to allow any confident detection. For HD 169392 A we were able to extract parameters of modes for ℓ = 0, 1, 2, and 3. The analysis of splittings and inclination angle gives two possible solutions: one with with splittings and inclination angles of 0.4-1.0 μHz and 20 - 40°, the other with 0.2-0.5 μHz and 55-86°. Modelling this star using the Asteroseismic Modeling Portal (AMP) gives a mass of 1.15 ± 0.01 M⊙, a radius of 1.88 ± 0.02 R⊙, and an age of 4.33 ± 0.12 Gyr. The uncertainties come from estimated errors on the observables but do not include uncertainties on the surface layer correction or the physics of stellar models. The CoRoT space mission, launched on December 27 2006, has been developed and is operated by

  17. HD 50844: a new look at δ Scuti stars from CoRoT space photometry

    NASA Astrophysics Data System (ADS)

    Poretti, E.; Michel, E.; Garrido, R.; Lefèvre, L.; Mantegazza, L.; Rainer, M.; Rodríguez, E.; Uytterhoeven, K.; Amado, P. J.; Martín-Ruiz, S.; Moya, A.; Niemczura, E.; Suárez, J. C.; Zima, W.; Baglin, A.; Auvergne, M.; Baudin, F.; Catala, C.; Samadi, R.; Alvarez, M.; Mathias, P.; Paparò, M.; Pápics, P.; Plachy, E.

    2009-10-01

    Context: Aims: This work presents the results obtained by CoRoT on HD 50844, the only δ Sct star observed in the CoRoT initial run (57.6 d). The aim of these CoRoT observations was to investigate and characterize for the first time the pulsational behaviour of a δ Sct star, when observed at a level of precision and with a much better duty cycle than from the ground. Methods: The 140 016 datapoints were analysed using independent approaches (SigSpec software and different iterative sine-wave fittings) and several checks performed (splitting of the timeseries in different subsets, investigation of the residual light curves and spectra). A level of 10-5 mag was reached in the amplitude spectra of the CoRoT timeseries. The space monitoring was complemented by ground-based high-resolution spectroscopy, which allowed the mode identification of 30 terms. Results: The frequency analysis of the CoRoT timeseries revealed hundreds of terms in the frequency range 0-30 d-1. All the cross-checks confirmed this new result. The initial guess that δ Sct stars have a very rich frequency content is confirmed. The spectroscopic mode identification gives theoretical support since very high-degree modes (up to ℓ=14) are identified. We also prove that cancellation effects are not sufficient in removing the flux variations associated to these modes at the noise level of the CoRoT measurements. The ground-based observations indicate that HD 50844 is an evolved star that is slightly underabundant in heavy elements, located on the Terminal Age Main Sequence. Probably due to this unfavourable evolutionary status, no clear regular distribution is observed in the frequency set. The predominant term (f_1=6.92 d-1) has been identified as the fundamental radial mode combining ground-based photometric and spectroscopic data. Conclusions: The CoRoT space mission was developed and is operated by the French space agency CNES, with participation of ESA's RSSD and Science Programmes, Austria

  18. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

    PubMed

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J; Wolber, Gerhard; Mohr, Klaus

    2016-07-29

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site. PMID:27298318

  19. A Potent and Site-Selective Agonist of TRPA1.

    PubMed

    Takaya, Junichiro; Mio, Kazuhiro; Shiraishi, Takuya; Kurokawa, Tatsuki; Otsuka, Shinya; Mori, Yasuo; Uesugi, Motonari

    2015-12-23

    TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation. PMID:26630251

  20. β2-adrenoceptor agonists in the regulation of mitochondrial biogenesis

    PubMed Central

    Peterson, Yuri K.; Cameron, Robert B.; Wills, Lauren P.; Trager, Richard E.; Lindsey, Chris C.; Beeson, Craig C.; Schnellmann, Rick G.

    2014-01-01

    The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of β2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of β2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB. PMID:23954364

  1. RoY peptide-modified chitosan-based hydrogel to improve angiogenesis and cardiac repair under hypoxia.

    PubMed

    Shu, Yao; Hao, Tong; Yao, Fanglian; Qian, Yufeng; Wang, Yan; Yang, Boguang; Li, Junjie; Wang, Changyong

    2015-04-01

    Myocardial infarction (MI) still represents the "Number One Killer" in the world. The lack of functional vasculature of the infracted myocardium under hypoxia is one of the main problems for cardiac repair. In this study, a thermosensitive chitosan chloride-RoY (CSCl-RoY) hydrogel was developed to improve angiogenesis under hypoxia after MI. First, RoY peptides were conjugated onto the CSCl chain via amide linkages, and our data show that the conjugation of RoY peptide to CSCl does not interfere with the temperature sensitivity. Then, the effect of CSCl-RoY hydrogels on vascularization in vitro under hypoxia was investigated using human umbilical vein endothelial cells (HUVECs). Results show that CSCl-RoY hydrogels can promote the survival, proliferation, migration and tube formation of HUVECs under hypoxia compared with CSCl hydrogel. Further investigations suggest that CSCl-RoY hydrogels can modulate the expression of membrane surface GRP78 receptor of HUVECs under hypoxia and then activate Akt and ERK1/2 signaling pathways related to cell survival/proliferation, thereby enhancing angiogenic activity of HUVECs under hypoxia. To assess its therapeutic properties in vivo, a MI model was induced in rats by the left anterior descending artery ligation. CSCl or CSCl-RoY hydrogels were injected into the border of infracted hearts. The results demonstrate that the introduction of RoY peptide can not only improve angiogenesis at MI region but also improve the cardiac functions. Overall, we conclude that the CSCl-RoY may represent an ideal scaffold material for injectable cardiac tissue engineering. PMID:25756853

  2. A Human Platelet Calcium Calculator Trained by Pairwise Agonist Scanning

    PubMed Central

    Lee, Mei Yan; Diamond, Scott L.

    2015-01-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  3. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    PubMed Central

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor. Abbreviation: AEA arylethanolamine AII 2-(arylimino)imidazolidine AIO 2-(arylimino)oxazolidine AIT 2-(arylimino)thiazolidine APAT 2-(α-phenylethylamino)-2-thiazoline BPAT 2-(β-phenylethylamino)-2-thiazoline CAO 2-(3-chlorobenzylamino)-2-oxazoline DCAO 2-(3,5-dichlorobenzylamino)-2-oxazoline DET5 2-(2,6-diethylphenylimino)-5-methylthiazolidine DET6 2-(2,6-diethylphenylimino)thiazine EGTA ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid GFA genetic function approximation G/PLS genetic partial least squares IND 2-aminomethyl-2-indanol LAH lithium aluminum hydride MCSG maximum common subgroup MCT6 2-(2-methyl-4-chlorophenylimino)thiazine OA octopamine PLS partial least squares QSAR quantitative structure-activity relationship SBAT 2-(substituted benzylamino)-2-thiazoline SD the sum of squared deviations of the dependent variable values from their mean SPIT 3-(substituted phenyl)imidazolidine-2-thione THI 2-amino-1-(2-thiazoyl)ethanol TMS tetramethyl silane PMID:15841226

  4. A human platelet calcium calculator trained by pairwise agonist scanning.

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  5. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K.

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  6. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    PubMed

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline. PMID:20030735

  7. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    PubMed Central

    Keane, Fergus; Navin, Patrick; Brett, Francesca; Dennedy, Michael C

    2016-01-01

    Summary Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH) agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour. Learning points While non-functioning gonadotropinomas represent the most common form of pituitary macroadenoma, functioning gonadotropinomas are exceedingly rare. Acute tumour enlargement, with potential pituitary apoplexy, is a rare but important adverse effect arising from GNRH agonist therapy in the presence of both functioning and non-functioning pituitary gonadotropinomas. GNRH antagonist therapy represents an alternative treatment option for patients with hormonal therapy-requiring prostate cancer, who also have diagnosed with a pituitary gonadotropinoma. PMID:27284452

  8. Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1.

    PubMed

    Aliouane, Lucie; Chao, Sovy; Brizuela, Leyre; Pfund, Emmanuel; Cuvillier, Olivier; Jean, Ludovic; Renard, Pierre-Yves; Lequeux, Thierry

    2014-09-01

    The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported. PMID:25047939

  9. Newspapers and newspaper ink contain agonists for the ah receptor.

    PubMed

    Bohonowych, Jessica E S; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T; Denison, Michael S

    2008-04-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [(3)H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  10. Covalent agonists for studying G protein-coupled receptor activation

    PubMed Central

    Weichert, Dietmar; Kruse, Andrew C.; Manglik, Aashish; Hiller, Christine; Zhang, Cheng; Hübner, Harald; Kobilka, Brian K.; Gmeiner, Peter

    2014-01-01

    Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating Gs-, Gi-, and Gq-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β2-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis. PMID:25006259

  11. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    PubMed

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes. PMID:24038158

  12. Biased signaling: potential agonist and antagonist of PAR2.

    PubMed

    Kakarala, Kavita Kumari; Jamil, Kaiser

    2016-06-01

    Protease activated receptor 2 (PAR2) has emerged as one of the promising therapeutic targets to inhibit rapidly metastasizing breast cancer cells. However, its elusive molecular mechanism of activation and signaling has made it a difficult target for drug development. In this study, in silico methods were used to unfold PAR2 molecular mechanism of signaling based on the concept of GPCR receptor plasticity. Although, there are no conclusive evidences of the presence of specific endogenous ligands for PAR2, the efficacy of synthetic agonist and antagonist in PAR2 signaling has opened up the possibilities of ligand-mediated signaling. Furthermore, it has been proved that ligands specific for one GPCR can induce signaling in GPCRs belonging to other subfamilies. Therefore, the aim of this study was to identify potential agonists and antagonists from the GPCR ligand library (GLL), which may induce biased signaling in PAR2 using the concept of existence of multiple ligand-stabilized receptor conformations. The results of our in silico study suggest that PAR2 may show biased signaling mainly with agonists of serotonin type 1, β-adrenergic type 1,3 and antagonists of substance K (NK1), serotonin type 2, dopamine type 4, and thromboxane receptors. Further, this study also throws light on the putative ligand-specific conformations of PAR2. Thus, the results of this study provide structural insights to putative conformations of PAR2 and also gives initial clues to medicinal chemists for rational drug design targeting this challenging receptor. PMID:26295578

  13. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    PubMed

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  14. Cryptochinones from Cryptocarya chinensis act as farnesoid X receptor agonists.

    PubMed

    Lin, Hsiang-Ru; Chou, Tsung-Hsien; Huang, Din-Wen; Chen, Ih-Sheng

    2014-09-01

    Cryptochinones A-D are tetrahydroflavanones isolated from the leaves of Cryptocarya chinensis, an evergreen tree whose extracts are believed to have a variety of health benefits. The origin of their possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and for hyperglycemia. We studied whether cryptochinones A-D, which are structurally similar to known FXR ligands, may act at this target. Indeed, in mammalian one-hybrid and transient transfection reporter assays, cryptochinones A-D transactivated FXR to modulate promoter action including GAL4, SHP, CYP7A1, and PLTP promoters in dose-dependent manner, while they exhibited similar agonistic activity as chenodeoxycholic acid (CDCA), an endogenous FXR agonist. Through molecular modeling docking studies we evaluated their ability to bind to the FXR ligand binding pocket. Our results indicate that cryptochinones A-D can behave as FXR agonists. PMID:25127166

  15. Dopamine-deficient mice are hypersensitive to dopamine receptor agonists.

    PubMed

    Kim, D S; Szczypka, M S; Palmiter, R D

    2000-06-15

    Dopamine-deficient (DA-/-) mice were created by targeted inactivation of the tyrosine hydroxylase gene in dopaminergic neurons. The locomotor activity response of these mutants to dopamine D1 or D2 receptor agonists and l-3,4-dihydroxyphenylalanine (l-DOPA) was 3- to 13-fold greater than the response elicited from wild-type mice. The enhanced sensitivity of DA-/- mice to agonists was independent of changes in steady-state levels of dopamine receptors and the presynaptic dopamine transporter as measured by ligand binding. The acute behavioral response of DA-/- mice to a dopamine D1 receptor agonist was correlated with c-fos induction in the striatum, a brain nucleus that receives dense dopaminergic input. Chronic replacement of dopamine to DA-/- mice by repeated l-DOPA administration over 4 d relieved the hypersensitivity of DA-/- mutants in terms of induction of both locomotion and striatal c-fos expression. The results suggest that the chronic presence of dopaminergic neurotransmission is required to dampen the intracellular signaling response of striatal neurons. PMID:10844009

  16. Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer

    PubMed Central

    Shukla, Nikunj M.; Salunke, Deepak B.; Balakrishna, Rajalakshmi; Mutz, Cole A.; Malladi, Subbalakshmi S.; David, Sunil A.

    2012-01-01

    Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen. PMID:22952720

  17. Emerging strategies for exploiting cannabinoid receptor agonists as medicines

    PubMed Central

    Pertwee, Roger G

    2009-01-01

    Medicines that activate cannabinoid CB1 and CB2 receptor are already in the clinic. These are Cesamet® (nabilone), Marinol® (dronabinol; Δ9-tetrahydrocannabinol) and Sativex® (Δ9-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol® can also be prescribed to stimulate appetite, while Sativex® is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB2 receptors; or (v) ‘multi-targeting’. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  18. Highly selective agonists for substance P receptor subtypes.

    PubMed Central

    Wormser, U; Laufer, R; Hart, Y; Chorev, M; Gilon, C; Selinger, Z

    1986-01-01

    The existence of a third tachykinin receptor (SP-N) in the mammalian nervous system was demonstrated by development of highly selective agonists. Systematic N-methylation of individual peptide bonds in the C-terminal hexapeptide of substance P gave rise to agonists which specifically act on different receptor subtypes. The most selective analog of this series, succinyl-[Asp6,Me-Phe8]SP6-11, elicits half-maximal contraction of the guinea pig ileum through the neuronal SP-N receptor at a concentration of 0.5 nM. At least 60,000-fold higher concentrations of this peptide are required to stimulate the other two tachykinin receptors (SP-P and SP-E). The action of selective SP-N agonists in the guinea pig ileum is antagonized by opioid peptides, suggesting a functional counteraction between opiate and SP-N receptors. These results indicate that the tachykinin receptors are distinct entities which may mediate different physiological functions. PMID:2431898

  19. Suppression of atherosclerosis by synthetic REV-ERB agonist

    SciTech Connect

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  20. Development of specific dopamine D-1 agonists and antagonists

    SciTech Connect

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo(a,d)cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo(1,2)cyclohepta(3,4,5d,e)isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC{sub 50} of compound 11 for displacement of {sup 3}H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of {sup 3}H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor.

  1. Comparison of COSMIC RO Data with European Digisondes and GPS TEC measurements

    NASA Astrophysics Data System (ADS)

    Zakharenkova, Irina; Krypiak-Gregorczyk, Anna; Shagimuratov, Irk; Krankowski, Andrzej; Lagovsky, Anatoly

    FormoSat-3/COSMIC now provides unprecedented global coverage of GPS occultations mea-surements, each of which yields the ionosphere electron density information with high vertical resolution. However systematic validation work is still needed before using the powerful RO technique for sounding the ionosphere on a routine basis. In the given study electron density profiles retrieved from the Formosat-3/COSMIC RO measurements were compared with differ-ent kinds of ground-based observations. We used the ionospheric data recorded by European digisondes of DIAS network (Rome, Ebro, Arenosillo, Athens, Chilton, Pruhonice and Julius-ruh) for temporal interval of 2007-2009 and compare these ground measured data with the GPS COSMIC RO ionospheric profiles. It was revealed that in general the form of COSMIC profile in the bottom side is in a good agreement with ionosonde profiles, the heights of the peak density value are also good comparable. Special attention was focused to the question of the topside part of electron density profile. Practically for all analyzed cases there are observed the understated values of electron density in the topside part of the ionosonde profiles in compare with RO profiles. As the topside ionosonde profile is obtained by fitting a model to the peak electron density value, the COSMIC radio occultation measurements can make an important contribution to the investigation of the topside part of the ionosphere. In order to assess the ac-curacy of the COSMIC ionospheric electron density retrievals, coincidences of ionosonde data with COSMIC NmF2 values have been examined. NmF2 was calculated from the observed critical plasma frequency foF2 of the F2 layer. Values of foF2 have been scaled manually from ionograms for all considered time-location cases to avoid the evident risks related with using of the autoscaled data. The created scatter plots show a high degree of correlation between two independent estimates of NmF2. Also it was analyzed the

  2. CoRoT-7b: Convection in a Tidally Locked Planet

    NASA Astrophysics Data System (ADS)

    Noack, Lena; Stamenkovic, Vlada; Wagner, Frank W.; Sohl, Frank; Breuer, Doris

    2010-05-01

    The number of terrestrial extrasolar planets found in the past few years is increasing rapidly. Some have masses ranging from 2 to 10 Earth masses, and the habitability of these planets is widely discussed in the planetary community. Due to observational limitations we will mostly be able to observe planets that are very close to its host star, resulting in a potentially tidally locked orbit. Our goal is to investigate if such planets can be habitable at all. But to do so, we first have to understand the convection behaviour of such planets. In this work we model the mantle convection of the recently discovered exoplanet CoRoT-7b [1], which is a planet believed to be tidally locked. The extreme intense insolation in the vicinity of its host star heats the day-side of CoRoT-7b, leading to surface temperatures about 2000 Kelvin higher than on the night-side [1]. CoRoT-7b is about 5 times more massive than the Earth and predominantly composed of dry silicate rock similar to Earth's Moon. A central iron core, if present, would be relatively small [2] with a core mass fraction of no more than 15 wt%. The mantle convection is modelled in a spherical shell [3] using a temperature- and pressure-dependent viscosity. We use a radioactive heat source density similar to present Earth. Coriolis forces are neglected and we assume that CoRoT-7b has no atmosphere. The results show that the lower mantle above the core-mantle boundary is in a more sluggish convection regime as a consequence of the viscosity increase with pressure. Depending on the strength of the viscosity increase, even a so-called low-lid [4] can form and conductive heat transport dominates from the core to the upper part of the mantle. The thermal state of such a deeply situated, conductive lower mantle of CoRoT-7b is not much influenced by the strongly laterally varying surface temperature. However, the temperatures of the upper convecting mantle are found to strongly vary from one side of the planet to the

  3. Nutrient removal by NF and RO membranes in a decentralized sanitation system.

    PubMed

    van Voorthuizen, Ellen M; Zwijnenburg, Arie; Wessling, Matthias

    2005-09-01

    Decentralized treatment of domestic wastewater offers the possibility of water and nutrient reuse. In a decentralized sanitation system the household wastewater streams are separated in a large diluted stream (gray water) and a small and concentrated stream (black water) containing important nutrients like ammonium and phosphate. Nanofiltration (NF) and reverse osmosis (RO) membranes might be used to recover the nutrients from anaerobically treated black water. The permeate might be used in a water reuse scheme. In case of water reuse the produced permeate should meet guidelines for potable water or meet new guidelines which might be applied in the future for intermediate quality of water, for example toilet flushwater; when this is not possible the permeate should meet guidelines for discharge. The most stringent guidelines apply for ammonium and phosphate. The focus of this paper is to test commercially available NF and RO membranes to remove nutrients from anaerobically treated black water in order to meet the Dutch guidelines. A large number of commercial tubular, capillary and flat sheet NF and RO membranes was tested on laboratory scale on their performance to meet the Dutch guidelines for ammonium and phosphate. The ammonium and phosphate concentrations used were based on the effluent composition of anaerobically treated black water. Ammonium and phosphate rejection were both measured in synthetic single salt and multi-ion mixtures and in anaerobic effluent. The rejection for ammonium (30-95%) is neither sufficient for discharge nor potable water use. The rejection of phosphate (74-99%) is in most cases almost sufficient to meet the standards for potable water. PMID:16054670

  4. Characteristics of atmospheric Kelvin waves during warm and cold ENSO phases observed with GPS RO

    NASA Astrophysics Data System (ADS)

    Scherllin-Pirscher, Barbara; Ladstädter, Florian; Steiner, Andrea; Kirchengast, Gottfried

    2015-04-01

    Inter-annual variability in the Earth's troposphere at low and middle latitudes is dominated by the El Niño-Southern Oscillation (ENSO) phenomenon. While ENSO emerges from an atmosphere-ocean interaction in the tropical Pacific, it has a significant impact on global weather and climate. Atmospheric wave dynamics plays a crucial role in this context. However, current understanding of this wave dynamics is mostly based on climate model output and reanalysis data. We use observational data from Global Positioning System (GPS) radio occultation (RO) measurements to investigate characteristics of atmospheric Kelvin waves during warm and cold ENSO phases. Due to their high accuracy and vertical resolution, RO data provide reliable and valuable information on wave-induced temperature oscillations with short vertical wavelengths of a few kilometers. After the launch of the six micro-satellites of the Formosat-3/COSMIC mission in April 2006, the number of RO measurements per day increased significantly compared to earlier time periods. With an appropriate binning strategy, the sampling is therefore sufficiently dense from mid-2006 onwards in order to capture the main characteristics of large-scale atmospheric waves. Frequencies and wavelengths of atmospheric Kelvin waves are extracted from space-time spectral analysis for overlapping 60-day time series centered on each month. In this study we focus on the northern hemisphere winter season DJF (December, January, February) using data from DJF 2006/07 to DJF 2011/12. Comparative results are presented for warm ENSO phases, which occurred in DJF 2006/07 and DJF 2009/10, and for cold ENSO phases in DJF 2007/08, DJF 2010/11, and DJF 2011/12.

  5. New RoF-PON architecture using polarization multiplexed wireless MIMO signals for NG-PON

    NASA Astrophysics Data System (ADS)

    Elmagzoub, M. A.; Mohammad, Abu Bakar; Shaddad, Redhwan Q.; Al-Gailani, Samir A.

    2015-06-01

    Next-generation access networks require provision of wireless services and high data rate to meet the huge demands for mobility and multiple services. Moreover, reusing the currently deployed optical distribution networks (ODNs) is highly beneficial and cost effective for providing the new high data rate wireless demands. In this paper, bidirectional radio over fiber passive optical network (RoF-PON) capable of handling multiple-input-multiple-output (MIMO) streams at low cost, high spectral efficiency and backward compatibility with currently deployed PON, is proposed. To the best of our knowledge, all the existing RoF MIMO solutions have not considered compatibility with currently deployed ODNs. Eight laser diodes (LDs) at the central office (CO) are enough for the whole system, instead of having LD or optical transmitter at each remote antenna unit (RAU), which makes a colorless and cost-effective RAU. Twenty four wavelengths are generated using optical comb technique. Each two 16-QAM MIMO signals that have the same carrier frequency in the downstream (DS) transmission are optically combined using polarization-division-multiplexing (PDM), where each two upstream (US) MIMO signals are time division multiplexed. The PDM configuration doubles spectral efficiency with a power penalty of only 1.5 dB. The proposed architecture is a bidirectional asymmetric RoF-PON with total 40/10 Gb/s for DS/US transmission. Even after transmission over 20 km SMF and splitting ratio of 32, acceptable transmission performance and widely separated constellation diagrams for the 16-QAM signals are achieved, with bit error rate (BER) of 10-6 for DS signals and 10-3 for the US signals which can be reduced down to 10-6 by using forward error correction (FEC).

  6. Variability in the CO ro-vibrational lines from HD163296

    NASA Astrophysics Data System (ADS)

    Hein Bertelsen, Rosina P.; Kamp, I.; van der Plas, G.; van den Ancker, M. E.; Waters, L. B. F. M.; Thi, W.-F.; Woitke, P.

    2016-05-01

    We present for the first time a direct comparison of multi-epoch (2001-2002 and 2012) CO ro-vibrational emission lines from HD 163296. We find that both the line shapes and the FWHM (full width at half-maximum) differ between these two epochs. The FWHM of the median observed line profiles are 10-25 km s-1 larger in the earlier epoch, and confirmed double peaks are only present in high J lines from 2001 to 2002. The line wings of individual transitions are similar in the two epochs making an additional central component in the later epoch a likely explanation for the single peaks and the lower FWHM. Variations in near-infrared brightness have been reported and could be linked to the observed variations. Additionally, we use the thermo-chemical disc code PRODIMO to compare for the first time the line shapes, peak separations, FWHM, and line fluxes, to those observed. The PRODIMO model reproduces the peak separations, and low and mid J line fluxes well. The FWHM however, are overpredicted and high J line fluxes are underpredicted. We propose that a variable non-Keplerian component of the CO ro-vibrational emission, such as a disc wind or an episodic accretion funnel, is causing the difference between the two data sets collected at different epochs, and between model and observations. Additional CO ro-vibrational line detections (with cryogenic high-resolution infrared echelle spectrograph/Very Large Telescope (VLT) or Near InfraRed SPECtrometer/Keck) or [Ne II] line observations with VLT Imager and Spectrometer for mid Infrared/VLT could help to clarify the cause of the variability.

  7. Animal pharmacokinetics and metabolism of the new antimalarial Ro 42-1611 (arteflene).

    PubMed

    Girometta, M A; Jauch, R; Ponelle, C; Guenzi, A; Wiegand-Chou, R C

    1994-09-01

    Ro 42-1611 (arteflene) is a new synthetic structural analogue of yingzhaosu, a Chinese traditional herbal drug, now under development for treatment of malaria. The in vivo activity of arteflene in a mouse animal model was 4-5 fold higher after parenteral than after oral administration. Pharmacokinetics of the drug were investigated in mice, rats, dogs, marmosets and cynomolgus monkeys. Plasma concentrations of arteflene were determined using a specific HPLC-UV method; the limit of quantification was 45 ng/ml using 0.5 ml plasma. The oral bioavailability was very low and variable (0.6% in mice, 4-5% in rats, 2.5 +/- 1% in dogs, < or = 0.5% in marmosets and < 0.5% in cynomolgus) as expected from the high metabolic clearance and the relative short apparent half-life (1.4-4.7 h). However, a metabolite (MA) was observed in plasma of all species indicating that drug was absorbed but underwent extensive first-pass metabolism. MA was also detected in samples of human plasma, collected during an oral tolerability study in healthy volunteers. After incubation of 14C-arteflene with liver microsomes of mice, rats, dogs and humans, the same major metabolite was detected and both samples were identical to Ro 47-6936 which was chemically synthesized as a reference compound. The in vitro activity of Ro 47-6936 was tested against Plasmodium falciparum and found to be about 1/4 that of the parent drug. Therefore, this metabolite makes a significant contribution to the biological activity in vivo, partially explaining the high activity of arteflene after oral administration in spite of its low bioavailability. Moreover, comparison of the metabolic patterns from human, rat and dog microsomes indicated that the dog is an appropriate species for toxicological evaluations. PMID:7899803

  8. 2-Triazole-Substituted Adenosines: A New Class of Selective A3 Adenosine Receptor Agonists, Partial Agonists, and Antagonists

    PubMed Central

    Cosyn, Liesbet; Palaniappan, Krishnan K.; Kim, Soo-Kyung; Duong, Heng T.; Gao, Zhan-Guo; Jacobson, Kenneth A.; Van Calenbergh, Serge

    2016-01-01

    “Click chemistry” was explored to synthesize two series of 2-(1,2,3-triazolyl)adenosine derivatives (1–14). Binding affinity at the human A1, A2A, and A3ARs (adenosine receptors) and relative efficacy at the A3AR were determined. Some triazol-1-yl analogues showed A3AR affinity in the low nanomolar range, a high ratio of A3/A2A selectivity, and a moderate-to-high A3/A1 ratio. The 1,2,3-triazol-4-yl regiomers typically showed decreased A3AR affinity. Sterically demanding groups at the adenine C2 position tended to reduce relative A3AR efficacy. Thus, several 5′-OH derivatives appeared to be selective A3AR antagonists, i.e., 10, with 260-fold binding selectivity in comparison to the A1AR and displaying a characteristic docking mode in an A3AR model. The corresponding 5′-ethyluronamide analogues generally showed increased A3AR affinity and behaved as full agonists, i.e., 17, with 910-fold A3/A1 selectivity. Thus, N6-substituted 2-(1,2,3-triazolyl)-adenosine analogues constitute a novel class of highly potent and selective nucleoside-based A3AR antagonists, partial agonists, and agonists. PMID:17149867

  9. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR.

    PubMed

    Huang, Wendong; Zhang, Jun; Wei, Ping; Schrader, William T; Moore, David D

    2004-10-01

    The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans. PMID:15272053

  10. Rotation period distribution of CoRoT and Kepler Sun-like stars

    NASA Astrophysics Data System (ADS)

    Leão, I. C.; Pasquini, L.; Ferreira Lopes, C. E.; Neves, V.; Valcarce, A. A. R.; de Oliveira, L. L. A.; Freire da Silva, D.; de Freitas, D. B.; Canto Martins, B. L.; Janot-Pacheco, E.; Baglin, A.; De Medeiros, J. R.

    2015-10-01

    Aims: We study the distribution of the photometric rotation period (Prot), which is a direct measurement of the surface rotation at active latitudes, for three subsamples of Sun-like stars: one from CoRoT data and two from Kepler data. For this purpose, we identify the main populations of these samples and interpret their main biases specifically for a comparison with the solar Prot. Methods: Prot and variability amplitude (A) measurements were obtained from public CoRoT and Kepler catalogs, which were combined with public data of physical parameters. Because these samples are subject to selection effects, we computed synthetic samples with simulated biases to compare with observations, particularly around the location of the Sun in the Hertzsprung-Russel (HR) diagram. Publicly available theoretical grids and empirical relations were used to combine physical parameters with Prot and A. Biases were simulated by performing cutoffs on the physical and rotational parameters in the same way as in each observed sample. A crucial cutoff is related with the detectability of the rotational modulation, which strongly depends on A. Results: The synthetic samples explain the observed Prot distributions of Sun-like stars as having two main populations: one of young objects (group I, with ages younger than ~1 Gyr) and another of main-sequence and evolved stars (group II, with ages older than ~1 Gyr). The proportions of groups I and II in relation to the total number of stars range within 64-84% and 16-36%, respectively. Hence, young objects abound in the distributions, producing the effect of observing a high number of short periods around the location of the Sun in the HR diagram. Differences in the Prot distributions between the CoRoT and Kepler Sun-like samples may be associated with different Galactic populations. Overall, the synthetic distribution around the solar period agrees with observations, which suggests that the solar rotation is normal with respect to Sun

  11. Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy.

    PubMed

    Zhang, Zhuming; Ding, Qingjie; Liu, Jin-Jun; Zhang, Jing; Jiang, Nan; Chu, Xin-Jie; Bartkovitz, David; Luk, Kin-Chun; Janson, Cheryl; Tovar, Christian; Filipovic, Zoran M; Higgins, Brian; Glenn, Kelli; Packman, Kathryn; Vassilev, Lyubomir T; Graves, Bradford

    2014-08-01

    The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994. PMID:24997575

  12. Molecular line lists: The ro-vibrational spectra of NaF and KF

    NASA Astrophysics Data System (ADS)

    Frohman, Daniel J.; Bernath, Peter F.; Brooke, James S. A.

    2016-01-01

    Rotation-vibration line lists for 23Na19F, 39K19F, and 41K19F in their ground electronic states are presented. Experimental data previously collected for infrared transitions up to v=8 and v=9 for KF [1] and NaF [2], respectively, and for pure rotational transitions have been used to construct potential energy curves to yield ro-vibrational energy levels. Dipole moment functions were generated from ab initio calculations using the SA-CASSCF and ACPF methods. Full line lists and partition functions are made available as supplementary data.

  13. Full-Dimensional Potential Energy Surface and Ro-vibrational Levels of Dioxirane.

    PubMed

    Li, Jun; Guo, Hua

    2016-05-19

    A full-dimensional potential energy surface is developed for dioxirane based on a high-fidelity fit of ∼46,000 ab initio points at the CCSD(T)-F12a/AVTZ level. The ro-vibrational levels of dioxirane were computed using the MULTIMODE method on this potential energy surface, and the agreement with the available experimental microwave spectrum is quite satisfactory. In addition, dipole moment surfaces have been constructed from ab initio data, and they allow the prediction of the infrared (IR) spectrum. PMID:26422048

  14. Asteroid spectroscopy with FoReRo2 at BNAO Rozhen --- first results

    NASA Astrophysics Data System (ADS)

    Vchova Bebekovska, E.; Borisov, G.; Apostolovska, G.; Donchev, Z.

    2014-07-01

    The Bulgarian National Astronomical Observatory (BNAO) in Rozhen (071 Rozhen), with astrometric observations, has been already involved in the Gaia Follow-Up Network for Solar System Objects since the end of 2011. One of our aims is to develop a coordinated program of asteroid spectroscopy complementary to Gaia's observations. In this paper, the first results of asteroid spectroscopy at BNAO Rozhen are presented. In order to contribute to the compositional characterization of the main-belt asteroids, we performed low-dispersion asteroid spectroscopy with 2-Channel-Focal-Reducer Rozhen (FoReRo2) on the 2-m Ritchey-Chrétien-Coudé (RCC) telescope at BNAO. We obtained optical spectra of few MBAs using the 2-m RCC telescope equiped with the CCD VarsArray 1300B camera (pixel size 20 μ m or 0.736 arcsec/px) in the spectroscopic mode of FoReRo2 in its red channel [1]. The spectroscopic characteristics are: a low-dispersion grism Bausch & Lomb, working in the parallel beam of FoReRo2, with 300 lines/mm which gives 4.3 Å/px and 200 μ m width slit which corresponds to 2.6 arcsec. We determined spectral types of the asteroids [2] by the overall shapes of the spectra between 440 nm and 830 nm. For spectral analysis in our work, we use the public software tool M4AST [3]. It covers aspects related to taxonomy, curve matching with laboratory spectra, space weathering models, and mineralogical diagnosis. Most of the observed asteroids belong to some families and there are no published spectra. Besides their spectra, for some asteroids, best matches derived from a comparison with laboratory spectra are presented. We are planning to use a polarimetric mode of FoReRo2 and a Wollaston prism in order for the results to be confirmed by obtaining the degree of linear polarization around asteroid phase angles of 10° --- around the minimum of polarization in the phase curve, where the deviation for different taxonomic classes is best resolvable.

  15. Metabolism and pharmacokinetics of JM6 in mice: JM6 is not a prodrug for Ro-61-8048.

    PubMed

    Beconi, Maria G; Yates, Dawn; Lyons, Kathryn; Matthews, Kim; Clifton, Steve; Mead, Tania; Prime, Michael; Winkler, Dirk; O'Connell, Catherine; Walter, Daryl; Toledo-Sherman, Leticia; Munoz-Sanjuan, Ignacio; Dominguez, Celia

    2012-12-01

    Understanding whether regulation of tryptophan metabolites can ameliorate neurodegeneration is of high interest to investigators. A recent publication describes 3,4-dimethoxy-N-(4-(3-nitrophenyl)-5-(piperidin-1-ylmethyl)thiazol-2-yl)benzenesulfonamide (JM6) as a novel prodrug for the kynurenine 3-monooxygenase (KMO) inhibitor 3,4-dimethoxy-N-(4-(3-nitrophenyl)thiazol-2-yl)benzenesulfonamide (Ro-61-8048) that elicits therapeutic effects in mouse models of Huntington's and Alzheimer's diseases (Cell 145:863-874, 2011). Our evaluation of the metabolism and pharmacokinetics of JM6 and Ro-61-8048 indicate instead that Ro-61-8048 concentrations in mouse plasma after JM6 administration originate from a Ro-61-8048 impurity (<0.1%) in JM6. After a 0.05 mg/kg Ro-61-8048 oral dose alone or coadministered with 10 mg/kg JM6 to mice, the Ro-61-8048 areas under the concentration-time curves (AUCs) from 0 to infinity were similar (4300 and 4900 nM × h, respectively), indicating no detectable contributions of JM6 metabolism to the Ro-61-8048 AUCs. JM6 was stable in incubations under acidic conditions and Ro-61-8048 was not a product of JM6 metabolism in vitro (plasma, blood, or hepatic models). Species differences in the quantitative rate of oxidative metabolism indicate that major circulating JM6 metabolite(s) in mice are unlikely to be major in humans: JM6 is rapidly metabolized via the piperidyl moiety in mouse (forming an iminium ion reactive intermediate) but is slowly metabolized in human (in vitro), primarily via O-dealkylation at the phenyl ring. Our data indicate that JM6 is not a prodrug for Ro-61-8048 and is not a potent KMO inhibitor. PMID:22942319

  16. Non-coding roX RNAs prevent the binding of the MSL-complex to heterochromatic regions.

    PubMed

    Figueiredo, Margarida L A; Kim, Maria; Philip, Philge; Allgardsson, Anders; Stenberg, Per; Larsson, Jan

    2014-12-01

    Long non-coding RNAs contribute to dosage compensation in both mammals and Drosophila by inducing changes in the chromatin structure of the X-chromosome. In Drosophila melanogaster, roX1 and roX2 are long non-coding RNAs that together with proteins form the male-specific lethal (MSL) complex, which coats the entire male X-chromosome and mediates dosage compensation by increasing its transcriptional output. Studies on polytene chromosomes have demonstrated that when both roX1 and roX2 are absent, the MSL-complex becomes less abundant on the male X-chromosome and is relocated to the chromocenter and the 4th chromosome. Here we address the role of roX RNAs in MSL-complex targeting and the evolution of dosage compensation in Drosophila. We performed ChIP-seq experiments which showed that MSL-complex recruitment to high affinity sites (HAS) on the X-chromosome is independent of roX and that the HAS sequence motif is conserved in D. simulans. Additionally, a complete and enzymatically active MSL-complex is recruited to six specific genes on the 4th chromosome. Interestingly, our sequence analysis showed that in the absence of roX RNAs, the MSL-complex has an affinity for regions enriched in Hoppel transposable elements and repeats in general. We hypothesize that roX mutants reveal the ancient targeting of the MSL-complex and propose that the role of roX RNAs is to prevent the binding of the MSL-complex to heterochromatin. PMID:25501352

  17. Different serotonin receptor agonists have distinct effects on sound-evoked responses in inferior colliculus.

    PubMed

    Hurley, Laura M

    2006-11-01

    The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing. PMID:16870843

  18. Understanding nuclear motions in molecules: Derivation of Eckart frame ro-vibrational Hamiltonian operators via a gateway Hamiltonian operator

    SciTech Connect

    Szalay, Viktor

    2015-05-07

    A new ro-vibrational Hamiltonian operator, named gateway Hamiltonian operator, with exact kinetic energy term, T-hat, is presented. It is in the Eckart frame and it is of the same form as Watson’s normal coordinate Hamiltonian. However, the vibrational coordinates employed are not normal coordinates. The new Hamiltonian is shown to provide easy access to Eckart frame ro-vibrational Hamiltonians with exact T-hat given in terms of any desired set of vibrational coordinates. A general expression of the Eckart frame ro-vibrational Hamiltonian operator is given and some of its properties are discussed.

  19. VizieR Online Data Catalog: Planetary transit candidates in CoRoT LRa01 field (Carone+, 2012)

    NASA Astrophysics Data System (ADS)

    Carone, L.; Gandolfi, D.; Cabrera, J.; Hatzes, A. P.; Deeg, H. J.; Csizmadia, Sz.; Paetzold, M.; Weingrill, J.; Aigrain, S.; Alonso, R.; Alapini, A.; Almenara, J.-M.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Borde, P.; Bouchy, F.; Bruntt, H.; Carpano, S.; Cochran, W. D.; Deleuil, M.; Diaz, R. F.; Dreizler, S.; Dvorak, R.; Eisloeffel, J.; Eigmueller, P.; Endl, M.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Gazzano, J.-C.; Gibson, N.; Gillon, M.; Gondoin, P.; Grziwa, S.; Guenther, E. W.; Guillot, T.; Hartmann, M.; Havel, M.; Hebrard, G.; Jorda, L.; Kabath, P.; Leger, A.; Llebaria, A.; Lammer, H.; Lovis, C.; MacQueen, P. J.; Mayor, M.; Mazeh, T.; Moutou, C.; Nortmann, L.; Ofir, A.; Ollivier, M.; Parviainen, H.; Pepe, F.; Pont, F.; Queloz, D.; Rabus, M.; Rauer, H.; Regulo, C.; Renner, S.; de La, Reza R.; Rouan, D.; Santerne, A.; Samuel, B.; Schneider, J.; Shporer, A.; Stecklum, B.; Tal-Or, L.; Tingley, B.; Udry, S.; Wuchterl, G.

    2012-04-01

    We present the list of planetary transit candidates from the CoRoT LRa01 star field in the Monoceros constellation toward the Galactic anti-center direction. The CoRoT observations of LRa01 lasted from 24 October 2007 to 3 March 2008. We acquired and analyzed 7470 chromatic and 3938 monochromatic lightcurves. Instrumental noise and stellar variability were treated with several filtering tools by different teams from the CoRoT community. Different transit search algorithms were applied to the lightcurves. (4 data files).

  20. Arrachements des épines iliaques antéro-supérieures et antéro-inférieures chez l'adolescent sportifs: à propos de deux cas

    PubMed Central

    Louaste, Jamal; Cherrad, Taoufik; Rachid, Khalid

    2015-01-01

    Les arrachements des épines iliaques antéro-supérieures et antéro-inférieures sont des entités rares qui touchent surtout l'enfant et l'adolescent. Elles se voient généralement lors d'une activité sportive. Le tableau clinique est dominé par une douleur brutale et importante de la hanche de type mécanique. Alors que le diagnostic est confirmé par les examens radiologiques. Nous rapportons deux cas de fractures arrachement des épines iliaques l'une antéro-supérieure et l'autre antéro-inférieure. PMID:26985274

  1. Dramatic improvement of anti-SS-A/Ro-associated interstitial lung disease after immunosuppressive treatment.

    PubMed

    Paola, Caramaschi; Giuliana, Festi; Giovanni, Orsolini; Cristian, Caimmi; Domenico, Biasi

    2016-07-01

    The aim of the study was to report three patients affected by interstitial lung disease associated with positive anti-SS-A/Ro autoantibody who showed a dramatic improvement after immunosuppressive treatment. Medical charts were reviewed to obtain clinical data, laboratory parameters, lung function tests, high-resolution computed tomography results and response to immunosuppressive treatment. The three patients showed a clinical picture of a lung-dominant connective tissue disease characterized by a sudden onset with dyspnea, cough and subtle extrathoracic features together with positive anti-SS-A/Ro antibody and weak titer antinuclear antibodies. All three patients responded favorably to immunosuppressive therapy: Two cases were treated with a combination of corticosteroid and cyclophosphamide followed by mycophenolate mofetil; in the third patient, clinical benefit was obtained after rituximab was added to corticosteroid and immunosuppressant drug. In spite of an abrupt onset with significant lung function impairment, all three patients had a favorable clinical response to immunosuppressive therapy. This report may be useful in making therapeutic decisions in case of interstitial lung disease associated with anti-SS-A antibody. PMID:27021338

  2. New light on the driving mechanism in roAp stars. I. Effects of metallicity

    NASA Astrophysics Data System (ADS)

    Théado, S.; Dupret, M.-A.; Noels, A.; Ferguson, J. W.

    2009-01-01

    Context: Observations suggest that a relationship exists between the driving mechanism of roAp star pulsations and the heavy element distribution in these stars. Aims: We attempt to study the effects of local and global metallicity variations on the excitation mechanism of high order p-modes in A star models. Methods: We developed stellar evolutionary models to describe magnetic A stars with different global metallicity or local metal accumulation profiles. These models were computed with CLES (“Code Liègeois d'évolution stellaire”), and the stability of our models was assessed with the non-adiabatic oscillation code MAD. Results: Our models reproduce the blue edge of the roAp star instability strip, but generate a red edge hotter than the observed one, regardless of metallicity. Surprisingly, we find that an increase in opacity inside the driving region can produce a lower amount of driving, which we refer to as the “inverse κ-mechanism”.

  3. RO concentrate minimization by electrodialysis: techno-economic analysis and environmental concerns.

    PubMed

    Zhang, Yang; Ghyselbrecht, Karel; Vanherpe, Ruben; Meesschaert, Boudewijn; Pinoy, Luc; Van der Bruggen, Bart

    2012-09-30

    This paper presents a systematic techno-economical analysis and an environmental impact evaluation of a reverse osmosis (RO) concentrate treatment process using electrodialysis (ED) in view of environmental management of brine discharges. The concentrate originates from a secondary effluent treated by RO. Without any treatment, the concentrate would have to be discharged; this is compared in this study to the costs and benefits of an effective treatment method in a pilot scale ED plant. A technical analysis was done both on lab scale and pilot scale for the determination of operational and maintenance costs for the ED installation at the required conditions of process performance and safety. Subsequently, an economical analysis was done to calculate the cost of the different parts of the ED system. It was shown that an operational cost of 0.19 EUR m(-3) can be achieved, assuming that the ED concentrate is to decarbonated at pH 6.0 to prevent membrane scaling. Finally, environmental impact issues were calculated and discussed for the overall system. Results imply that if renewable energy is applied for the ED power source, CO(2) emission from membrane processes can be much less than from the conventional treatment methods. PMID:22579771

  4. Novel cost-effective PON-to-RoF photonic bridge for multigigabit access networks.

    PubMed

    Aldaya, Ivan; Campuzano, Gabriel; Castañón, Gerardo; Gosset, Christophe

    2013-12-30

    Telecommunication operators are investing significant resources in developing passive optical networks (PONs) to meet the increasing capacity requirements. Therefore, wireless transmission has become the bottleneck for the wireless broadband internet access due to the spectrum saturation. This issue can be solved taking advantage of the huge portions of unused spectrum at high-microwave / millimeter-wave (mm-wave) bands, but their generation is power consuming. Radio over fiber (RoF) is a cost-efficient solution for the distribution of high-frequency broadband signals to remote base stations. We present a novel photonic PON-to-RoF bridge based on heterodyning a PON signal with an unmodulated tone generated by an independent laser. The proposed scheme is transparent to modulation format and can generate RF signals in the entire microwave band. The feasibility of the bridge is experimentally shown converting a 2-Gbps orthogonal frequency division multiplexing PON signal using inexepensive distributed feedback lasers, whose phase noise is cancelled employing an envelope detection based mobile terminal. PMID:24514776

  5. Ab initio ro-vibronic spectroscopy of SiCCl (X{sup ~2}Π)

    SciTech Connect

    Brites, Vincent; Mitrushchenkov, Alexander O.; Léonard, Céline; Peterson, Kirk A.

    2014-07-21

    The full dimensional potential energy surfaces of the {sup 2}A{sup ′} and {sup 2}A{sup ′′} electronic components of X{sup ~2}Π SiCCl have been computed using the explicitly correlated coupled cluster method, UCCSD(T)-F12b, combined with a composite approach taking into account basis set incompleteness, core-valence correlation, scalar relativity, and higher order excitations. The spin-orbit and dipole moment surfaces have also been computed ab initio. The ro-vibronic energy levels and absorption spectrum at 5 K have been determined from variational calculations. The influence of each correction on the fundamental frequencies is discussed. An assignment is proposed for bands observed in the LIF experiment of Smith et al. [J. Chem. Phys. 117, 6446 (2002)]. The overall agreement between the experimental and calculated ro-vibronic levels is better than 7 cm{sup −1} which is comparable with the 10–20 cm{sup −1} resolution of the emission spectrum.

  6. Accuracy Assessments of ATMS Upper-Level Temperature Sounding Channels Using COSMIC RO Data

    NASA Astrophysics Data System (ADS)

    Lin, L.; Weng, F.; Zou, X.

    2012-12-01

    The Advanced Technology Microwave Sounder (ATMS) on board Suomi National Polar-orbiting Partnership (NPP) is a 22-channel passive microwave radiometer that can provide high-spatial-resolution data for generating temperature and moisture soundings in cloudy conditions. Global Positioning System (GPS) radio occultation (RO) data have high vertical resolution, are not affected by clouds, and are most accurate from 8 to 30 km, making them ideally suited for estimating the precision of ATMS measurements for upper level temperature sounding channels. In this study, Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC) RO data are collocated with ATMS observation from December 10, 2011 to June 30, 2012. Compared with GPS simulations using the U.S. Joint Center of Satellite Data Assimilation (JCSDA) Community Radiative Transfer Model (CRTM), the global biases of brightness temperatures from ATMS measurements are within 0.5K for channels 6 to 13 for clear-sky data over ocean. This value is well within the pre-launch specification, indicating that the ATMS upper level temperature sounding channels have high accuracy. The monthly variation and angular dependence of ATMS bias are also examined.

  7. 3D atmospheric structure of the prototypical roAp star HD 24712 (HR1217)

    NASA Astrophysics Data System (ADS)

    Lüftinger, T.; Kochukhov, O.; Ryabchikova, T.; Piskunov, N.; Weiss, W. W.; Ilyin, I.

    2008-04-01

    The first analysis of the structure of the surface magnetic field of a rapidly oscillating Ap (roAp) star is presented. We obtain information about abundance distributions of a number of chemical elements on the surface of the prototypical roAp star HD 24712 and about magnetic field geometry. Inverting rotationally modulated spectra in Stokes parameters I and V obtained with the SOFIN spectropolarimeter attached to the NOT, we recover surface abundance structures of sixteen different chemical elements, including Mg, Ca, Sc, Ti, Cr, Fe, Co, Ni, Y, La, Ce, Pr, Nd, Gd, Tb, and Dy. Our analysis reveal a pure dipolar structure of the stellar magnetic field and surprising and unexpected correlations of the various elemental surface abundance structures to this field geometry. Stratification analysis at phases of both magnetic extrema enable us to obtain the vertical dimension in the atmosphere of HD 24712. High time resolved spectroscopic data and observations obtained with the MOST space photometer give us the possibility to compare (Lüftinger, 2007) our results to detailed pulsational analysis.

  8. Physical state of the deep interior of the CoRoT-7b exoplanet

    NASA Astrophysics Data System (ADS)

    Wagner, Frank W.; Sohl, Frank; Rückriemen, Tina; Rauer, Heike

    2011-11-01

    The present study takes the CoRoT-7b exoplanet as an analogue for massive terrestrial planets to investigate conditions, under which intrinsic magnetic fields could be sustained in liquid cores. We examine the effect of depth-dependent transport parameters (e.g., activation volume of mantle rock) on a planet's thermal structure and the related heat flux across the core mantle boundary. For terrestrial planets more massive than the Earth, our calculations suggest that a substantial part of the lowermost mantle is in a sluggish convective regime, primarily due to pressure effects on viscosity. Hence, we find substantially higher core temperatures than previously reported from parameterized convection models. We also discuss the effect of melting point depression in the presence of impurities (e.g., sulfur) in iron-rich cores and compare corresponding melting relations to the calculated thermal structure. Since impurity effects become less important at the elevated pressure and temperature conditions prevalent in the deep interior of CoRoT-7b, iron-rich cores are likely solid, implying that a self-sustained magnetic field would be absent.

  9. Heterochromatin dynamics during the differentiation process revealed by the DNA methylation reporter mouse, MethylRO.

    PubMed

    Ueda, Jun; Maehara, Kazumitsu; Mashiko, Daisuke; Ichinose, Takako; Yao, Tatsuma; Hori, Mayuko; Sato, Yuko; Kimura, Hiroshi; Ohkawa, Yasuyuki; Yamagata, Kazuo

    2014-06-01

    In mammals, DNA is methylated at CpG sites, which play pivotal roles in gene silencing and chromatin organization. Furthermore, DNA methylation undergoes dynamic changes during development, differentiation, and in pathological processes. The conventional methods represent snapshots; therefore, the dynamics of this marker within living organisms remains unclear. To track this dynamics, we made a knockin mouse that expresses a red fluorescent protein (RFP)-fused methyl-CpG-binding domain (MBD) protein from the ROSA26 locus ubiquitously; we named it MethylRO (methylation probe in ROSA26 locus). Using this mouse, we performed RFP-mediated methylated DNA immunoprecipitation sequencing (MeDIP-seq), whole-body section analysis, and live-cell imaging. We discovered that mobility and pattern of heterochromatin as well as DNA methylation signal intensity inside the nuclei can be markers for cellular differentiation status. Thus, the MethylRO mouse represents a powerful bioresource and technique for DNA methylation dynamics studies in developmental biology, stem cell biology, as well as in disease states. PMID:24936475

  10. MOST observations of the roAp stars HD 9289, HD 99563, and HD 134214

    NASA Astrophysics Data System (ADS)

    Gruberbauer, M.; Huber, D.; Kuschnig, R.; Weiss, W. W.; Guenther, D. B.; Matthews, J. M.; Moffat, A. F. J.; Rowe, J. F.; Rucinski, S. M.; Sasselov, D.; Fischer, M.

    2011-06-01

    We report on the analysis of high-precision space-based photometry of the roAp (rapidly oscillating Ap) stars HD 9289, HD 99563, and HD 134214. All three stars were observed by the MOST satellite for more than 25 days, allowing unprecedented views of their pulsation. We find previously unknown candidate frequencies in all three stars. We establish the rotation period of HD 9289 (8.5 d) for the first time and show that the star is pulsating in two modes that show different mode geometries. We present a detailed analysis of HD 99563's mode multiplet and find a new candidate frequency that appears to be independent of the previously known mode. Finally, we report on 11 detected pulsation frequencies in HD 134214, nine of which have never before been detected in photometry, and three of which are completely new detections. Thanks to the unprecedentedly small frequency uncertainties, the p-mode spectrum of HD 134214 can be seen to have a well-defined large frequency spacing similar to the well-studied roAp star HD 24712 (HR 1217). Based on data from the MOST satellite, a Canadian Space Agency mission, jointly operated by Dynacon Inc., the University of Toronto Institute for Aerospace Studies and the University of British Columbia, with the assistance of the University of Vienna.

  11. Heterochromatin Dynamics during the Differentiation Process Revealed by the DNA Methylation Reporter Mouse, MethylRO

    PubMed Central

    Ueda, Jun; Maehara, Kazumitsu; Mashiko, Daisuke; Ichinose, Takako; Yao, Tatsuma; Hori, Mayuko; Sato, Yuko; Kimura, Hiroshi; Ohkawa, Yasuyuki; Yamagata, Kazuo

    2014-01-01

    Summary In mammals, DNA is methylated at CpG sites, which play pivotal roles in gene silencing and chromatin organization. Furthermore, DNA methylation undergoes dynamic changes during development, differentiation, and in pathological processes. The conventional methods represent snapshots; therefore, the dynamics of this marker within living organisms remains unclear. To track this dynamics, we made a knockin mouse that expresses a red fluorescent protein (RFP)-fused methyl-CpG-binding domain (MBD) protein from the ROSA26 locus ubiquitously; we named it MethylRO (methylation probe in ROSA26 locus). Using this mouse, we performed RFP-mediated methylated DNA immunoprecipitation sequencing (MeDIP-seq), whole-body section analysis, and live-cell imaging. We discovered that mobility and pattern of heterochromatin as well as DNA methylation signal intensity inside the nuclei can be markers for cellular differentiation status. Thus, the MethylRO mouse represents a powerful bioresource and technique for DNA methylation dynamics studies in developmental biology, stem cell biology, as well as in disease states. PMID:24936475

  12. [Phase II study of recombinant leukocyte A interferon (Ro 22-8181) in skin malignant tumors].

    PubMed

    1985-04-01

    A clinical phase II study of recombinant human leukocyte interferon A (rIFN-alpha A, Ro 22-8181) for various skin malignant tumors was jointly conducted at nine medical institutes across the country in order to study its clinical effect and side effects. Patients received Ro 22-8181 alone in doses ranging from 3 X 10(6) U/day to 50 X 10(6) U/day either by intramuscular injection or by local injection. Good response was obtained in one (4.8%) of 21 patients treated by intramuscular injection and in 26 (72.2%) of 36 patients treated by local injection. The percentage of good responses achieved by local injection for individual diseases was 55.6% (5/9) for metastatic malignant skin melanoma, 100% (11/11) for cutaneous malignant lymphoma, 100% (5/5) for extramammary Paget's disease, 75% (3/4) for intraepidermal cancer and 50% (2/4) for metastatic skin cancer. Main side effects were fever, anorexia, general fatigue, chills, nausea and vomiting. Abnormal laboratory data included leukopenia, and elevation of GOT and GPT, although their incidence was lower with local injection than with intramuscular injection. Side effects were mostly improved by reduction of the dose or discontinuation of the treatment. PMID:2985007

  13. Tailoring the structure of thin film nanocomposite membranes to achieve seawater RO membrane performance.

    PubMed

    Lind, Mary Laura; Eumine Suk, Daniel; Nguyen, The-Vinh; Hoek, Eric M V

    2010-11-01

    Herein we report on the formation and characterization of pure polyamide thin film composite (TFC) and zeolite-polyamide thin film nanocomposite (TFN) reverse osmosis (RO) membranes. Four different physical-chemical post-treatment combinations were applied after the interfacial polymerization reaction to change the molecular structure of polyamide and zeolite-polyamide thin films. Both TFC and TFN hand-cast membranes were more permeable, hydrophilic, and rough than a commercial seawater RO membrane. Salt rejection by TFN membranes was consistently below that of hand-cast TFC membranes; however, two TFN membranes exhibited 32 g/L NaCl rejections above 99.4%, which was better than the commercial membrane under the test conditions employed. The nearly defect-free TFN films that produced such high rejections were achieved only with wet curing, regardless of other post-treatments. Polyamide films formed in the presence of zeolite nanoparticles were less cross-linked than similarly cast pure polyamide films. At the very low nanoparticle loadings evaluated, differences between pure polyamide and zeolite-polyamide membrane water and salt permeability correlated weakly with extent of cross-linking of the polyamide film, which suggests that defects and molecular-sieving largely govern transport through zeolite-polyamide thin film nanocomposite membranes. PMID:20942398

  14. Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders.

    PubMed

    Geoffroy, Pierre Alexis; Etain, Bruno; Franchi, Jean-Arthur Micoulaud; Bellivier, Frank; Ritter, Philipp

    2015-01-01

    Bipolar disorders (BD) present with abnormalities of circadian rhythmicity and sleep homeostasis, even during phases of remission. These abnormalities are linked to the underlying neurobiology of genetic susceptibility to BD. Melatonin is a pineal gland secreted neurohormone that induces circadian-related and sleep-related responses. Exogenous melatonin has demonstrated efficacy in treating primary insomnia, delayed sleep phase disorder, improving sleep parameters and overall sleep quality, and some psychiatric disorders like autistic spectrum disorders. In order to evaluate the efficacy of melatonin among patients with BD, this comprehensive review emphasizes the abnormal melatonin function in BD, the rationale of melatonin action in BD, the available data about the exogenous administration of melatonin, and melatonin agonists (ramelteon and tasimelteon), and recommendations of use in patients with BD. There is a scientific rationale to propose melatonin-agonists as an adjunctive treatment of mood stabilizers in treating sleep disorders in BD and thus to possibly prevent relapses when administered during remission phases. We emphasized the need to treat insomnia, sleep delayed latencies and sleep abnormalities in BD that are prodromal markers of an emerging mood episode and possible targets to prevent future relapses. An additional interesting adjunctive therapeutic effect might be on preventing metabolic syndrome, particularly in patients treated with antipsychotics. Finally, melatonin is well tolerated and has little dependence potential in contrast to most available sleep medications. Further studies are expected to be able to produce stronger evidence-based therapeutic guidelines to confirm and delineate the routine use of melatonin-agonists in the treatment of BD. PMID:26088111

  15. Comparative endpoint sensitivity of in vitro estrogen agonist assays.

    PubMed

    Dreier, David A; Connors, Kristin A; Brooks, Bryan W

    2015-07-01

    Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less

  16. Pharmacological properties of acid N-thiazolylamide FFA2 agonists

    PubMed Central

    Brown, Andrew J; Tsoulou, Christina; Ward, Emma; Gower, Elaine; Bhudia, Nisha; Chowdhury, Forhad; Dean, Tony W; Faucher, Nicolas; Gangar, Akanksha; Dowell, Simon J

    2015-01-01

    FFA2 is a receptor for short-chain fatty acids. Propionate (C3) and 4-chloro-α-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide (4-CMTB), the prototypical synthetic FFA2 agonist, evoke calcium mobilization in neutrophils and inhibit lipolysis in adipocytes via this G-protein-coupled receptor. 4-CMTB contains an N-thiazolylamide motif but no acid group, and 4-CMTB and C3 bind to different sites on FFA2 and show allosteric cooperativity. Recently, FFA2 agonists have been described that contain both N-thiazolylamide and carboxylate groups, reminiscent of bitopic ligands. These are thought to engage the carboxylate-binding site on FFA2, but preliminary evidence suggests they do not bind to the same site as 4-CMTB even though both contain N-thiazolylamide. Here, we describe the characterization of four FFA2 ligands containing both N-thiazolylamide and carboxylate. (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid (compound 14) exhibits allosteric agonism with 4-CMTB but not C3. Three other compounds agonize FFA2 in [35S]GTPγS-incorporation or cAMP assays but behave as inverse agonists in yeast-based gene-reporter assays, showing orthosteric antagonism of C3 responses but allosteric antagonism of 4-CMTB responses. Thus, the bitopic-like FFA2 ligands engage the orthosteric site but do not compete at the site of 4-CMTB binding on an FFA2 receptor molecule. Compound 14 activates FFA2 on human neutrophils and mouse adipocytes, but appears not to inhibit lipolysis upon treatment of human primary adipocytes in spite of the presence of a functional FFA2 receptor in these cells. Hence, these new ligands may reveal differences in coupling of FFA2 between human and rodent adipose tissues. PMID:26236484

  17. Defining Nicotinic Agonist Binding Surfaces through Photoaffinity Labeling†

    PubMed Central

    Tomizawa, Motohiro; Maltby, David; Medzihradszky, Katalin F.; Zhang, Nanjing; Durkin, Kathleen A.; Presley, Jack; Talley, Todd T.; Taylor, Palmer; Burlingame, Alma L.; Casida, John E.

    2016-01-01

    Nicotinic acetylcholine (ACh) receptor (nAChR) agonists are potential therapeutic agents for neurological dysfunction. In the present study, the homopentameric mollusk ACh binding protein (AChBP), used as a surrogate for the extracellular ligand-binding domain of the nAChR, was specifically derivatized by the highly potent agonist azidoepibatidine (AzEPI) prepared as a photoaffinity probe and radioligand. One EPI-nitrene photoactivated molecule was incorporated in each subunit interface binding site based on analysis of the intact derivatized protein. Tryptic fragments of the modified AChBP were analyzed by collision-induced dissociation and Edman sequencing of radiolabeled peptides. Each specific EPI-nitrene-modified site involved either Tyr195 of loop C on the principal or (+)-face or Met116 of loop E on the complementary or (−)-face. The two derivatization sites were observed in similar frequency, providing evidence of the reactivity of the azido/nitrene probe substituent and close proximity to both residues. [3H]AzEPI binds to the α4β2 nAChR at a single high-affinity site and photoaffinity-labels only the α4 subunit, presumably modifying Tyr225 spatially corresponding to Tyr195 of AChBP. Phe137 of the β2 nAChR subunit, equivalent to Met116 of AChBP, conceivably lacks sufficient reactivity with the nitrene generated from the probe. The present photoaffinity labeling in a physiologically relevant condition combined with the crystal structure of AChBP allows development of precise structural models for the AzEPI interactions with AChBP and α4β2 nAChR. These findings enabled us to use AChBP as a structural surrogate to define the nAChR agonist site. PMID:17614369

  18. AGONISTIC AUTOANTIBODIES AS VASODILATORS IN ORTHOSTATIC HYPOTENSION: A NEW MECHANISM

    PubMed Central

    Li, Hongliang; Kem, David C.; Reim, Sean; Khan, Muneer; Vanderlinde-Wood, Megan; Zillner, Caitlin; Collier, Daniel; Liles, Campbell; Hill, Michael A.; Cunningham, Madeleine W.; Aston, Christopher E.; Yu, Xichun

    2012-01-01

    Agonistic autoantibodies to the β-adrenergic and muscarinic receptors are a novel investigative and therapeutic target for certain orthostatic disorders. We have identified the presence of autoantibodies to β2-adrenergic and/or M3 muscarinic receptors by enzyme-linked immunosorbent assay in 75% (15 of 20) of patients with significant orthostatic hypotension. Purified serum IgG from all 20 patients and 10 healthy control subjects were examined in a receptor-transfected cell-based cAMP assay for β2 receptor activation and β-arrestin assay for M3 receptor activation. There was a significant increase in IgG-induced activation of β2 and M3 receptors in the patient group compared to controls. A dose response was observed for both IgG activation of β2 and M3 receptors and inhibition of their activation with the non-selective β blocker propranolol and muscarinic blocker atropine. The antibody effects on β2 and/or M3 (via production of nitric oxide) receptor-mediated vasodilation were studied in a rat cremaster resistance arteriole assay. Infusion of IgG from patients with documented β2 and/or M3 receptor agonistic activity produced a dose-dependent vasodilation. Sequential addition of the β blocker propranolol and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester partially inhibited IgG-induced vasodilation (% of maximal dilatory response: from 57.7±10.4 to 35.3±4.6 and 24.3±5.8, respectively, p<0.01, n=3), indicating antibody activation of vascular β2 and/or M3 receptors may contribute to systemic vasodilation. These data support the concept that circulating agonistic autoantibodies serve as vasodilators and may cause or exacerbate orthostatic hypotension. PMID:22215709

  19. Antinociceptive properties of selective MT(2) melatonin receptor partial agonists.

    PubMed

    López-Canul, Martha; Comai, Stefano; Domínguez-López, Sergio; Granados-Soto, Vinicio; Gobbi, Gabriella

    2015-10-01

    Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5-40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT2 partial agonists were blocked by the pre-treatment with the MT2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT2 melatonin receptor may be a novel target for analgesic drug development. PMID:26162699

  20. Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine.

    PubMed

    Simeon, D; Hollander, E; Stein, D J; DeCaria, C; Cohen, L J; Saoud, J B; Islam, N; Hwang, M

    1995-09-29

    Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization. PMID:8570768

  1. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    PubMed

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight. PMID:26198605

  2. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    NASA Technical Reports Server (NTRS)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  3. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter. PMID:26585147

  4. Enzymatic cleaning of biofouled thin-film composite reverse osmosis (RO) membrane operated in a biofilm membrane reactor.

    PubMed

    Khan, Mohiuddin; Danielsen, Steffen; Johansen, Katja; Lorenz, Lindsey; Nelson, Sara; Camper, Anne

    2014-02-01

    Application of environmentally friendly enzymes to remove thin-film composite (TFC) reverse osmosis (RO) membrane biofoulants without changing the physico-chemical properties of the RO surface is a challenging and new concept. Eight enzymes from Novozyme A/S were tested using a commercially available biofouling-resistant TFC polyamide RO membrane (BW30, FilmTech Corporation, Dow Chemical Co.) without filtration in a rotating disk reactor system operated for 58 days. At the end of the operation, the accumulated biofoulants on the TFC RO surfaces were treated with the three best enzymes, Subtilisin protease and lipase; dextranase; and polygalacturonase (PG) based enzymes, at neutral pH (~7) and doses of 50, 100, and 150 ppm. Contact times were 18 and 36 h. Live/dead staining, epifluorescence microscopy measurements, and 5 μm thick cryo-sections of enzyme and physically treated biofouled membranes revealed that Subtilisin protease- and lipase-based enzymes at 100 ppm and 18 h contact time were optimal for removing most of the cells and proteins from the RO surface. Culturable cells inside the biofilm declined by more than five logs even at the lower dose (50 ppm) and shorter incubation period (18 h). Subtilisin protease- and lipase-based enzyme cleaning at 100 ppm and for 18 h contact time restored the hydrophobicity of the TFC RO surface to its virgin condition while physical cleaning alone resulted in a 50° increase in hydrophobicity. Moreover, at this optimum working condition, the Subtilisin protease- and lipase-based enzyme treatment of biofouled RO surface also restored the surface roughness measured with atomic force microscopy and the mass percentage of the chemical compositions on the TFC surface estimated with X-ray photoelectron spectroscopy to its virgin condition. This novel study will encourage the further development and application of enzymes to remove biofoulants on the RO surface without changing its surface properties. PMID:24329165

  5. The Roles of Tidal Evolution and Evaporative Mass Loss in the Origin of CoRoT-7 b

    NASA Technical Reports Server (NTRS)

    Jackson, Brian; Miller, Neil; Barnes, Rory; Raymond, Sean N.; Fortney, Jonathan J.; Greenberg, Richard

    2010-01-01

    CoRoT-7 b is the first confirmed rocky exoplanet, but, with an orbital semimajor axis of 0.0172 au, its origins may be unlike any rocky planet in our Solar System. In this study, we consider the roles of tidal evolution and evaporative mass loss in CoRoT-7 b's history, which together have modified the planet's mass and orbit. If CoRoT-7 b has always been a rocky body, evaporation may have driven off almost half its original mass, but the mass loss may depend sensitively on the extent of tidal decay of its orbit. As tides caused CoRoT-7 b's orbit to decay, they brought the planet closer to its host star, thereby enhancing the mass loss rate. Such a large mass loss also suggests the possibility that CoRoT-7 b began as a gas giant planet and had its original atmosphere completely evaporated. In this case, we find that CoRoT-7 b's original mass probably did not exceed 200 Earth masses (about two-third of a Jupiter mass). Tides raised on the host star by the planet may have significantly reduced the orbital semimajor axis, perhaps causing the planet to migrate through mean-motion resonances with the other planet in the system, CoRoT-7 c. The coupling between tidal evolution and mass loss may be important not only for CoRoT-7 b but also for other close-in exoplanets, and future studies of mass loss and orbital evolution may provide insight into the origin and fate of close-in planets, both rocky and gaseous.

  6. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    SciTech Connect

    Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  7. Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.

    PubMed

    Sheppeck, James E; Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Nirschl, David; Doweyko, Arthur M; Sack, Jack S; Corbett, Martin J; Malley, Mary F; Gougoutas, Jack Z; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Dodd, John H; Nadler, Steven G; Somerville, John E; Barrish, Joel C

    2013-10-01

    Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. PMID:23953070

  8. An Evolutionarily Conserved Domain of roX2 RNA Is Sufficient for Induction of H4-Lys16 Acetylation on the Drosophila X Chromosome

    PubMed Central

    Park, Seung-Won; Kang, Yool Ie; Sypula, Joanna G.; Choi, Jiyeon; Oh, Hyangyee; Park, Yongkyu

    2007-01-01

    The male-specific lethal (MSL) complex, which includes two noncoding RNA on X (roX)1 and roX2 RNAs, induces histone H4-Lys16 acetylation for twofold hypertranscription of the male X chromosome in Drosophila melanogaster. To characterize the role of roX RNAs in this process, we have identified evolutionarily conserved functional domains of roX RNAs in several Drosophila species (eight for roX1 and nine for roX2). Despite low homology between them, male-specific expression and X chromosome-specific binding are conserved. Within roX RNAs of all Drosophila species, we found conserved primary sequences, such as GUUNUACG, in the 3′ end of both roX1 (three repeats) and roX2 (two repeats). A predicted stem–loop structure of roX2 RNA contains this sequence in the 3′ stem region. Six tandem repeats of this stem–loop region (72 nt) of roX2 were enough for targeting the MSL complex and inducing H4-Lys16 acetylation on the X chromosome without other parts of roX2 RNA, suggesting that roX RNAs might play important roles in regulating enzymatic activity of the MSL complex. PMID:18039876

  9. Site of action of a pentapeptide agonist at the glucagon-like peptide-1 receptor. Insight into a small molecule agonist-binding pocket

    PubMed Central

    Dong, Maoqing; Pinon, Delia I.; Miller, Laurence J.

    2011-01-01

    The development of small molecule agonists for class B G protein-coupled receptors (GPCRs) has been quite challenging. With proof-of-concept that exenatide, the parenterally administered peptide agonist of the glucagon-like peptide-1 (GLP1) receptor, is an effective treatment for patients with diabetes mellitus, the development of small molecule agonists could have substantial advantages. We previously reported a lead for small molecule GLP1 receptor agonist development representing the pentapeptide NRTFD. In this work, we have prepared an NRTFD derivative incorporating a photolabile benzoylphenylalanine and used it to define its site of action. This peptide probe was a full agonist with potency similar to NRTFD, which bound specifically and saturably to a single, distinct site within the GLP1 receptor. Peptide mapping using cyanogen bromide and endoproteinase Lys-C cleavage of labeled wild type and M397L mutant receptor constructs identified the site of covalent attachment of NRTFD within the third extracellular loop above the sixth transmembrane segment. This region is the same as that identified using an analogous photolabile probe based on secretin receptor sequences, and has been shown in mutagenesis studies to be important for natural agonist action of several members of this family. While these observations suggest that small molecule ligands can act at a site bordering the third extracellular loop to activate this class B GPCR, the relationship of this site to the site of action of the amino-terminal end of the natural agonist peptide is unclear. PMID:22079758

  10. Evaluation of the ethanol antagonist' Ro15-4513 on cardiovascular and metabolic responses induced by ethanol

    SciTech Connect

    Lerner, M.R.; Gauvin, D.V.; Holloway, F.A.; Wilson, M.F.; Brackett, D.J. Veterans Affairs Medical Center, Oklahoma City, OK )

    1992-02-26

    The putative ethanol antagonist Ro15-4513 has been reported to attenuate many behavioral responses induced by ethanol, including motor coordination, narcosis, ethanol self administration and intake, and anticonvulsant actions. This study was designed to study the effect of Ro15-4513 on cardiovascular and metabolic responses elicited by intragastric ethanol in conscious rats. Four groups of rats were catheterized under enflurane anesthesia and allowed to regain consciousness. Each group was given either 3.2, 10.0, or 32.0 mg/kg Ro15-4513 or equivalent Tween (i.p.) following ethanol. Ro15-4513 had no effect at any concentration on the decreases in mean arterial pressure, cardiac output, central venous pressure, respiration rate, and cardiac stroke volume and the increases in systemic vascular resistance, heart rate, and glucose evoked by the ethanol challenge. Blood alcohol concentrations measured throughout the study were not affected by any concentration of Ro15-4513. These data suggest that even though Ro15-4513 has significant effects on behavioral responses induced by ethanol it has no effect on the cardiovascular and metabolic responses elicited during ethanol intoxication.

  11. Determination of the in vivo redox potential using roGFP and fluorescence spectra obtained from one-wavelength excitation

    NASA Astrophysics Data System (ADS)

    Wierer, S.; Elgass, K.; Bieker, S.; Zentgraf, U.; Meixner, A. J.; Schleifenbaum, F.

    2011-02-01

    The analysis of molecular processes in living (plant) cells such as signal transduction, DNA replication, carbon metabolism and senescence has been revolutionized by the use of green fluorescent protein (GFP) and its variants as specific cellular markers. Many cell biological processes are accompanied by changes in the intracellular redox potential. To monitor the redox potential, a redox-sensitive mutant of GFP (roGFP) was created, which shows changes in its optical properties in response to changes in the redox state of its surrounding medium. For a quantitative analysis in living systems, it is essential to know the optical properties of roGFP in vitro. Therefore, we applied spectrally resolved fluorescence spectroscopy on purified roGFP exposed to different redox potentials to determine shifts in both the absorption and the emission spectra of roGFP. Based on these in vitro findings, we introduce a new approach using one-wavelength excitation to use roGFP for the in vivo analysis of cell biological processes. We demonstrate the ability this technique by investigating chloroplast-located Grx1-roGFP2 expressing Arabidopsis thaliana cells as example for dynamically moving intracellular compartments. This is not possible with the two-wavelength excitation technique established so far, which hampers a quantitative analysis of highly mobile samples due to the time delay between the two measurements and the consequential displacement of the investigated area.

  12. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy

    PubMed Central

    Iribarren, Kristina; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Špíšek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-01-01

    ABSTRACT Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy. PMID:27141345

  13. Synthesis and biological activities of indolizine derivatives as alpha-7 nAChR agonists.

    PubMed

    Xue, Yu; Tang, Jingshu; Ma, Xiaozhuo; Li, Qing; Xie, Bingxue; Hao, Yuchen; Jin, Hongwei; Wang, Kewei; Zhang, Guisen; Zhang, Liangren; Zhang, Lihe

    2016-06-10

    Human α7 nicotinic acetylcholine receptor (nAChR) is a promising therapeutic target for the treatment of schizophrenia accompanied with cognitive impairment. Herein, we report the synthesis and agonistic activities of a series of indolizine derivatives targeting to α7 nAChR. The results show that all synthesized compounds have affinity to α7 nAChR and some give strong agonistic activity, particularly most active agonists show higher potency than control EVP-6124. The docking and structure-activity relationship studies provide insights to develop more potent novel α7 nAChR agonists. PMID:26994846

  14. Dopamine agonist-induced substance addiction: the next piece of the puzzle.

    PubMed

    Evans, Andrew

    2011-02-01

    Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor "off" periods. The recent recognition of a range of "behavioural addictions" that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions. PMID:20980151

  15. Sustained wash-resistant receptor activation responses of GPR119 agonists.

    PubMed

    Hothersall, J Daniel; Bussey, Charlotte E; Brown, Alastair J; Scott, James S; Dale, Ian; Rawlins, Philip

    2015-09-01

    G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses. PMID:26101059

  16. Mapping the agonist binding site of the nicotinic acetylcholine receptor. Orientation requirements for activation by covalent agonist.

    PubMed

    Sullivan, D A; Cohen, J B

    2000-04-28

    To characterize the structural requirements for ligand orientation compatible with activation of the Torpedo nicotinic acetylcholine receptor (nAChR), we used Cys mutagenesis in conjunction with sulfhydryl-reactive reagents to tether primary or quaternary amines at defined positions within the agonist binding site of nAChRs containing mutant alpha- or gamma-subunits expressed in Xenopus oocytes. 4-(N-Maleimido)benzyltrimethylammonium and 2-aminoethylmethanethiosulfonate acted as irreversible antagonists when tethered at alphaY93C, alphaY198C, or gammaE57C, as well as at alphaN94C (2-aminoethylmethanethiosulfonate only). [2-(Trimethylammonium)-ethyl]-methanethiosulfonate (MTSET), which attaches thiocholine to binding site Cys, also acted as an irreversible antagonist when tethered at alphaY93C, alphaN94C, or gammaE57C. However, MTSET modification of alphaY198C resulted in prolonged activation of the nAChR not reversible by washing but inhibitable by subsequent exposure to non-competitive antagonists. Modification of alphaY198C (or any of the other positions tested) by [(trimethylammonium)methyl]methanethiosulfonate resulted only in irreversible inhibition, while modification of alphaY198C by [3-(trimethylammonium)propyl]methanethiosulfonate resulted in irreversible activation of nAChR, but at lower efficacy than by MTSET. Thus changing the length of the tethering arm by less than 1 A in either direction markedly effects the ability of the covalent trimethylammonium to activate the nAChR, and agonist activation depends on a very selective orientation of the quaternary ammonium within the agonist binding site. PMID:10777557

  17. The response of the RO-2 survey meter to mixed radiation fields

    SciTech Connect

    Shonka, J.J. ); Tschaeche, A.N.; Tomblison, M.R.; Gibeault, G.L.; Moon, U.Y.; McCoy, G.C.; Schrader, B.J. )

    1989-12-01

    Reactor fuel reprocessing can sometimes result in radiation fields originating from nearly-pure Ru-106/Rh-106 (E{sub max} = 3.5 MeV), and field measurements are often made where beta-to-gamma ratios exceed 100-to-1. If the range of the high energy beta particles exceeds the density-thickness of the side wall and/or end window of the radiation detector, a significant fraction of the beta radiation can easily be interpreted as gamma radiation. The magnitude of the error increases as the beta-to-gamma radio increases. Calculations and measurements are presented which show the magnitude of the resulting errors. To address this problem, a modification kit was developed for the Eberline RO-2A which increased the density-thickness of both the sidewall and slide to 1040 mg/cm{sup 2}. In this paper experimental results showing the effectiveness of the modification are discussed.

  18. Ro-vibrational averaging of the isotropic hyperfine coupling constant for the methyl radical

    SciTech Connect

    Adam, Ahmad Y.; Jensen, Per; Yachmenev, Andrey; Yurchenko, Sergei N.

    2015-12-28

    We present the first variational calculation of the isotropic hyperfine coupling constant of the carbon-13 atom in the CH{sub 3} radical for temperatures T = 0, 96, and 300 K. It is based on a newly calculated high level ab initio potential energy surface and hyperfine coupling constant surface of CH{sub 3} in the ground electronic state. The ro-vibrational energy levels, expectation values for the coupling constant, and its temperature dependence were calculated variationally by using the methods implemented in the computer program TROVE. Vibrational energies and vibrational and temperature effects for coupling constant are found to be in very good agreement with the available experimental data. We found, in agreement with previous studies, that the vibrational effects constitute about 44% of the constant’s equilibrium value, originating mainly from the large amplitude out-of-plane bending motion and that the temperature effects play a minor role.

  19. Satellite-receiving-system overlay with WDM RoF on 10Gb/s link

    NASA Astrophysics Data System (ADS)

    Chinen, Koyu; Uchima, Yuki

    2009-11-01

    Received signal from weather satellite is overlaid with WDM RoF technique on 10.7Gb/s (OTU2) data stream. For extending the signal transmission distance between the antenna and the receiver, a low noise amplifier is designed by using an EP-HEMT to achieve lower noise and higher gain so that the received signal level is as low as -130dBm. The received signal is amplified by using a laser driver which is also designed by using the EP-HEMT. A low noise and linear 1550nm DFB laser is modulated by the laser driver. The converted optical signal is overlaid on a 10.7Gb/ (OTU2) data streams by using a 1310/1550nm WDM . A clear image from the weather satellite is received after 40km SMF. There was no degradation in the eye diagram and total jitter of the 10.7Gb/s data signal.

  20. A hybrid ED/RO process for TDS reduction of produced waters

    SciTech Connect

    Tsai, S.P.; Datta, R.; Frank, J.R.

    1995-12-31

    Large volumes of produced waters are generated from natural gas production. In the United States the prevailing management practice for produced waters is deep well injection, but this practice is costly. Therefore minimizing the need for deep well injection is desirable. A major treatment issue for produced waters is the reduction of total dissolved solids (TDS), which consist mostly of inorganic salts. A hybrid electrodialysis/reverse-osmosis (ED/RO) treatment process is being developed to concentrate the salts in produced waters and thereby reduce the volume of brine that needs to be managed for disposal. The desalted water can be used beneficially or discharged. In this study, laboratory feasibility experiments were conducted by using produced waters from multiple sites. A novel-membrane configuration approach to prevent fouling and scale formation was developed and demonstrated. Results of laboratory experiments and plans for field demonstration are discussed.

  1. Variational Calculations of Ro-Vibrational Energy Levels and Transition Intensities for Tetratomic Molecules

    NASA Technical Reports Server (NTRS)

    Schwenke, David W.; Langhoff, Stephen R. (Technical Monitor)

    1995-01-01

    A description is given of an algorithm for computing ro-vibrational energy levels for tetratomic molecules. The expressions required for evaluating transition intensities are also given. The variational principle is used to determine the energy levels and the kinetic energy operator is simple and evaluated exactly. The computational procedure is split up into the determination of one dimensional radial basis functions, the computation of a contracted rotational-bending basis, followed by a final variational step coupling all degrees of freedom. An angular basis is proposed whereby the rotational-bending contraction takes place in three steps. Angular matrix elements of the potential are evaluated by expansion in terms of a suitable basis and the angular integrals are given in a factorized form which simplifies their evaluation. The basis functions in the final variational step have the full permutation symmetries of the identical particles. Sample results are given for HCCH and BH3.

  2. Pharmacokinetics of Ro 03-8799 in mice bearing melanosarcoma: comparison with tumors without melanin

    SciTech Connect

    Laurent, F.; Canal, P.; Soula, G.

    1989-04-01

    The pharmacokinetics of Ro 03-8799 has been studied in melanic and non-melanic tumor bearing mice after iv administration of 150 mg/kg. The peak concentration in B16 melanosarcoma tumor reached 152 micrograms/g, that is 7.6-fold higher than the plasma concentration at the same time. This concentration is 3-times greater than that obtained in the tumor of mice bearing non-melanic sarcoma (DB16) or Lewis lung carcinoma (3LL). The exposure of B16 tumor (AUC) is respectively 15-times and 11-times higher than the 3LL and the DB16 ones. These experimental data confirm that this 2-nitro-imidazol compound has an important affinity for melanin and suggest that it might be used as a radiosensitizer for the treatment of malignant melanoma.

  3. Performance analysis of an OSSB RoF link using 90o & 120o Hybrid coupler

    NASA Astrophysics Data System (ADS)

    Kumar, Parvin; Kumar Sharma, Sanjay; Singla, Shelly

    2016-08-01

    This paper presents an analysis, simulation and comparison of the performance of Optical single sideband (OSSB) radio over fiber (RoF) system based on a dual drive Mach Zehender modulator (DD-MZM) using 90o and 120o hybrid coupler including the effects of phase noise from RF signal oscillator and laser source, input RF signal power and fiber dispersion. Signal to Noise ratio (SNR) is significantly influenced by phase noise from RF signal oscillator and input RF signal power. On comparison with conventional 90o hybrid coupler system, the performance of the considered system improves by 5.64 and 0.67 dB in terms of SNR, when RF and laser phase noises are increased.

  4. The variability behaviour of CoRoT M-giant stars⋆

    NASA Astrophysics Data System (ADS)

    Ferreira Lopes, C. E.; Neves, V.; Leão, I. C.; de Freitas, D. B.; Canto Martins, B. L.; da Costa, A. D.; Paz-Chinchón, F.; Das Chagas, M. L.; Baglin, A.; Janot-Pacheco, E.; De Medeiros, J. R.

    2015-11-01

    Context. For six years the Convection, Rotation, and planetary Transits (CoRoT) space mission has been acquiring photometric data from more than 100 000 point sources towards and directly opposite the inner and outer regions of the Galaxy. The high temporal resolution of the CoRoT data, combined with the wide time span of the observations, enabled the study of short- and long-time variations in unprecedented detail. Aims: The aim of this work is to study the variability and evolutionary behaviour of M-giant stars using CoRot data. Methods: From the initial sample of 2534 stars classified as M giants in the CoRoT databases, we selected 1428 targets that exhibit well defined variability, by visual inspection. Then, we defined three catalogues: C1 - stars with Teff< 4200 K and LCs displaying semi-sinusoidal signatures; C2 - rotating variable candidates with Teff> 4200 K; C3 - long-period variable candidates (with LCs showing a variability period up to the total time span of the observations). The variability period and amplitude of C1 stars were computed using Lomb-Scargle and harmonic fit methods. Finally, we used C1 and C3 stars to study the variability behaviour of M-giant stars. Results: The trends found in the V-I vs. J-K colour-colour diagram are in agreement with standard empirical calibrations for M giants. The sources located towards the inner regions of the Galaxy are distributed throughout the diagram, while the majority of the stars towards the outer regions of the Galaxy are spread between the calibrations of M giants and the predicted position for carbon stars. The stars classified as supergiants follow a different sequence from the one found for giant stars. We also performed a Kolmogorov-Smirnov (KS) test of the period and amplitude of stars towards the inner and outer regions of the Galaxy. We obtained a low probability that the two samples came from the same parent distribution. The observed behaviour of the period-amplitude and period

  5. [Degradation kinetics of ozone oxidation on landfill leachate rejected by RO treatment].

    PubMed

    Zheng, Ke; Zhou, Shao-Qi; Sha, Shuang; Yang, Mei-Mei

    2011-10-01

    This study kinetically investigated landfill leachate rejected by reverse osmosis (RO) oxidation degradation by ozonation. Initial pH, ozone dosage, temperature and initial COD had significant impact on the oxidation rate. The results demonstrated that for the removal efficiencies of COD 67.6% under the conditions of 8.0 pH, 5.02 g/h ozone dosage, 303K temperature. The empirical kinetic equation of ozonation degradation for landfill leachate under the conditions of 2.0-8.0 pH, 2.53-6.90 g/h ozone dosage, 934-4 037 mg/L initial COD, 283-323 K temperature fitted well with the experimental data(R2 0.969-0.996), with low activation energy E(a) = 1.43 x1094) J x mol(-1). PMID:22279910

  6. High-efficiency optical coupling single-sideband modulation for OFDM-RoF-PON systems

    NASA Astrophysics Data System (ADS)

    Xue, Xuwei; Ji, Wei; Kang, Zhaoyuan; Huang, Kangrui; Li, Xiao

    2015-12-01

    We report on an OFDM-RoF-PON system based on novel optical coupling single-sideband (O-SSB) modulation for one wavelength carrying one baseband and two radio frequency (RF) signals. The impact of nonlinear distortion consisting of harmonic distortion (HD) and intermodulation distortion (IMD) in this system is theoretically investigated. Transmission over 0 km and 40 km of standard single mode fiber is successfully demonstrated and it is indicated that modulation index 0.6 is more adapted to O-SSB modulation. The error vector magnitude (EVM) of system based on O-SSB modulation after transmission over 40 km is <0.1. For O-SSB modulation, bit error rate (BER) after 40 km transmission is below forward error correction (FEC) limit of 10-3.

  7. Ro-vibrational averaging of the isotropic hyperfine coupling constant for the methyl radical.

    PubMed

    Adam, Ahmad Y; Yachmenev, Andrey; Yurchenko, Sergei N; Jensen, Per

    2015-12-28

    We present the first variational calculation of the isotropic hyperfine coupling constant of the carbon-13 atom in the CH3 radical for temperatures T = 0, 96, and 300 K. It is based on a newly calculated high level ab initio potential energy surface and hyperfine coupling constant surface of CH3 in the ground electronic state. The ro-vibrational energy levels, expectation values for the coupling constant, and its temperature dependence were calculated variationally by using the methods implemented in the computer program TROVE. Vibrational energies and vibrational and temperature effects for coupling constant are found to be in very good agreement with the available experimental data. We found, in agreement with previous studies, that the vibrational effects constitute about 44% of the constant's equilibrium value, originating mainly from the large amplitude out-of-plane bending motion and that the temperature effects play a minor role. PMID:26723670

  8. Ro-vibrational averaging of the isotropic hyperfine coupling constant for the methyl radical

    NASA Astrophysics Data System (ADS)

    Adam, Ahmad Y.; Yachmenev, Andrey; Yurchenko, Sergei N.; Jensen, Per

    2015-12-01

    We present the first variational calculation of the isotropic hyperfine coupling constant of the carbon-13 atom in the CH3 radical for temperatures T = 0, 96, and 300 K. It is based on a newly calculated high level ab initio potential energy surface and hyperfine coupling constant surface of CH3 in the ground electronic state. The ro-vibrational energy levels, expectation values for the coupling constant, and its temperature dependence were calculated variationally by using the methods implemented in the computer program TROVE. Vibrational energies and vibrational and temperature effects for coupling constant are found to be in very good agreement with the available experimental data. We found, in agreement with previous studies, that the vibrational effects constitute about 44% of the constant's equilibrium value, originating mainly from the large amplitude out-of-plane bending motion and that the temperature effects play a minor role.

  9. Novel full-duplex SSB WDM-RoF system with SLM technique for decreasing PAPR

    NASA Astrophysics Data System (ADS)

    Xiao, Yao-qiang; Chen, Lin; Li, Fan; He, Hai-zhen

    2013-07-01

    A novel full-duplex single-sideband (SSB) wavelength division multiplexing radio over fiber (WDM-RoF) system with selected mapping (SLM) technique for decreasing peak-to-average power ratio (PAPR) is proposed in this paper. At the central office (CO), the generated SSB signal carrying 10 Gbit/s 16-ary quadrature amplitude modulation orthogonal frequency division multiplexing (16QAM-OFDM) downstream signal with SLM technique is sent to the base station, and 60 GHz SSB optical signal carrying 10 Gbit/s 16QAM-OFDM upstream signal is sent back to CO utilizing the wavelength-reuse technology. Simulation results show the proposed method for PAPR reduction can effectively improve the sensitivity of receiver, and the power penalty of the 16QAM-OFDM downlink (uplink) signal is about 2 dB (3 dB) at BER of 1×10-3 after 42 km standard single-mode fiber (SSMF) transmission.

  10. The Domain of δ Scuti Stars: First CoRoT IRa01 Results

    NASA Astrophysics Data System (ADS)

    Kaiser, Alexander; Weiss, Werner; Guenther, Eike; Balaguer, Lola; Maceroni, Carla; Ribas, Ignasi

    2009-09-01

    We present the first results of determing the δ Scuti population observed with CoRoT during the Initial Run (IRa01). From more than 10000 stars observed continuously in the exoplanet-channel during 58 days, 397 stars show pulsation in the δ Scuti domain. For 39 of the 397 stars low resolution classification spectra and Strömgren uvby photometry were available; thus fundamental parameters like effective temperature and surface gravity could be derived. Classical Fourier techniques and least squares multi-sine fits were applied to identify the pulsation frequencies. For additional 90 stars a pair of radial modes were found and by comparing with pulsation models it was possible to estimate the corresponding fundamental parameters.

  11. Isothiouronium compounds as gamma-aminobutyric acid agonists.

    PubMed Central

    Allan, R. D.; Dickenson, H. W.; Hiern, B. P.; Johnston, G. A.; Kazlauskas, R.

    1986-01-01

    Analogues of gamma-aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea-pig ileum; [3H]-GABA and [3H]-diazepam binding to rat brain membranes; and GABA uptake and transamination. For the homologous series of omega-isothiouronium alkanoic acids, maximum GABA-mimetic activity was found at 3-[(aminoiminomethyl)thio]propanoic acid. Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites. Both isomers were moderately potent at inhibiting the uptake of [3H]-GABA into rat brain slices. Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites. PMID:3015310

  12. Cold Suppresses Agonist-induced Activation of TRPV1

    PubMed Central

    Chung, M.-K.; Wang, S.

    2011-01-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction. PMID:21666106

  13. Antidiabetic Actions of an Estrogen Receptor β Selective Agonist

    PubMed Central

    Alonso-Magdalena, Paloma; Ropero, Ana B.; García-Arévalo, Marta; Soriano, Sergi; Quesada, Iván; Muhammed, Sarheed J.; Salehi, Albert; Gustafsson, Jan-Ake; Nadal, Ángel

    2013-01-01

    The estrogen receptor β (ERβ) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERβ selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic β-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide–induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic β-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic β-cell mass. We conclude that ERβ agonists should be considered as new targets for the treatment of diabetes. PMID:23349481

  14. Anti-cancer flavonoids are mouse selective STING agonists

    PubMed Central

    Kim, Sujeong; Li, Lingyin; Maliga, Zoltan; Yin, Qian; Wu, Hao; Mitchison, Timothy J.

    2013-01-01

    The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice, but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other anti-tumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the anti-tumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy. PMID:23683494

  15. Aging changes agonist induced contractile responses in permeabilized rat bladder.

    PubMed

    Durlu-Kandilci, N Tugba; Denizalti, Merve; Sahin-Erdemli, Inci

    2015-08-01

    Aging alters bladder functions where a decrease in filling, storage and emptying is observed. These changes cause urinary incontinence, especially in women. The aim of this study is to examine how aging affects the intracellular calcium movements due to agonist-induced contractions in permeabilized female rat bladder. Urinary bladder isolated from young and old female Sprague-Dawley rats were used. Small detrusor strips were permeabilized with β-escin. The contractile responses induced with agonists were compared between young and old groups. Carbachol-induced contractions were decreased in permeabilized detrusor from old rats compared to young group. Heparin and ryanodine decreased carbachol-induced contractions in young rats where only heparin inhibited these contractions in olds. Caffeine-induced contractions but not inositol triphosphate (IP3)-induced contractions were decreased in old group compared to youngs. The cumulative calcium response curves (pCa 8-4) were also decreased in old rats. Carbachol-induced calcium sensitization responses did not alter by age where GTP-β-S and GF-109203X but not Y-27632 inhibited these responses. Carbachol-induced contractions decrease with aging in rat bladder detrusor. It can be postulated as IP3-induced calcium release (IICR) is primarily responsible for the contractions in older rats where the decrease in carbachol contractions in aging may be as a result of a decrease in calcium-induced calcium release (CICR), rather than carbachol-induced calcium sensitization. PMID:26153091

  16. A Sphingosine 1-phosphate receptor 2 selective allosteric agonist

    PubMed Central

    Satsu, Hideo; Schaeffer, Marie-Therese; Guerrero, Miguel; Saldana, Adrian; Eberhart, Christina; Hodder, Peter; Cayanan, Charmagne; Schürer, Stephan; Bhhatarai, Barun; Roberts, Ed; Rosen, Hugh; Brown, Steven J.

    2013-01-01

    Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. PMID:23849205

  17. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists. PMID:19832688

  18. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    SciTech Connect

    Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.

    1985-10-28

    The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with (/sup 3/H)-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT/sub 2/ antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT/sub 2/ type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures.

  19. Suppression of atherosclerosis by synthetic REV-ERB agonist.

    PubMed

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M; Solt, Laura A; Burris, Thomas P

    2015-05-01

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. PMID:25800870

  20. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID:24752777

  1. How does agonistic behaviour differ in albino and pigmented fish?

    PubMed Central

    Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  2. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

    Knight, John M.; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O.; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A.; Milner, Joshua D.; Zhang, Yuan; Mandal, Pijus K.; Luong, Amber; Kheradmand, Farrah

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  3. Cariprazine:New dopamine biased agonist for neuropsychiatric disorders.

    PubMed

    De Deurwaerdère, P

    2016-02-01

    Cariprazine (RGH-188, MP-214, Vraylar[TM]) is a new dopamine receptor ligand developed for the treatment of several neuropsychiatric diseases including schizophrenia and bipolar disorders. Cariprazine displays higher affinity at dopamine D3 receptors and a similar affinity at D2 and 5-HT2B receptors. At variance with some atypical antipsychotics, its affinity at 5-HT1A, 5-HT2A and histamine H1 receptors is modest compared with its three main targets. Cariprazine could correspond to a biased agonist at dopamine receptors, displaying either antagonist or partial agonist properties depending on the signaling pathways linked to D2/D3 receptors. The compound crosses the blood-brain barrier, as revealed by positron emission tomography and pharmacokinetic studies in various species. Two main metabolites result mainly from the activity of CYP34A and display properties similar to those of the parent drug. Behavioral data report that cariprazine is efficacious in animal models addressing positive, negative and cognitive symptoms of schizophrenia with no extrapyramidal side effects. In September 2015, the FDA approved the use of cariprazine for the treatment of schizophrenia and type I bipolar disorder. The efficacy of cariprazine in other neuropsychiatric diseases is currently being evaluated in preclinical and clinical studies. Side effects have been observed in humans, including extrapyramidal side effects and akathisia of mild to moderate intensity. PMID:27092339

  4. Long-Acting Beta Agonists Enhance Allergic Airway Disease.

    PubMed

    Knight, John M; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A; Milner, Joshua D; Zhang, Yuan; Mandal, Pijus K; Luong, Amber; Kheradmand, Farrah; McMurray, John S; Corry, David B

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  5. The Risk of Paradoxical Embolism (RoPE) Study: Initial description of the completed database

    PubMed Central

    Thaler, David E.; Angelantonio, Emanuele Di; Di Tullio, Marco R.; Donovan, Jennifer S.; Elkind, Mitchell S. V.; Griffith, John; Homma, Shunichi; Jaigobin, Cheryl; Mas, Jean-Louis; Mattle, Heinrich P.; Michel, Patrik; Mono, Marie-Luise; Nedeltchev, Krassen; Papetti, Federica; Ruthazer, Robin; Serena, Joaquín; Weimar, Christian; Kent, David M.

    2014-01-01

    Background Detecting a benefit from closure of patent foramen ovale (PFO) in patients with cryptogenic stroke (CS) is hampered by low rates of stroke recurrence and uncertainty about the causal role of PFO in the index event. A method to predict PFO-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence. Aims To develop a database to support modeling of PFO-attributable recurrence risk by combining extant data sets. Methods We identified investigators with extant databases including subjects with CS investigated for PFO; determined the availability and characteristics of data in each database; collaboratively specified the variables to be included in the Risk of Paradoxical Embolism (RoPE) database; harmonized the variables across databases, and collected new primary data when necessary and feasible. Results The RoPE database has individual clinical, radiologic, and echocardiographic data from 12 component databases including subjects with CS both with (n=1925) and without (n=1749) PFO. In the PFO subjects, a total of 381 outcomes (stroke, TIA, death) occurred (median follow-up = 2.2yrs). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling. Conclusion While individual studies are inadequate for modeling PFO-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a PFO-related stroke recurrence who may have the greatest potential benefit from PFO closure. PMID:22883936

  6. Bacterial attachment to RO membranes surface-modified by concentration-polarization-enhanced graft polymerization.

    PubMed

    Bernstein, Roy; Belfer, Sofia; Freger, Viatcheslav

    2011-07-15

    Concentration polarization-enhanced radical graft polymerization, a facile surface modification technique, was examined as an approach to reduce bacterial deposition onto RO membranes and thus contribute to mitigation of biofouling. For this purpose an RO membrane ESPA-1 was surface-grafted with a zwitterionic and negatively and positively charged monomers. The low monomer concentrations and low degrees of grafting employed in modifications moderately reduced flux (by 20-40%) and did not affect salt rejection, yet produced substantial changes in surface chemistry, charge and hydrophilicity. The propensity to bacterial attachment of original and modified membranes was assessed using bacterial deposition tests carried out in a parallel plate flow setup using a fluorescent strain of Pseudomonas fluorescens. Compared to unmodified ESPA-1 the deposition (mass transfer) coefficient was significantly increased for modification with the positively charged monomer. On the other hand, a substantial reduction in bacterial deposition rates was observed for membranes modified with zwitterionic monomer and, still more, with very hydrophilic negatively charged monomers. This trend is well explained by the effects of surface charge (as measured by ζ-potential) and hydrophilicity (contact angle). It also well correlated with force distance measurements by AFM using surrogate spherical probes with a negative surface charge mimicking the bacterial surface. The positively charged surface showed a strong hysteresis with a large adhesion force, which was weaker for unmodified ESPA-1 and still weaker for zwitterionic surface, while negatively charged surface showed a long-range repulsion and negligible hysteresis. These results demonstrate the potential of using the proposed surface- modification approach for varying surface characteristics, charge and hydrophilicity, and thus minimizing bacterial deposition and potentially reducing propensity biofouling. PMID:21682251

  7. Magnetic Doppler imaging of the roAp star HD 24712

    NASA Astrophysics Data System (ADS)

    Lüftinger, T.; Kochukhov, O.; Ryabchikova, T.; Piskunov, N.; Weiss, W. W.; Ilyin, I.

    2010-01-01

    Aims: We present the first magnetic Doppler images of a rapidly oscillating Ap (roAp) star. Methods: We deduce information about magnetic field geometry and abundance distributions of a number of chemical elements on the surface of the hitherto best studied roAp star, HD 24712, using the magnetic Doppler imaging (MDI) code, invers10, which allows us to reconstruct simultaneously and consistently the magnetic field geometry and elemental abundance distributions on a stellar surface. For this purpose we analyse time series spectra obtained in Stokes I and V parameters with the SOFIN polarimeter at the Nordic Optical Telescope and recover surface abundance structures of sixteen different chemical elements, respectively ions, including Mg, Ca, Sc, Ti, Cr, Fe, Co, Ni, Y, La, Ce, Pr, Nd, Gd, Tb, and Dy. For the rare earth elements (REE) Pr and Nd separate maps were obtained using lines of the first and the second ionization stage. Results: We find and confirm a clear dipolar structure of the surface magnetic field and an unexpected correlation of elemental abundance with respect to this field: one group of elements accumulates solely where the positive magnetic pole is visible, whereas the other group avoids this region and is enhanced where the magnetic equatorial region dominates the visible stellar surface. We also observe relative shifts of abundance enhancement- or depletion regions between the various elements exhibiting otherwise similar behaviour. Based on observations made with the Nordic Optical Telescope, operated on the island of La Palma jointly by Denmark, Finland, Iceland, Norway, and Sweden, in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofisica de Canarias.

  8. On the Southern Gravity Wave Hot Spot: An Individual Waves Study with Cosmic GPS-RO

    NASA Astrophysics Data System (ADS)

    Hindley, N.; Wright, C.; Mitchell, N. J.

    2014-12-01

    The mountainous Southern Andes and Antarctic Peninsula (SAAP) region is one of the most intense sources of Gravity Waves (GWs) on Earth. In austral winter, momentum deposition from orographic GWs into the lower stratosphere from this region can exert a strong drag effect on winds in the polar stratospheric jet. The exact nature of this drag effect is difficult to parameterise operationally in GCMs, and as a result such wave parameterisations are generally poorly constrained by observations. Using COSMIC GPS-RO, we observe high Gravity Wave Potential Energy (GWPE) both directly over the SAAP region and downwind in a long leeward wake stretching more than half way around the globe, and comment on possible relationships between the two features. We also observe a vertical column of GWPE directly over the Southern Andes in both zonal and meridional cross-sections, the latter of which suggests a strong southward advection of orographic GWs into the polar stratospheric jet. We investigate the observed difference in monthly GW climatologies when an approach using only COSMIC profiles in which GW signals have been clearly identified is applied in preference to the traditional all-measurement time-averaged approach, and use this to obtain an estimate of GW intermittency in the SAAP region. Finally, we take advantage of the deployment phase of the COSMIC constellation to obtain an estimate of momentum flux in the SAAP region, using the phase difference between pairs of closely spaced profiles to estimate the horizontal wavelengths of resolved GWs. We demonstrate that during the deployment phase, momentum flux estimates derived from COSMIC GPS-RO are comparable to those derived from HIRDLS.

  9. Effects of localised tumour hyperthermia on pimonidazole (Ro 03-8799) pharmacokinetics in mice.

    PubMed Central

    Walton, M. I.; Bleehen, N. M.; Workman, P.

    1989-01-01

    We have investigated the effects of localised tumour hyperthermia (LTH; 43.5 degrees C x 30 min) on the acute toxicity and pharmacokinetics of the hypoxic cell sensitizer pimonidazole (Ro 03-8799) in mice. There were three treatment groups: unrestrained controls, sham-treated and LTH treated mice. LTH had minimal effects on the acute toxicity (LD50/7d) of pimonidazole with no significant difference between the three treatment groups. Pharmacokinetic studies were carried out at the maximum tolerated dose (MTD; approximately 60% LD50) of 437 micrograms g-1 i.v. in plasma, brain and tumour. Sham tumour treatment consistently increased plasma drug concentrations compared to unrestrained controls but had minimal effects on the elimination t1/2. The AUC0-infinitive was increased by 35% and the plasma clearance decreased by 26%. By contrast, LTH had minimal effects on these parameters compared to sham treatment. Brain pimonidazole concentrations were increased in restrained mice (sham and LTH treatments) compared to unrestrained controls, but average brain/plasma ratios were similar in all three groups at between 400 and 500%. Sham tumour treatment markedly reduced peak tumour pimonidazole concentrations compared to unrestrained controls giving a 29% lower AUC0-180min. Average tumour/plasma ratios were reduced from 236 to 129%. The most important finding was that LTH further reduced pimonidazole tumour concentrations, giving a 31% lower AUC0-180 min compared to sham treated tumours. Tumour/plasma ratios for pimonidazole were reduced by 41%. Plasma exposure to the pimonidazole N-oxide metabolite, Ro 31-0313, was unaltered by LTH. The markedly reduced drug concentrations in heated tumours may be a result of hyperthermia-stimulated bioreductive drug activation. PMID:2736198

  10. The CoRoT and Kepler Revolution in Stellar Variability Studies

    NASA Astrophysics Data System (ADS)

    Degroote, Pieter; Debosscher, Jonas

    2012-04-01

    Space-based observations of variable stars have revolutionized the field of variability studies. Dedicated satellites such as the CoRoT and Kepler missions have duty cycles which are unachievable from the ground, and effectively solve many of the aliasing problems prevalent in ground-based observation campaigns. Moreover, the location above the Earth's atmosphere eliminates a major source of scatter prevalent in observations from the ground. These two major improvements in instrumentation have triggered significant increases in our knowledge of the stars, but in order to reap the full benefits they are also obliging the community to adopt more efficient techniques for handling, analysing and interpreting the vast amounts of new, high-precision data in an effective yet comprehensive manner. This workshop heard an outline of the history and development of asteroseismology, and descriptions of the two space missions (CoRoT and Kepler) which have been foremost in accelerating those recent developments. Informal discussions on numerous points peppered the proceedings, and involved the whole audience at times. The conclusions which the workshop reached have been distilled into a list of seven recommendations (Section 5) for the asteroseismology community to study and absorb. In fact, while addressing activities (such as stellar classification or analysing and modelling light curves) that could be regarded as specific to the community in question, the recommendations include advice on matters such as improving communication, incorporating trans-disciplinary knowledge and involving the non-scientific public that are broad enough to serve as guidelines for the astrophysical community at large.

  11. Presenting new exoplanet candidates for the CoRoT chromatic light curves

    NASA Astrophysics Data System (ADS)

    Boufleur, Rodrigo; Emilio, Marcelo; Andrade, Laerte; Janot-Pacheco, Eduardo; De La Reza, Ramiro

    2015-08-01

    One of the most promising topics of modern Astronomy is the discovery and characterization of extrasolar planets due to its importance for the comprehension of planetary formation and evolution. Missions like MOST (Microvariability and Oscillations of Stars Telescope) (Walker et al., 2003) and especially the satellites dedicated to the search for exoplanets CoRoT (Convection, Rotation and planetary Transits) (Baglin et al., 1998) and Kepler (Borucki et al., 2003) produced a great amount of data and together account for hundreds of new discoveries. An important source of error in the search for planets with light curves obtained from space observatories are the displacements occuring in the data due to external causes. This artificial charge generation phenomenon associated with the data is mainly caused by the impact of high energy particles onto the CCD (Pinheiro da Silva et al. 2008), although other sources of error, not as well known also need to be taken into account. So, an effective analysis of the light curves depends a lot on the mechanisms employed to deal with these phenomena. To perform our research, we developed and applied a different method to fix the light curves, the CDAM (Corot Detrend Algorithm Modified), inspired by the work of Mislis et al. (2012). The paradigms were obtained using the BLS method (Kovács et al., 2002). After a semiautomatic pre-analysis associated with a visual inspection of the planetary transits signatures, we obtained dozens of exoplanet candidates in very good agreement with the literature and also new unpublished cases. We present the study results and characterization of the new cases for the chromatic channel public light curves of the CoRoT satellite.

  12. The CoRoT chemical peculiar target star HD 49310

    NASA Astrophysics Data System (ADS)

    Paunzen, E.; Fröhlich, H.-E.; Netopil, M.; Weiss, W. W.; Lüftinger, T.

    2015-02-01

    Context. The magnetic chemically peculiar (CP) stars of the upper main sequence are well-suited laboratories for investigating the influence of local magnetic fields on the stellar surface because they produce inhomogeneities (spots) that can be investigated in detail as the star rotates. Aims: We studied the inhomogeneous surface structure of the CP2 star HD 49310 based on high-quality CoRoT photometry obtained during 25 days. The data have nearly no gaps. This analysis is similar to a spectroscopic Doppler-imaging analysis, but it is not a tomographic method. Methods: We performed detailed light-curve fitting in terms of stationary circular bright spots. Furthermore, we derived astrophysical parameters with which we located HD 49310 within the Hertzsprung-Russell diagram. We also investigated the possible connection of this star to the nearby young open cluster NGC 2264. Results: With a Bayesian technique, we produced a surface map that shows six bright spots. After removing some artefacts, the residuals of the observed and synthetic photometric data are ± 0.123 mmag. The rotational period of the star is P = 1.91909 ± 0.00001 days. Our photometric observations therefore cover about 13 full rotational cycles. Three spots are very large with diameters of ≃ 40deg. The spots are brighter by 40% than the unperturbed stellar photosphere. Conclusions: HD 49310 is a classical silicon (CP2) star with a mass of about 3 M⊙. It is not a member of NGC 2264. Our analysis shows the potential of using high-quality photometric data to analyse the surface structure of CP stars. A comprehensive analysis of similar archival data, preferrably from space missions, would contribute significantly to our understanding of surface phenomena of CP stars and their temporal evolution. The CoRoT space mission was developed and is operated by the French space agency CNES, with participation of ESA's RSSD and Science Programmes, Austria, Belgium, Brazil, Germany, and Spain.

  13. The CoRoT satellite in flight: description and performance

    NASA Astrophysics Data System (ADS)

    Auvergne, M.; Bodin, P.; Boisnard, L.; Buey, J.-T.; Chaintreuil, S.; Epstein, G.; Jouret, M.; Lam-Trong, T.; Levacher, P.; Magnan, A.; Perez, R.; Plasson, P.; Plesseria, J.; Peter, G.; Steller, M.; Tiphène, D.; Baglin, A.; Agogué, P.; Appourchaux, T.; Barbet, D.; Beaufort, T.; Bellenger, R.; Berlin, R.; Bernardi, P.; Blouin, D.; Boumier, P.; Bonneau, F.; Briet, R.; Butler, B.; Cautain, R.; Chiavassa, F.; Costes, V.; Cuvilho, J.; Cunha-Parro, V.; de Oliveira Fialho, F.; Decaudin, M.; Defise, J.-M.; Djalal, S.; Docclo, A.; Drummond, R.; Dupuis, O.; Exil, G.; Fauré, C.; Gaboriaud, A.; Gamet, P.; Gavalda, P.; Grolleau, E.; Gueguen, L.; Guivarc'h, V.; Guterman, P.; Hasiba, J.; Huntzinger, G.; Hustaix, H.; Imbert, C.; Jeanville, G.; Johlander, B.; Jorda, L.; Journoud, P.; Karioty, F.; Kerjean, L.; Lafond, L.; Lapeyrere, V.; Landiech, P.; Larqué, T.; Laudet, P.; Le Merrer, J.; Leporati, L.; Leruyet, B.; Levieuge, B.; Llebaria, A.; Martin, L.; Mazy, E.; Mesnager, J.-M.; Michel, J.-P.; Moalic, J.-P.; Monjoin, W.; Naudet, D.; Neukirchner, S.; Nguyen-Kim, K.; Ollivier, M.; Orcesi, J.-L.; Ottacher, H.; Oulali, A.; Parisot, J.; Perruchot, S.; Piacentino, A.; Pinheiro da Silva, L.; Platzer, J.; Pontet, B.; Pradines, A.; Quentin, C.; Rohbeck, U.; Rolland, G.; Rollenhagen, F.; Romagnan, R.; Russ, N.; Samadi, R.; Schmidt, R.; Schwartz, N.; Sebbag, I.; Smit, H.; Sunter, W.; Tello, M.; Toulouse, P.; Ulmer, B.; Vandermarcq, O.; Vergnault, E.; Wallner, R.; Waultier, G.; Zanatta, P.

    2009-10-01

    Context: CoRoT is a space telescope dedicated to stellar seismology and the search for extrasolar planets. The mission is led by the CNES in association with French laboratories and has a large international participation. The European Space Agency (ESA), Austria, Belgium, and Germany contribute to the payload, and Spain and Brazil contribute to the ground segment. Development of the spacecraft, which is based on a PROTEUS low earth orbit (LEO) recurrent platform, commenced in October 2000, and the satellite was launched on December 27, 2006. Aims: The instrument and platform characteristics prior to launch have been described in ESA publication (SP-1306). In the present paper we explain the behaviour in flight, based on raw and corrected data. Methods: Five runs have been completed since January 2007. The data used here are essentially those acquired during the commissioning phase and from a long run that lasted 146 days. These enable us to give a complete overview of the instrument and platform behaviour for all environmental conditions. The ground based data processing is not described in detail because the most important method has been published elsewhere. Results: We show that the performance specifications are easily satisfied when the environmental conditions are favourable. Most of the perturbations, hence data corrections, are related to LEO perturbations: high energy particles inside the South Atlantic Anomaly (SAA), eclipses and temperature variations, and line of sight fluctuations due to the attitude control system. Straylight due to the reflected light from the earth, which is controlled by the telescope and baffle design, appears to be negligible. The CoRoT space mission, launched on December 27th 2006, has been developed and is operated by CNES, with contributions from Austria, Belgium, Brazil, ESA, Germany and Spain. Four French laboratories associated with the CNRS (LESIA, LAM, IAS, OMP) collaborate with CNES on the satellite development. The

  14. The extreme physical properties of the CoRoT-7b super-Earth

    NASA Astrophysics Data System (ADS)

    Léger, A.; Grasset, O.; Fegley, B.; Codron, F.; Albarede, A. F.; Barge, P.; Barnes, R.; Cance, P.; Carpy, S.; Catalano, F.; Cavarroc, C.; Demangeon, O.; Ferraz-Mello, S.; Gabor, P.; Grießmeier, J.-M.; Leibacher, J.; Libourel, G.; Maurin, A.-S.; Raymond, S. N.; Rouan, D.; Samuel, B.; Schaefer, L.; Schneider, J.; Schuller, P. A.; Selsis, F.; Sotin, C.

    2011-05-01

    The search for rocky exoplanets plays an important role in our quest for extra-terrestrial life. Here, we discuss the extreme physical properties possible for the first characterised rocky super-Earth, CoRoT-7b ( R pl = 1.58 ± 0.10 R Earth, M pl = 6.9 ± 1.2 M Earth). It is extremely close to its star ( a = 0.0171 AU = 4.48 R st), with its spin and orbital rotation likely synchronised. The comparison of its location in the ( M pl, R pl) plane with the predictions of planetary models for different compositions points to an Earth-like composition, even if the error bars of the measured quantities and the partial degeneracy of the models prevent a definitive conclusion. The proximity to its star provides an additional constraint on the model. It implies a high extreme-UV flux and particle wind, and the corresponding efficient erosion of the planetary atmosphere especially for volatile species including water. Consequently, we make the working hypothesis that the planet is rocky with no volatiles in its atmosphere, and derive the physical properties that result. As a consequence, the atmosphere is made of rocky vapours with a very low pressure ( P ⩽ 1.5 Pa), no cloud can be sustained, and no thermalisation of the planet is expected. The dayside is very hot (2474 ± 71 K at the sub-stellar point) while the nightside is very cold (50-75 K). The sub-stellar point is as hot as the tungsten filament of an incandescent bulb, resulting in the melting and distillation of silicate rocks and the formation of a lava ocean. These possible features of CoRoT-7b could be common to many small and hot planets, including the recently discovered Kepler-10b. They define a new class of objects that we propose to name " Lava-ocean planets".

  15. Selective labelling of diazepam-insensitive GABAA receptors in vivo using [3H]Ro 15-4513

    PubMed Central

    Pym, Luanda J; Cook, Susan M; Rosahl, Thomas; McKernan, Ruth M; Atack, John R

    2005-01-01

    Classical benzodiazepines (BZs), such as diazepam, bind to GABAA receptors containing α1, α2, α3 or α5 subunits that are therefore described as diazepam-sensitive (DS) receptors. However, the corresponding binding site of GABAA receptors containing either an α4 or α6 subunit do not bind the classical BZs and are therefore diazepam-insensitive (DIS) receptors; a difference attributable to a single amino acid (histidine in α1, α2, α3 and α5 subunits and arginine in α4 and α6). Unlike classical BZs, the imidazobenzodiazepines Ro 15-4513 and bretazenil bind to both DS and DIS populations of GABAA receptors. In the present study, an in vivo assay was developed using lorazepam to fully occupy DS receptors such that [3H]Ro 15-4513 was then only able to bind to DIS receptors. When dosed i.v., [3H]Ro 15-4513 rapidly entered and was cleared from the brain, with approximately 70% of brain radioactivity being membrane-bound. Essentially all membrane binding to DS+DIS receptors could be displaced by unlabelled Ro 15-4513 or bretazenil, with respective ID50 values of 0.35 and 1.2 mg kg−1. A dose of 30 mg kg−1 lorazepam was used to block all DS receptors in a [3H]Ro 15-1788 in vivo binding assay. When predosed in a [3H]Ro 15-4513 binding assay, lorazepam blocked [3H]Ro 15-4513 binding to DS receptors, with the remaining binding to DIS receptors accounting for 5 and 23% of the total (DS plus DIS) receptors in the forebrain and cerebellum, respectively. The in vivo binding of [3H]Ro 15-4513 to DIS receptors in the presence of lorazepam was confirmed using α1H101R knock-in mice, in which α1-containing GABAA receptors are rendered diazepam insensitive by mutation of the histidine that confers diazepam sensitivity to arginine. In these mice, and in the presence of lorazepam, there was an increase of in vivo [3H]Ro 15-4513 binding in the forebrain and cerebellum from 4 and 15% to 36 and 59% of the total (i.e. DS plus DIS) [3H]Ro 15-4513 binding observed in the

  16. Temporal Spectral Analysis of Be stars observed with CoRoT satellite

    NASA Astrophysics Data System (ADS)

    Emilio, Marcelo; Janot Pacheco, Eduardo; Andrade, Laerte

    . Nevertheless, to measure frequencies with great accuracy in stars requires both high photometric precision and high time-frequency resolution. The CoRoT (Convection, Rotation and planetary Transits) satellite opens for the first time in history the possibility of fulfilling this goal. CoRoT is an experiment of astronomy dedicated to seismology and the detection of extrasolar planet transits. It was launched on December 2006 in an inertial polar orbit at an altitude of 897 mathrm{km}. The instrument is fed by a phi=27 textrm{cm} telescope. Its scientific program is three-fold consisting of: (1) The seismology core program (SISMO), which concerns the seismic study of ˜10 bright (6RoT ID 102761769 observed by CoRoT satellite. We found two close frequencies related to the .CoRoT ID 102761769 star. They are 2.465 c d(-1) (28.5 mathrm{mu Hz}) and 2.441 c d(-1) (28.2 mathrm{mu Hz}). The precision to which those frequencies were found is 0.018 c d(-1) (0.2 mathrm{mu Hz}). The projected stellar rotation was estimated to be 120 km s(-1) from the Fourier transform of spectral lines. If CoRoT-ID 102761769 is a typical Galactic Be star it rotates near the critical velocity. The critical rotation frequency of a typical B5-6 star is about 3.5 c d(-1) (40.5 mathrm{mu Hz}), which implies that the above frequencies are really caused by stellar pulsations rather than star's rotation. HD 171219 frequencies 1.113, 1.130, 1.146 c * d(-1) form a triplet with the

  17. The zipcode-binding protein ZBP1 influences the subcellular location of the Ro 60-kDa autoantigen and the noncoding Y3 RNA

    PubMed Central

    Sim, Soyeong; Yao, Jie; Weinberg, David E.; Niessen, Sherry; Yates, John R.; Wolin, Sandra L.

    2012-01-01

    The Ro 60-kDa autoantigen, a ring-shaped RNA-binding protein, traffics between the nucleus and cytoplasm in vertebrate cells. In some vertebrate nuclei, Ro binds misfolded noncoding RNAs and may function in quality control. In the cytoplasm, Ro binds noncoding RNAs called Y RNAs. Y RNA binding blocks a nuclear accumulation signal, retaining Ro in the cytoplasm. Following UV irradiation, this signal becomes accessible, allowing Ro to accumulate in nuclei. To investigate how other cellular components influence the function and subcellular location of Ro, we identified several proteins that copurify with the mouse Ro protein. Here, we report that the zipcode-binding protein ZBP1 influences the subcellular localization of both Ro and the Y3 RNA. Binding of ZBP1 to the Ro/Y3 complex increases after UV irradiation and requires the Y3 RNA. Despite the lack of an identifiable CRM1-dependent export signal, nuclear export of Ro is sensitive to the CRM1 inhibitor leptomycin B. In agreement with a previous report, we find that ZBP1 export is partly dependent on CRM1. Both Ro and Y3 RNA accumulate in nuclei when ZBP1 is depleted. Our data indicate that ZBP1 may function as an adapter to export the Ro/Y3 RNA complex from nuclei. PMID:22114317

  18. The autoantigen Ro52 is an E3 ligase resident in the cytoplasm but enters the nucleus upon cellular exposure to nitric oxide

    SciTech Connect

    Espinosa, Alexander; Oke, Vilija; Elfving, Ase; Nyberg, Filippa; Covacu, Ruxandra; Wahren-Herlenius, Marie

    2008-12-10

    Patients with the systemic autoimmune diseases Sjoegrens's syndrome and systemic lupus erythematosus often have autoantibodies against the intracellular protein Ro52. Ro52 is an E3 ligase dependent on the ubiquitin conjugation enzymes UBE2D1 and UBE2E1. While Ro52 and UBE2D1 are cytoplasmic proteins, UBE2E1 is localized to the nucleus. Here, we investigate how domains of human Ro52 regulate its intracellular localization. By expressing fluorescently labeled Ro52 and Ro52 mutants in HeLa cells, an intact coiled-coil domain was found to be necessary for the cytoplasmic localization of Ro52. The amino acids 381-470 of the B30.2 region were essential for translocation into the nucleus. Furthermore, after exposure of HeLa cells to the inflammatory mediator nitric oxide (NO), Ro52 translocated to the nucleus. A nuclear localization of Ro52 in inflamed tissue expressing inducible NO synthetase (iNOS) from cutaneous lupus patients was observed by immunohistochemistry and verified in NO-treated cultures of patient-derived primary keratinocytes. Our results show that the localization of Ro52 is regulated by endogenous sequences, and that nuclear translocation is induced by an inflammatory mediator. This suggests that Ro52 has both cytoplasmic and nuclear substrates, and that Ro52 mediates ubiquitination through UBE2D1 in the cytoplasm and through UBE2E1 in the nucleus.

  19. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification.

    PubMed

    Zaware, Pandurang; Shah, Shailesh R; Pingali, Harikishore; Makadia, Pankaj; Thube, Baban; Pola, Suresh; Patel, Darshit; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Jamili, Jeevankumar; Sairam, Kalapatapu V V M; Giri, Suresh; Patel, Lala; Patel, Harilal; Sudani, Hareshkumar; Patel, Hiren; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh

    2011-01-15

    A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders. PMID:21195611

  20. Impact of Efficacy at the μ-Opioid Receptor on Antinociceptive Effects of Combinations of μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

    PubMed Central

    Maguire, David R.

    2014-01-01

    Cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain. PMID:25194020

  1. Protein Kinase C-Independent Inhibition of Organic Cation Transporter 1 Activity by the Bisindolylmaleimide Ro 31-8220

    PubMed Central

    Mayati, Abdullah; Bruyere, Arnaud; Moreau, Amélie; Jouan, Elodie; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

    2015-01-01

    Ro 31–8220 is a potent protein kinase C (PKC) inhibitor belonging to the chemical class of bisindolylmaleimides (BIMs). Various PKC-independent effects of Ro 31–8220 have however been demonstrated, including inhibition of the ATP-binding cassette drug transporter breast cancer resistance protein. In the present study, we reported that the BIM also blocks activity of the solute carrier organic cation transporter (OCT) 1, involved in uptake of marketed drugs in the liver, in a PKC-independent manner. Ro 31–8220, in contrast to other pan-PKC inhibitors such as staurosporine and chelerythrine, was thus shown to cis-inhibit uptake of the reference OCT1 substrate tetraethylammonium in OCT1-transfected HEK293 cells in a concentration-dependent manner (IC50 = 0.18 μM) and without altering membrane expression of OCT1. This blockage of OCT1 was also observed in human hepatic HepaRG cells that constitutionally express OCT1. It likely occurred through a mixed mechanism of inhibition. Ro 31–8220 additionally trans-inhibited TEA uptake in OCT1-transfected HEK293 cells, which likely discards a transport of Ro 31–8220 by OCT1. Besides Ro 31–8220, 7 additional BIMs, including the PKC inhibitor LY 333531, inhibited OCT1 activity, whereas 4 other BIMs were without effect. In silico analysis of structure-activity relationships next revealed that various molecular descriptors, especially 3D-WHIM descriptors related to total size, correspond to key physico-chemical parameters for inhibition of OCT1 activity by BIMs. In addition to activity of OCT1, Ro 31–8220 inhibited those of other organic cation transporters such as multidrug and toxin extrusion protein (MATE) 1 and MATE2-K, whereas, by contrast, it stimulated that of OCT2. Taken together, these data extend the nature of cellular off-targets of the BIM Ro 31–8220 to OCT1 and other organic cation transporters, which has likely to be kept in mind when using Ro 31–8220 and other BIMs as PKC inhibitors in experimental

  2. 1,4-Benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonists.

    PubMed

    Sherrill, R G; Berman, J M; Birkemo, L; Croom, D K; Dezube, M; Ervin, G N; Grizzle, M K; James, M K; Johnson, M F; Queen, K L; Rimele, T J; Vanmiddlesworth, F; Sugg, E E

    2001-05-01

    A series of 1,4-benzodiazepines, N-1-substituted with an N-isopropyl-N-phenylacetamide moiety, was synthesized and screened for CCK-A agonist activity. In vitro agonist activity on isolated guinea pig gallbladder along with in vivo induction of satiety following intraperitoneal administration in a rat feeding assay was demonstrated. PMID:11354363

  3. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    PubMed

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics. PMID:26675887

  4. Functional desensitization of the β2 adrenoceptor is not dependent on agonist efficacy

    PubMed Central

    Rosethorne, Elizabeth M; Bradley, Michelle E; Kent, Toby C; Charlton, Steven J

    2015-01-01

    Chronic treatment with β2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure. The data show that upon repeat exposure, all agonists produced functional desensitization to the same degree and rate. In addition, β2 adrenoceptor internalization and β-arrestin-2 recruitment were monitored using β2·eGFP visualization and the PathHunter™ β-arrestin-2 assay, respectively. All agonists were capable of causing robust receptor internalization and β-arrestin-2 recruitment, the rate of which was influenced by agonist efficacy, as measured in those assays. In summary, although a relationship exists between agonist efficacy and the rate of both receptor internalization and β-arrestin-2 recruitment, there is no correlation between agonist efficacy and the rate or extent of functional desensitization. PMID:25692019

  5. Classical and atypical agonists activate M1 muscarinic acetylcholine receptors through common mechanisms.

    PubMed

    Randáková, Alena; Dolejší, Eva; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; El-Fakahany, Esam E; Jakubík, Jan

    2015-07-01

    We mutated key amino acids of the human variant of the M1 muscarinic receptor that target ligand binding, receptor activation, and receptor-G protein interaction. We compared the effects of these mutations on the action of two atypical M1 functionally preferring agonists (N-desmethylclozapine and xanomeline) and two classical non-selective orthosteric agonists (carbachol and oxotremorine). Mutations of D105 in the orthosteric binding site and mutation of D99 located out of the orthosteric binding site decreased affinity of all tested agonists that was translated as a decrease in potency in accumulation of inositol phosphates and intracellular calcium mobilization. Mutation of D105 decreased the potency of the atypical agonist xanomeline more than that of the classical agonists carbachol and oxotremorine. Mutation of the residues involved in receptor activation (D71) and coupling to G-proteins (R123) completely abolished the functional responses to both classical and atypical agonists. Our data show that both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site. Furthermore, our data demonstrate a key role of D105 in xanomeline wash-resistant binding and persistent activation of hM1 by wash-resistant xanomeline. PMID:25882246

  6. Prolonging Survival of Corneal Transplantation by Selective Sphingosine-1-Phosphate Receptor 1 Agonist

    PubMed Central

    Gao, Min; Liu, Yong; Xiao, Yang; Han, Gencheng; Jia, Liang; Wang, Liqiang; Lei, Tian; Huang, Yifei

    2014-01-01

    Corneal transplantation is the most used therapy for eye disorders. Although the cornea is somewhat an immune privileged organ, immune rejection is still the major problem that reduces the success rate. Therefore, effective chemical drugs that regulate immunoreactions are needed to improve the outcome of corneal transplantations. Here, a sphingosine-1-phosphate receptor 1 (S1P1) selective agonist was systematically evaluated in mouse allogeneic corneal transplantation and compared with the commonly used immunosuppressive agents. Compared with CsA and the non-selective sphingosine 1-phosphate (S1P) receptor agonist FTY720, the S1P1 selective agonist can prolong the survival corneal transplantation for more than 30 days with a low immune response. More importantly, the optimal dose of the S1P1 selective agonist was much less than non-selective S1P receptor agonist FTY720, which would reduce the dose-dependent toxicity in drug application. Then we analyzed the mechanisms of the selected S1P1 selective agonist on the immunosuppression. The results shown that the S1P1 selective agonist could regulate the distribution of the immune cells with less CD4+ T cells and enhanced Treg cells in the allograft, moreover the expression of anti-inflammatory cytokines TGF-β1 and IL-10 unregulated which can reduce the immunoreactions. These findings suggest that S1P1 selective agonist may be a more appropriate immunosuppressive compound to effectively prolong mouse allogeneic corneal grafts survival. PMID:25216235

  7. BCFtools/RoH: a hidden Markov model approach for detecting autozygosity from next-generation sequencing data

    PubMed Central

    Narasimhan, Vagheesh; Danecek, Petr; Scally, Aylwyn; Xue, Yali; Tyler-Smith, Chris; Durbin, Richard

    2016-01-01

    Summary: Runs of homozygosity (RoHs) are genomic stretches of a diploid genome that show identical alleles on both chromosomes. Longer RoHs are unlikely to have arisen by chance but are likely to denote autozygosity, whereby both copies of the genome descend from the same recent ancestor. Early tools to detect RoH used genotype array data, but substantially more information is available from sequencing data. Here, we present and evaluate BCFtools/RoH, an extension to the BCFtools software package, that detects regions of autozygosity in sequencing data, in particular exome data, using a hidden Markov model. By applying it to simulated data and real data from the 1000 Genomes Project we estimate its accuracy and show that it has higher sensitivity and specificity than existing methods under a range of sequencing error rates and levels of autozygosity. Availability and implementation: BCFtools/RoH and its associated binary/source files are freely available from https://github.com/samtools/BCFtools. Contact: vn2@sanger.ac.uk or pd3@sanger.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26826718

  8. Li and Ag Co-Doped ZnO Photocatalyst for Degradation of RO 4 Dye Under Solar Light Irradiation.

    PubMed

    Dhatshanamurthi, P; Shanthi, M

    2016-06-01

    The synthesis of Li doped Ag-ZnO (Li-Ag-ZnO) has been successfully achieved by a sonochemically assisted precipitation-decomposition method. The synthesized catalyst was characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), energy dispersive spectroscopy (EDS), diffuse reflectance spectra (DRS), photoluminescence spectra (PL), X-ray photoelectron spectra (XPS) and BET surface area measurements. The photocatalytic activity of Li-Ag-ZnO was investigated for the degradation of Reactive orange 4 (RO 4) dye in aqueous solution under solar light irradiation. Co-dopants shift the absorbance of ZnO to the visible region. Li-Ag-ZnO is found to be more efficient than Ag-ZnO, Li-ZnO, commercial ZnO and prepared ZnO at pH 7 for the mineralization of RO 4 dye under solar light irradiation. The influences of operational parameters such as the amount of photocatalyst, dye concentration, initial pH on photo-mineralization of RO 4 have been analyzed. The mineralization of RO 4 dye has been confirmed by COD measurements. A degradation mechanism is proposed for the degradation of RO 4 under solar light. The catalyst was found to be more stable and reusable. PMID:27427652

  9. Refractory depression: mechanisms and evaluation of radically open dialectical behaviour therapy (RO-DBT) [REFRAMED]: protocol for randomised trial

    PubMed Central

    Lynch, T R; Whalley, B; Hempel, R J; Byford, S; Clarke, P; Clarke, S; Kingdon, D; O'Mahen, H; Russell, I T; Shearer, J; Stanton, M; Swales, M; Watkins, A; Remington, B

    2015-01-01

    Introduction Only 30–40% of depressed patients treated with medication achieve full remission. Studies that change medication or augment it by psychotherapy achieve only limited benefits, in part because current treatments are not designed for chronic and complex patients. Previous trials have excluded high-risk patients and those with comorbid personality disorder. Radically Open Dialectical Behaviour Therapy (RO-DBT) is a novel, transdiagnostic treatment for disorders of emotional over-control. The REFRAMED trial aims to evaluate the effectiveness and cost-effectiveness of RO-DBT for patients with treatment-resistant depression. Methods and analysis REFRAMED is a multicentre randomised controlled trial, comparing 7 months of individual and group RO-DBT treatment with treatment as usual (TAU). Our primary outcome measure is depressive symptoms 12 months after randomisation. We shall estimate the cost-effectiveness of RO-DBT by cost per quality-adjusted life year. Causal analyses will explore the mechanisms by which RO-DBT is effective. Ethics and dissemination The National Research Ethics Service (NRES) Committee South Central – Southampton A first granted ethical approval on 20 June 2011, reference number 11/SC/0146. Trial registration number ISRCTN85784627. PMID:26187121

  10. Evaluation of an MBR-RO system to produce high quality reuse water: microbial control, DBP formation and nitrate.

    PubMed

    Comerton, Anna M; Andrews, Robert C; Bagley, David M

    2005-10-01

    A membrane bioreactor and reverse osmosis (MBR-RO) system was developed to assess potential reuse applications of municipal wastewater. The objective of the study was to examine the water quality throughout the system with a focus on waterborne pathogens, disinfection by-products (DBPs) and nitrate. This paper will discuss the presence of these contaminants in MBR effluent and focus on their subsequent removal by RO. This study has shown that high quality reuse water can be produced from municipal wastewater through the use of an MBR-RO system. The water meets California Title 22 reuse regulations for non-potable applications and US EPA drinking water limits for trihalomethanes (THM) (80 microg/L), haloacetic acids (HAA) (60 microg/L), chlorite (1.0 mg/L), total coliform (not detectable), viruses (not detectable), and nitrate/nitrite (10 mg N/L). However, THM formation (182-689 microg/L) attributed to cleaning of the MBR with chlorine and incomplete removal by subsequent RO treatment resulted in reuse water with THM levels (40.2+/-19.9 microg/L) high enough to present a potential concern when considering drinking water applications. Nitrate levels of up to 3.6 mg N/L, which resulted from incomplete removal by the RO membrane, are also a potential concern. A denitrification step in the MBR should be considered in potable water applications. PMID:16112164

  11. The iRoCS Toolbox--3D analysis of the plant root apical meristem at cellular resolution.

    PubMed

    Schmidt, Thorsten; Pasternak, Taras; Liu, Kun; Blein, Thomas; Aubry-Hivet, Dorothée; Dovzhenko, Alexander; Duerr, Jasmin; Teale, William; Ditengou, Franck A; Burkhardt, Hans; Ronneberger, Olaf; Palme, Klaus

    2014-03-01

    To achieve a detailed understanding of processes in biological systems, cellular features must be quantified in the three-dimensional (3D) context of cells and organs. We described use of the intrinsic root coordinate system (iRoCS) as a reference model for the root apical meristem of plants. iRoCS enables direct and quantitative comparison between the root tips of plant populations at single-cell resolution. The iRoCS Toolbox automatically fits standardized coordinates to raw 3D image data. It detects nuclei or segments cells, automatically fits the coordinate system, and groups the nuclei/cells into the root's tissue layers. The division status of each nucleus may also be determined. The only manual step required is to mark the quiescent centre. All intermediate outputs may be refined if necessary. The ability to learn the visual appearance of nuclei by example allows the iRoCS Toolbox to be easily adapted to various phenotypes. The iRoCS Toolbox is provided as an open-source software package, licensed under the GNU General Public License, to make it accessible to a broad community. To demonstrate the power of the technique, we measured subtle changes in cell division patterns caused by modified auxin flux within the Arabidopsis thaliana root apical meristem. PMID:24417645

  12. Hyperthermia induced by the dopamine D1 receptor agonist SK&F38393 in combination with the dopamine D2 receptor agonist talipexole in the rat.

    PubMed

    Nagashima, M; Yamada, K; Kimura, H; Matsumoto, S; Furukawa, T

    1992-12-01

    The present experiments were performed to investigate the effects of dopamine D1 receptor agonists given alone or in combination with dopamine D2 receptor agonists on body temperature in rats. The selective dopamine D1 receptor agonist, 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SK&F38393), produced hyperthermia. However, the dopamine D2 receptor agonist, B-HT 920 (talipexole), and the newly synthesized dopamine D2 receptor agonist, (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (SND 919), did not change the temperature. Interestingly, the SK&F38393-induced hyperthermia was enhanced by talipexole and SND 919. The drastic hyperthermia induced by combined administration of dopamine D1 and D2 receptor agonists was blocked by either the dopamine D1 receptor antagonist, SCH23390, or the dopamine D2 receptor antagonist, spiperone. On the other hand, treatment with prazosin, yohimbine, propranolol, scopolamine, or methysergide failed to affect the marked hyperthermia. The present results suggest that a functional link between dopamine D1 and D2 receptors may be synergistic in the regulation of body temperature and that concurrent stimulation of both dopamine D1 and D2 receptors thereby produces marked hyperthermia in the rat. PMID:1361996

  13. Transiting exoplanets from the CoRoT space mission. XIV. CoRoT-11b: a transiting massive ``hot-Jupiter'' in a prograde orbit around a rapidly rotating F-type star

    NASA Astrophysics Data System (ADS)

    Gandolfi, D.; Hébrard, G.; Alonso, R.; Deleuil, M.; Guenther, E. W.; Fridlund, M.; Endl, M.; Eigmüller, P.; Csizmadia, Sz.; Havel, M.; Aigrain, S.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Bruntt, H.; Cabrera, J.; Carpano, S.; Carone, L.; Cochran, W. D.; Deeg, H. J.; Dvorak, R.; Eislöffel, J.; Erikson, A.; Ferraz-Mello, S.; Gazzano, J.-C.; Gibson, N. B.; Gillon, M.; Gondoin, P.; Guillot, T.; Hartmann, M.; Hatzes, A.; Jorda, L.; Kabath, P.; Léger, A.; Llebaria, A.; Lammer, H.; MacQueen, P. J.; Mayor, M.; Mazeh, T.; Moutou, C.; Ollivier, M.; Pätzold, M.; Pepe, F.; Queloz, D.; Rauer, H.; Rouan, D.; Samuel, B.; Schneider, J.; Stecklum, B.; Tingley, B.; Udry, S.; Wuchterl, G.

    2010-12-01

    The CoRoT exoplanet science team announces the discovery of CoRoT-11b, a fairly massive hot-Jupiter transiting a V = 12.9 mag F6 dwarf star (M_* = 1.27±0.05 M⊙, R_* = 1.37±0.03 R⊙, Teff = 6440±120 K), with an orbital period of P = 2.994329±0.000011 days and semi-major axis a = 0.0436±0.005 AU. The detection of part of the radial velocity anomaly caused by the Rossiter-McLaughlin effect shows that the transit-like events detected by CoRoT are caused by a planet-sized transiting object in a prograde orbit. The relatively high projected rotational velocity of the star (v sin i = 40±5 km s-1) places CoRoT-11 among the most rapidly rotating planet host stars discovered so far. With a planetary mass of Mp = 2.33±0.34 MJup and radius Rp =1.43±0.03 RJup, the resulting mean density of CoRoT-11b (ρp = 0.99±0.15 g/cm3) can be explained with a model for an inflated hydrogen-planet with a solar composition and a high level of energy dissipation in its interior. The CoRoT space mission, launched on 2006 December 27, has been developed and is operated by CNES, with the contribution of Austria, Belgium, Brazil, ESA (RSSD and Science Programme), Germany and Spain.

  14. Chemistry of silica scale mitigation for RO desalination with particular reference to remote operations.

    PubMed

    Milne, Nicholas A; O'Reilly, Tom; Sanciolo, Peter; Ostarcevic, Eddy; Beighton, Mark; Taylor, Kelvin; Mullett, Mark; Tarquin, Anthony J; Gray, Stephen R

    2014-11-15

    Silica scaling in reverse osmosis of groundwater is a significant issue in water stressed areas due to the limitations that scaling imposes on water recovery. While calcium and magnesium scaling potential can be significantly reduced by the use of ion exchange or other softening processes, the silica scaling potential typically remains. Improving the recovery of reverse osmosis by limiting the potential for silica scale is important in ensuring maximum water recovery. This is particularly important for mining and natural gas industries that are located in remote regions. The remote nature of these sites imposes three major restrictions on the silica scale mitigation process. Firstly, the generation of poorly dewaterable sludges must be avoided. Also, the quality of any reverse osmosis (RO) permeate must be able to meet the end use requirements, particularly for boilers. Finally, silica removal should not impact upon other potentially useful or valuable components within the brine, and should not make the disposal of the unusable waste brine components more difficult. Reduction of scaling potential can be achieved in three main ways: operating RO at high pH after hardness has been removed, operating at low pH, and reducing the silica concentration either in pretreatment or by using an interstage technique. Operating at high pH has the initial requirement of hardness removal to prevent scaling and this could be an issue on some sites. Hardness removal operations that use ion exchange resins may be challenged by water chemistry and the operational costs associated with high chemical regeneration costs. Operating at low pH may be more desirable than high pH operation as this can help to reduce the risk of scale formation from calcium or magnesium salts. The drawback comes from the cost of acid, particularly for high-alkalinity waters. There are numerous silica removal techniques including chemical dosing of lime, or aluminium or iron salts, electrocoagulation

  15. SDN based millimetre wave radio over fiber (RoF) network

    NASA Astrophysics Data System (ADS)

    Amate, Ahmed; Milosavljevic, Milos; Kourtessis, Pandelis; Robinson, Matthew; Senior, John M.

    2015-01-01

    This paper introduces software-defined, millimeter Wave (mm-Wave) networks with Radio over Fiber (RoF) for the delivery of gigabit connectivity required to develop fifth generation (5G) mobile. This network will enable an effective open access system allowing providers to manage and lease the infrastructure to service providers through unbundling new business models. Exploiting the inherited benefits of RoF, complete base station functionalities are centralized at the edges of the metro and aggregation network, leaving remote radio heads (RRHs) with only tunable filtering and amplification. A Software Defined Network (SDN) Central Controller (SCC) is responsible for managing the resource across several mm-Wave Radio Access Networks (RANs) providing a global view of the several network segments. This ensures flexible resource allocation for reduced overall latency and increased throughput. The SDN based mm-Wave RAN also allows for inter edge node communication. Therefore, certain packets can be routed between different RANs supported by the same edge node, reducing latency. System level simulations of the complete network have shown significant improvement of the overall throughput and SINR for wireless users by providing effective resource allocation and coordination among interfering cells. A new Coordinated Multipoint (CoMP) algorithm exploiting the benefits of the SCC global network view for reduced delay in control message exchange is presented, accounting for a minimum packet delay and limited Channel State Information (CSI) in a Long Term Evolution-Advanced (LTE-A), Cloud RAN (CRAN) configuration. The algorithm does not require detailed CSI feedback from UEs but it rather considers UE location (determined by the eNB) as the required parameter. UE throughput in the target sector is represented using a Cumulative Distributive Function (CDF). The drawn characteristics suggest that there is a significant 60% improvement in UE cell edge throughput following the

  16. The roAp star α Circinus as seen by BRITE-Constellation

    NASA Astrophysics Data System (ADS)

    Weiss, W. W.; Fröhlich, H.-E.; Pigulski, A.; Popowicz, A.; Huber, D.; Kuschnig, R.; Moffat, A. F. J.; Matthews, J. M.; Saio, H.; Schwarzenberg-Czerny, A.; Grant, C. C.; Koudelka, O.; Lüftinger, T.; Rucinski, S. M.; Wade, G. A.; Alves, J.; Guedel, M.; Handler, G.; Mochnacki, St.; Orleanski, P.; Pablo, B.; Pamyatnykh, A.; Ramiaramanantsoa, T.; Rowe, J.; Whittaker, G.; Zawistowski, T.; Zocłońska, E.; Zwintz, K.

    2016-04-01

    We report on an analysis of high-precision, multi-colour photometric observations of the rapidly-oscillating Ap (roAp) star α Cir. These observations were obtained with the BRITE-Constellation, which is a coordinated mission of five nanosatellites that collects continuous millimagnitude-precision photometry of dozens of bright stars for up to 180 days at a time in two colours (≈Johnson B and R). BRITE stands for BRight Target Explorer. The object α Cir is the brightest roAp star and an ideal target for such investigations, facilitating the determination of oscillation frequencies with high resolution. This star is bright enough for complementary interferometry and time-resolved spectroscopy. Four BRITE satellites observed α Cir for146 d or 33 rotational cycles. Phasing the photometry according to the 4.4790 d rotational period reveals qualitatively different light variations in the two photometric bands. The phased red-band photometry is in good agreement with previously-published WIRE data, showing a light curve symmetric about phase 0.5 with a strong contribution from the first harmonic. The phased blue-lband data, in contrast, show an essentially sinusoidal variation. We model both light curves with Bayesian Photometric Imaging, which suggests the presence of two large-scale, photometrically bright (relative to the surrounding photosphere) spots. We also examine the high-frequency pulsation spectrum as encoded in the BRITE photometry. Our analysis establishes the stability of the main pulsation frequency over the last ≈20 yr, confirms the presence of frequency f7, which was not detected (or the mode not excited) prior to 2006, and excludes quadrupolar modes for the main pulsation frequency. Based on data collected by the BRITE-Constellation satellite mission, built, launched and operated thanks to support from the Austrian Aeronautics and Space Agency, the University of Vienna, the Canadian Space Agency (CSA), the Foundation for Polish Science

  17. Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis

    PubMed Central

    Pitari, Giovanni M

    2013-01-01

    Agonists of the transmembrane intestinal receptor guanylyl cyclase C (GCC) have recently attracted interest as promising human therapeutics. Peptide ligands that can specifically induce GCC signaling in the intestine include endogenous hormones guanylin and uroguanylin, diarrheagenic bacterial enterotoxins (ST), and synthetic drugs linaclotide, plecanatide, and SP-333. These agonists bind to GCC at intestinal epithelial surfaces and activate the receptor’s intracellular catalytic domain, an event initiating discrete biological responses upon conversion of guanosine-5′-triphosphate to cyclic guanosine monophosphate. A principal action of GCC agonists in the colon is the promotion of mucosal homeostasis and its dependent barrier function. Herein, GCC agonists are being developed as new medications to treat inflammatory bowel diseases, pathological conditions characterized by mucosal barrier hyperpermeability, abnormal immune reactions, and chronic local inflammation. This review will present important concepts underlying the pharmacology and therapeutic utility of GCC agonists for patients with ulcerative colitis, one of the most prevalent inflammatory bowel disease disorders. PMID:23637522

  18. Voltage dependence of agonist effectiveness at the frog neuromuscular junction: resolution of a paradox.

    PubMed Central

    Dionne, V E; Stevens, C F

    1975-01-01

    1. End-plate currents produced by nerve-released acetylcholine and iontophoretically applied acetylcholine and carbachol have been recorded from voltage-clamped frog cutaneous pectoris neuromuscular junctions made visible with Nomarski differential interference contrast optics. 2. The effectiveness of agonists - that is, the end-plate conductance change produced by a given dose-has been determined as a function of post-junctional membrane potential. 3. As the post-junctional membrane potential is made more negative, nerve-released acetylcholine becomes less effective whereas iontophoretically-applied agonists become more effective. 4. This voltage dependence of agonist effectiveness is mediated neither by end-plate current iontophoresis of agonist into the cleft nor through electric field effects on the esterase. 5. Influences of membrane potential on the opening and closing of end-plate channel gates can account quantitatively for the voltage-dependent effectiveness of both nerve-released and iontophoretically applied agonist. PMID:1081139

  19. The link between non-ergot-derived dopamine agonists and heart failure: how strong is it?

    PubMed

    Lockett, Katrina; DeBacker, Danielle; Cauthon, Kimberly A B

    2015-03-01

    Dopamine agonists are commonly used as initial monotherapy and adjunct treatment for Parkinson's disease. However, the Food and Drug Administration recently linked pramipexole use with an increased risk of heart failure (HF). Several case-control studies demonstrate a possible increased risk of the development of HF in patients taking non-ergot-derived dopamine agonists compared with patients not taking dopamine agonists. In patients taking non-ergot-derived dopamine agonists, the studies associated the risk of increased HF with pramipexole. These studies did not find a possible increased risk with ropinirole, but to date no randomized, controlled trials have been conducted to directly compare ropinirole with pramipexole and the risk of HF. The mechanism by which HF occurs is unknown, but the development of edema after dopamine agonist use could increase the risk of HF. If patients with a history of cardiovascular disease or edema are prescribed pramipexole, additional monitoring for HF signs and symptoms is recommended. PMID:25760663

  20. [Is the LHRH Agonist Recommended for Fertility Preservation ?].

    PubMed

    Kimura, Kosei; Iwamoto, Mitsuhiko; Tanaka, Satoru; Watanabe, Toru; Aihara, Tomohiko; Sugimoto, Takeki; Miyara, Kyuichiro; Hayashi, Mitsuhiro; Kouno, Tsutomu; Baba, Shinichi; Kawashima, Hiroaki; Hashimoto, Naoki; Uchiyama, Kazuhisa

    2015-08-01

    The POEMS reportedan effect of goserelin for fertility preservation. The Clinical Practice Guideline for Breast Cancer by The Japanese Breast Cancer Society indicates that the use of the LHRH agonist (LHRHa) for preventing chemotherapy-induced early menopause is a grade C-1 recommendation, and its use for fertility preservation is a grade C-2 recommendation. Results from previous studies on the effects of LHRHa for fertility preservation have varied owing to differences in chemotherapy regimens, definitions of ovarian failure, and dosages of tamoxifen. In the POEMS, the primary endpoint of ovarian failure at 2 years was significantly lower, and the secondary endpoint of pregnancy outcomes was better in the combination group; however, precise interpretation is difficult because many cases were excluded. Currently, it is not necessary to revise The Clinical Practice Guideline; however, desirable results from future studies may allow the recommendation of a specific dosage of LHRHa for fertility preservation. PMID:26321722

  1. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity

    PubMed Central

    Crane, James; McGowan, Barbara

    2015-01-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  2. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist.

    PubMed

    Kühnen, Peter; Clément, Karine; Wiegand, Susanna; Blankenstein, Oliver; Gottesdiener, Keith; Martini, Lea L; Mai, Knut; Blume-Peytavi, Ulrike; Grüters, Annette; Krude, Heiko

    2016-07-21

    Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2). PMID:27468060

  3. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis

    PubMed Central

    Dietrich, Johannes W.; Landgrafe, Gabi; Fotiadou, Elisavet H.

    2012-01-01

    This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range. PMID:23365787

  4. The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity.

    PubMed

    Crane, James; McGowan, Barbara

    2016-03-01

    There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID:26977279

  5. Saralasin and Sarile Are AT2 Receptor Agonists

    PubMed Central

    2014-01-01

    Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists. PMID:25313325

  6. Use of Thrombopoietin Receptor Agonists in Childhood Immune Thrombocytopenia

    PubMed Central

    Garzon, Angelica Maria; Mitchell, William Beau

    2015-01-01

    Most children with immune thrombocytopenia (ITP) will have spontaneous remission regardless of therapy, while about 20% will go on to have chronic ITP. In those children with chronic ITP who need treatment, standard therapies for acute ITP may have adverse effects that complicate their long-term use. Thus, alternative treatment options are needed for children with chronic ITP. Thrombopoietin receptor agonists (TPO-RA) have been shown to be safe and efficacious in adults with ITP, and represent a new treatment option for children with chronic ITP. One TPO-RA, eltrombopag, is now approved for children. Clinical trials in children are ongoing and data are emerging on safety and efficacy. This review will focus on the physiology of TPO-RA, their clinical use in children, as well as the long-term safety issues that need to be considered when using these agents. PMID:26322297

  7. Antiinfective applications of toll-like receptor 9 agonists.

    PubMed

    Krieg, Arthur M

    2007-07-01

    The innate immune system detects pathogens by the presence of highly conserved pathogen-expressed molecules, which trigger host immune defenses. Toll-like receptor (TLR) 9 detects unmethylated CpG dinucleotides in bacterial or viral DNA, and can be stimulated for therapeutic applications with synthetic oligodeoxynucleotides containing immune stimulatory "CpG motifs." TLR9 activation induces both innate and adaptive immunity. The TLR9-induced innate immune activation can be applied in the prevention or treatment of infectious diseases, and the adaptive immune-enhancing effects can be harnessed for improving vaccines. This article highlights the current understanding of the mechanism of action of CpG oligodeoxynucleotides, and provides an overview of the preclinical data and early human clinical trial results, applying these TLR9 agonists in the field of infectious diseases. PMID:17607015

  8. Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist

    PubMed Central

    Tai, Sherrica; Nikas, Spyros P.; Shukla, Vidyanand G.; Vemuri, Kiran; Makriyannis, Alexandros; Järbe, Torbjörn U.C.

    2015-01-01

    Rationale Previous reports shows rimonabant's inverse properties may be a limiting factor for treating cannabinoid dependence. To overcome this limitation neutral antagonists were developed, to address mechanisms by which an inverse agonist and neutral antagonist elicit withdrawal. Objective Introduces an animal model to study cannabinoid dependence by incorporating traditional methodologies and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor (CB1R) related physiological/behavioral endpoints. Methods The cannabinergic AM2389 was acutely characterized in the tetrad (locomotor activity, analgesia, inverted screen/catalepsy bar test and temperature); with some comparisons made to Δ9-tetrahydrocannabinol (THC). Tolerance was measured in mice repeatedly administered AM2389. Antagonist-precipitated withdrawal was characterized in cannabinoid-adapted mice induced by either centrally acting antagonists, rimonabant and AM4113, or an antagonist with limited brain penetration, AM6545. Results In the tetrad, AM2389 was more potent and longer acting than THC, suggesting a novel approach for inducing dependence. Repeated administration of AM2389 led to tolerance by attenuating hypothermia that was induced by acute AM2389 administration. Antagonist-precipitated withdrawal signs were induced by rimonabant or AM4113, but not by AM6545. Antagonist-precipitated withdrawal was reversed by reinstating AM2389 or THC. Conclusions These findings suggest cannabinoid-precipitated withdrawal may not be ascribed to the inverse properties of rimonabant, but rather to rapid competition with the agonist at the CB1R. This withdrawal syndrome is likely centrally-mediated, since only the centrally acting CB1R antagonists elicited withdrawal, i.e., such responses were absent after the purported peripherally selective CB1R antagonist AM6545. PMID:25772338

  9. RS 30026: a potent and effective calcium channel agonist.

    PubMed Central

    Patmore, L.; Duncan, G. P.; Clarke, B.; Anderson, A. J.; Greenhouse, R.; Pfister, J. R.

    1990-01-01

    1. A series of dihydropyridine derivatives has been evaluated for calcium channel agonist activity using reversal of nisoldipine-induced inhibition of beating of aggregates of embryonic chick myocytes. This test appears to be specific for calcium channel agonists since isoprenaline and cardiac glycosides are inactive. 2. RS 30026 was the most potent of the series, was significantly more potent than CGP 28392 and of similar potency to Bay K 8644 (pEC50 = 7.45, 6.16 and 7.20, respectively). RS 30026 increased edge movement of individual aggregates, in the absence of nisoldipine, by 50% at 2 nM. 3. Compounds were also evaluated for their effects on guinea-pig papillary muscle and porcine coronary artery rings. RS 30026 displayed positive inotropism at concentrations between 10(-9) and 10(-6) M (pEC200 = 8.21), but was a much more powerful inotrope than Bay K 8644, increasing contractility to 1300% of control at 10(-6) M (compared to 350% of control for Bay K 8644). RS 30026 caused vasoconstriction at concentrations between 10(-10) and 10(-7) M. 4. Calcium channel currents in single embryonic chick myocytes were recorded by whole-cell voltage clamp techniques. RS 30026 (100 nM-500 nM) produced large increases in peak current amplitude and shifted the voltage for threshold and maximal currents to more negative values. RS 30026 (500 nM) also produced large increases in the inward tail currents evoked upon repolarization. The effects of Bay K 8644 (50 and 500 nM) were much less marked.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1694461

  10. Asimadoline, a κ-Opioid Agonist, and Visceral Sensation

    PubMed Central

    Camilleri, Michael

    2009-01-01

    SUMMARY Asimadoline is a potent κ-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the κ receptor, with IC50 of 5.6 nM (guinea pig) and 1.2 nM (human recombinant), and high selectively with κ: μ: δ binding ratios of 1:501:498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in IBS patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 hours post-on-demand treatment with asimadoline was not significantly reduced. Post-hoc analyses suggest asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with asimadoline, 0.5 mg and 1.0 mg, was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date. PMID:18715494

  11. Agonist and antagonist effects of cytisine in vivo.

    PubMed

    Radchenko, Elena V; Dravolina, Olga A; Bespalov, Anton Y

    2015-08-01

    Varenicline, the most successful smoking cessation aid, is a selective partial agonists at α4β2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including cytisine. The present study aimed to characterize behavioral effects of cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not cytisine (0.3-3 mg/kg), lowered ICSS thresholds and cytisine dose-dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), stimulated locomotor activity and cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self-administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects. PMID:25839895

  12. Could dopamine agonists aid in drug development for anorexia nervosa?

    PubMed

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  13. Gonadotropin-Releasing Hormone Agonist Therapy and Obesity in Girls

    PubMed Central

    Shiasi Arani, Kobra; Heidari, Fatemeh

    2015-01-01

    Background: Depot preparations of gonadotropin-releasing hormone agonists (GnRHa) are the gold standard drugs for the treatment of central precocious puberty. A concern about these drugs is obesity. Objectives: This study aimed to investigate the effect of gonadotropin-releasing hormone agonists (GnRHa) therapy on body mass index (BMI) in girls with central precocious puberty (CPP). Patients and Methods: The girls with onset of puberty before eight years of age or menarche before nine years of age were studied. The weight, height, BMI, and pubertal stage were determined before and at sixth and 12th months of treatment. The GnRHa (Triptorelin) was administered intramuscularly for patients with rapidly progressive forms of CPP. Patients with slowly progressive forms of CPP were considered as control group. Results: From 110 subjects with CPP, 46 girls (41.8%) were considered as intervention and 64 (58.2%) as control groups. The mean age at initial visit was 7.46 ± 1.03 years. The BMI standard deviation scores in both groups was not significantly different at sixth and 12th months of treatment compared with baseline (P = 0.257 and P = 0.839, respectively). The prevalence of obesity was not significantly different between study groups at baseline and at and sixth and 12th months of therapy (P = 0.11, P = 0.068, and P = 0.052, respectively). Conclusions: The GnRHa therapy has no effect on BMI and the prevalence of obesity. PMID:26401141

  14. Recent advances in the development of farnesoid X receptor agonists

    PubMed Central

    Carey, Elizabeth J.; Lindor, Keith D.

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  15. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    PubMed Central

    Frank, Guido K. W.

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways. PMID:25988121

  16. Recent advances in the development of farnesoid X receptor agonists.

    PubMed

    Ali, Ahmad H; Carey, Elizabeth J; Lindor, Keith D

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  17. Interaction of a radiolabeled agonist with cardiac muscarinic cholinergic receptors

    SciTech Connect

    Harden, T.K.; Meeker, R.B.; Martin, M.W.

    1983-12-01

    The interaction of a radiolabeled muscarinic cholinergic receptor agonist, (methyl-/sup 3/H)oxotremorine acetate ((/sup 3/H)OXO), with a washed membrane preparation derived from rat heart, has been studied. In binding assays at 4 degrees C, the rate constants for association and dissociation of (/sup 3/H)OXO were 2 X 10(7) M-1 min-1 and 5 X 10(-3) min-1, respectively, Saturation binding isotherms indicated that binding was to a single population of sites with a Kd of approximately 300 pM. The density of (/sup 3/H)OXO binding sites (90-100 fmol/mg of protein) was approximately 75% of that determined for the radiolabeled receptor antagonist (/sup 3/H)quinuclidinyl benzilate. Both muscarinic receptor agonists and antagonists inhibited the binding of (/sup 3/H)OXO with high affinity and Hill slopes of approximately one. Guanine nucleotides completely inhibited the binding of (/sup 3/H)OXO. This effect was on the maximum binding (Bmax) of (/sup 3/H)OXO with no change occurring in the Kd; the order of potency for five nucleotides was guanosine 5'-O-(3-thio-triphosphate) greater than 5'-guanylylimidodiphosphate greater than GTP greater than or equal to guanosine/diphosphate greater than GMP. The (/sup 3/H)OXO-induced interaction of muscarinic receptors with a guanine nucleotide binding protein was stable to solubilization. That is, membrane receptors that were prelabeled with (/sup 3/H)OXO could be solubilized with digitonin, and the addition of guanine nucleotides to the soluble, (/sup 3/H)OXO-labeled complex resulted in dissociation of (/sup 3/H)OXO from the receptor. Pretreatment of membranes with relatively low concentrations of N-ethylmaleimide inhibited (/sup 3/H)OXO binding by 85% with no change in the Kd of (/sup 3/H)OXO, and with no effect on (/sup 3/H)quinuclidinyl benzilate binding.

  18. GITR agonist enhances vaccination responses in lung cancer

    PubMed Central

    Zhu, Li X; Davoodi, Michael; Srivastava, Minu K; Kachroo, Puja; Lee, Jay M; St. John, Maie; Harris-White, Marni; Huang, Min; Strieter, Robert M; Dubinett, Steven; Sharma, Sherven

    2015-01-01

    An immune tolerant tumor microenvironment promotes immune evasion of lung cancer. Agents that antagonize immune tolerance will thus aid the fight against this devastating disease. Members of the tumor necrosis factor receptor (TNFR) family modulate the magnitude, duration and phenotype of immune responsiveness to antigens. Among these, GITR expressed on immune cells functions as a key regulator in inflammatory and immune responses. Here, we evaluate the GITR agonistic antibody (DTA-1) as a mono-therapy and in combination with therapeutic vaccination in murine lung cancer models. We found that DTA-1 treatment of tumor-bearing mice increased: (i) the frequency and activation of intratumoral natural killer (NK) cells and T lymphocytes, (ii) the antigen presenting cell (APC) activity in the tumor, and (iii) systemic T-cell specific tumor cell cytolysis. DTA-1 treatment enhanced tumor cell apoptosis as quantified by cleaved caspase-3 staining in the tumors. DTA-1 treatment increased expression of IFNγ, TNFα and IL-12 but reduced IL-10 levels in tumors. Furthermore, increased anti-angiogenic chemokines corresponding with decreased pro-angiogenic chemokine levels correlated with reduced expression of the endothelial cell marker Meca 32 in the tumors of DTA-1 treated mice. In accordance, there was reduced tumor growth (8-fold by weight) in the DTA-1 treatment group. NK cell depletion markedly inhibited the antitumor response elicited by DTA-1. DTA-1 combined with therapeutic vaccination caused tumor rejection in 38% of mice and a 20-fold reduction in tumor burden in the remaining mice relative to control. Mice that rejected tumors following therapy developed immunological memory against subsequent re-challenge. Our data demonstrates GITR agonist antibody activated NK cell and T lymphocyte activity, and enhanced therapeutic vaccination responses against lung cancer. PMID:26137407

  19. Immobilized thrombin receptor agonist peptide accelerates wound healing in mice.

    PubMed

    Strukova, S M; Dugina, T N; Chistov, I V; Lange, M; Markvicheva, E A; Kuptsova, S; Zubov, V P; Glusa, E

    2001-10-01

    To accelerate the healing processes in wound repair, attempts have been repeatedly made to use growth factors including thrombin and its peptide fragments. Unfortunately, the employment of thrombin is limited because of its high liability and pro-inflammatory actions at high concentrations. Some cellular effects of thrombin in wound healing are mediated by the activation of protease activated receptor-1 (PAR-1). The thrombin receptor agonist peptide (TRAP:SFLLRN) activates this receptor and mimics the effects of thrombin, but TRAP is a relatively weak agonist. We speculated that the encapsulated peptide may be more effective for PAR-1 activation than nonimmobilized peptide and developed a novel method for TRAP encapsulation in hydrogel films based on natural and synthetic polymers. The effects of an encapsulated TRAP in composite poly(N-vinyl caprolactam)-calcium alginate (PVCL) hydrogel films were investigated in a mouse model of wound healing. On day 7 the wound sizes decreased by about 60% under TRAP-chitosan-containing PVCL films, as compared with control films without TRAP. In the case of TRAP-polylysine-containing films no significant decrease in wound sizes was found. The fibroblast/macrophage ratio increased under TRAP-containing films on day 3 and on day 7. The number of proliferating fibroblasts increased to 150% under TRAP-chitosan films on day 7 as compared with control films. The number of [3H]-thymidine labeled endothelial and epithelial cells in granulation tissues was also enhanced. Thus, the immobilized TRAP to PVCL-chitosan hydrogel films were found to promote wound healing following the stimulation of fibroblast and epithelial cell proliferation and neovascularization. Furthermore, TRAP was shown to inhibit the secretion of the inflammatory mediator PAF from stimulated rat peritoneal mast cells due to augmentation of NO release from the mast cells. The encapsulated TRAP is suggested to accelerate wound healing due to the anti-inflammatory effects

  20. Agonist-specific behaviour of the intracellular Ca2+ response in rat hepatocytes.

    PubMed Central

    Chatton, J Y; Cao, Y; Stucki, J W

    1997-01-01

    A variety of agonists stimulate in hepatocytes a response that takes the shape of repetitive cytosolic free Ca2+ transients called Ca2+ oscillations. The shape of spikes and the pattern of oscillations in a given cell differ depending on the agonist of the phosphoinositide pathway that is applied. In this study, the response of individual rat hepatocytes to maximal stimulation by arginine vasopressin (AVP), phenylephrine and ADP was investigated by fluorescence microscopy and flash photolysis. Hepatocytes loaded with Ca2+-sensitive probes were stimulated with a first agonist to evoke a maximal response, and then a second agonist was added. When phenylephrine or ADP was used as the first agonist, AVP applied subsequently could elicit an additional response, which did not happen when AVP was first applied and phenylephrine or ADP was applied later. Cells microinjected with caged myo-inositol 1,4,5-trisphosphate (IP3) were challenged with the different agonists and, when a maximal response was obtained, photorelease of IP3 was triggered. Cells maximally stimulated with AVP did not respond to IP3 photorelease, whereas those stimulated with phenylephrine or ADP responded with a fast Ca2+ spike above the elevated steady-state level, which was followed by an undershoot. In contrast, with all three agonists, IP3 photorelease triggered at the top of an oscillatory Ca2+ transient was able to mobilize additional Ca2+. These experiments indicate that the differential response of cells to agonists is found not only during Ca2+ oscillations but also during maximal agonist stimulation and that potency and efficacy differences exist among agonists. PMID:9371717

  1. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

    PubMed

    Yu, Shan; Li, Sijia; Henke, Adam; Muse, Evan D; Cheng, Bo; Welzel, Gustav; Chatterjee, Arnab K; Wang, Danling; Roland, Jason; Glass, Christopher K; Tremblay, Matthew

    2016-07-01

    Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases. PMID:27025962

  2. Allosteric coupling from G protein to the agonist-binding pocket in GPCRs.

    PubMed

    DeVree, Brian T; Mahoney, Jacob P; Vélez-Ruiz, Gisselle A; Rasmussen, Soren G F; Kuszak, Adam J; Edwald, Elin; Fung, Juan-Jose; Manglik, Aashish; Masureel, Matthieu; Du, Yang; Matt, Rachel A; Pardon, Els; Steyaert, Jan; Kobilka, Brian K; Sunahara, Roger K

    2016-07-01

    G-protein-coupled receptors (GPCRs) remain the primary conduit by which cells detect environmental stimuli and communicate with each other. Upon activation by extracellular agonists, these seven-transmembrane-domain-containing receptors interact with heterotrimeric G proteins to regulate downstream second messenger and/or protein kinase cascades. Crystallographic evidence from a prototypic GPCR, the β2-adrenergic receptor (β2AR), in complex with its cognate G protein, Gs, has provided a model for how agonist binding promotes conformational changes that propagate through the GPCR and into the nucleotide-binding pocket of the G protein α-subunit to catalyse GDP release, the key step required for GTP binding and activation of G proteins. The structure also offers hints about how G-protein binding may, in turn, allosterically influence ligand binding. Here we provide functional evidence that G-protein coupling to the β2AR stabilizes a ‘closed’ receptor conformation characterized by restricted access to and egress from the hormone-binding site. Surprisingly, the effects of G protein on the hormone-binding site can be observed in the absence of a bound agonist, where G-protein coupling driven by basal receptor activity impedes the association of agonists, partial agonists, antagonists and inverse agonists. The ability of bound ligands to dissociate from the receptor is also hindered, providing a structural explanation for the G-protein-mediated enhancement of agonist affinity, which has been observed for many GPCR–G-protein pairs. Our data also indicate that, in contrast to agonist binding alone, coupling of a G protein in the absence of an agonist stabilizes large structural changes in a GPCR. The effects of nucleotide-free G protein on ligand-binding kinetics are shared by other members of the superfamily of GPCRs, suggesting that a common mechanism may underlie G-protein-mediated enhancement of agonist affinity. PMID:27362234

  3. Computing Ro in a population with heterogeneity in sexual activity and proportionate mixing using a STM-solver

    NASA Astrophysics Data System (ADS)

    Gutierrez A., Natalia A.

    2014-06-01

    A model to determinate the reproductive basic number, detonated Ro, for the case of population with heterogeneity in sexual activity and proportionate mixing is solved using computer algebra and SMT solvers. Specifically Maple and Z3 were used. The code for the solution of the model was written in Z3-Python, but it can also be played by Z3-SMT-Lib. Ro represents an algebraic synthesis of every epidemiological parameter. Numerical simulations were done to prove the effectiveness of the model and the code. The algebraic structure of Ro suggests the possible control measurements that should be implemented to avoid the propagation of the sexual transmitted diseases. The obtained results are important on the computational epidemiology field. As a future investigation, it is suggested to apply the STM solvers to analyze models for other kinds of epidemic diseases.

  4. A Single-Chip Speech Dialogue Module and Its Evaluation on a Personal Robot, PaPeRo-Mini

    NASA Astrophysics Data System (ADS)

    Sato, Miki; Iwasawa, Toru; Sugiyama, Akihiko; Nishizawa, Toshihiro; Takano, Yosuke

    This paper presents a single-chip speech dialogue module and its evaluation on a personal robot. This module is implemented on an application processor that was developed primarily for mobile phones to provide a compact size, low power-consumption, and low cost. It performs speech recognition with preprocessing functions such as direction-of-arrival (DOA) estimation, noise cancellation, beamforming with an array of microphones, and echo cancellation. Text-to-speech (TTS) conversion is also equipped with. Evaluation results obtained on a new personal robot, PaPeRo-mini, which is a scale-down version of PaPeRo, demonstrate an 85% correct rate in DOA estimation, and as much as 54% and 30% higher speech recognition rates in noisy environments and during robot utterances, respectively. These results are shown to be comparable to those obtained by PaPeRo.

  5. KIC 7582608: a new Kepler roAp star with frequency variability

    NASA Astrophysics Data System (ADS)

    Holdsworth, D. L.; Smalley, B.; Kurtz, D. W.; Southworth, J.; Cunha, M. S.; Clubb, K. I.

    2015-09-01

    We analyse the fifth roAp star reported in the Kepler field, KIC 7582608, discovered with the SuperWASP project. The object shows a high frequency pulsation at 181.7324d-1 (P = 7.9 min) with an amplitude of 1.45 mmag, and low frequency rotational modulation corresponding to a period of 20.4339 d. Spectral analysis confirms the Ap nature of the target, with characteristic lines of rare earth elements present. From our spectral observations we derive a lower limit on the mean magnetic field modulus of =3.05 ± 0.23 kG. Long Cadence Kepler observations show a frequency quintuplet split by the rotational period of the star, typical for an oblique pulsator. We suggest the star is a quadrupole pulsator with a geometry such that i ~ 66° and β ~ 33°. We detect frequency variations of the pulsation in both the WASP and Kepler data sets on many time scales. Linear, non-adiabatic stability modelling allows us to constrain a region on the HR diagram where the pulsations are unstable, an area consistent with observations.

  6. KIC 4768731: a bright long-period roAp star in the Kepler field

    NASA Astrophysics Data System (ADS)

    Smalley, B.; Niemczura, E.; Murphy, S. J.; Lehmann, H.; Kurtz, D. W.; Holdsworth, D. L.; Cunha, M. S.; Balona, L. A.; Briquet, M.; Bruntt, H.; De Cat, P.; Lampens, P.; Thygesen, A. O.; Uytterhoeven, K.

    2015-10-01

    We report the identification of 61.45 d-1 (711.2 μHz) oscillations, with amplitudes of 62.6 μmag, in KIC 4768731 (HD 225914) using Kepler photometry. This relatively bright (V = 9.17) chemically peculiar star with spectral type A5 Vp SrCr(Eu) has previously been found to exhibit rotational modulation with a period of 5.21 d. Fourier analysis reveals a simple dipole pulsator with an amplitude that has remained stable over a 4-yr time span, but with a frequency that is variable. Analysis of high-resolution spectra yields stellar parameters of Teff = 8100 ± 200 K, log g = 4.0 ± 0.2, [Fe/H] = +0.31 ± 0.24 and v sin i = 14.8 ± 1.6 km s-1. Line profile variations caused by rotation are also evident. Lines of Sr, Cr, Eu, Mg and Si are strongest when the star is brightest, while Y and Ba vary in antiphase with the other elements. The abundances of rare earth elements are only modestly enhanced compared to other roAp stars of similar Teff and log g. Radial velocities in the literature suggest a significant change over the past 30 yr, but the radial velocities presented here show no significant change over a period of 4 yr.

  7. Unravelling Boléro: progressive aphasia, transmodal creativity and the right posterior neocortex.

    PubMed

    Seeley, William W; Matthews, Brandy R; Crawford, Richard K; Gorno-Tempini, Maria Luisa; Foti, Dean; Mackenzie, Ian R; Miller, Bruce L

    2008-01-01

    Most neurological lesion studies emphasize performance deficits that result from focal brain injury. Here, we describe striking gains of function in a patient with primary progressive aphasia, a degenerative disease of the human language network. During the decade before her language deficits arose, Anne Adams (AA), a lifelong scientist, developed an intense drive to produce visual art. Paintings from AA's artistic peak revealed her capacity to create expressive transmodal art, such as renderings of music in paint, which may have reflected an increased subjective relatedness among internal perceptual and conceptual images. AA became fascinated with Maurice Ravel, the French composer who also suffered from a progressive aphasia, and painted his best-known work, 'Boléro', by translating its musical elements into visual form. Later paintings, achieved when AA was nearly mute, moved towards increasing photographic realism, perhaps because visual representations came to dominate AA's mental landscape during this phase of her illness. Neuroimaging analyses revealed that, despite severe degeneration of left inferior frontal-insular, temporal and striatal regions, AA showed increased grey matter volume and hyperperfusion in right posterior neocortical areas implicated in heteromodal and polysensory integration. The findings suggest that structural and functional enhancements in non-dominant posterior neocortex may give rise to specific forms of visual creativity that can be liberated by dominant inferior frontal cortex injury. PMID:18057074

  8. Validation of MIPAS IMK/IAA V5R_O3_224 ozone profiles

    NASA Astrophysics Data System (ADS)

    Laeng, A.; Grabowski, U.; von Clarmann, T.; Stiller, G.; Glatthor, N.; Höpfner, M.; Kellmann, S.; Kiefer, M.; Linden, A.; Lossow, S.; Sofieva, V.; Petropavlovskikh, I.; Hubert, D.; Bathgate, T.; Bernath, P.; Boone, C. D.; Clerbaux, C.; Coheur, P.; Damadeo, R.; Degenstein, D.; Frith, S.; Froidevaux, L.; Gille, J.; Hoppel, K.; McHugh, M.; Kasai, Y.; Lumpe, J.; Rapoe, N.; Toon, G.; Sano, T.; Suzuki, M.; Tamminen, J.; Urban, J.; Walker, K.; Weber, M.; Zawodny, J.

    2014-04-01

    We present the results of an extensive validation program of the most recent version of ozone vertical profiles retrieved with the IMK/IAA MIPAS research level 2 processor from version 5 spectral Level 1 data. The time period covered corresponds to the reduced spectral resolution period of the MIPAS instrument, i.e. January 2005-April 2012. The comparison with satellite instruments includes all post-2005 satellite limb and occultation sensors having measured the vertical profiles of tropospheric and stratospheric ozone: ACE-FTS, GOMOS, HALOE, HIRDLS, MLS, OSIRIS, POAM, SAGE II, SCIAMACHY, SMILES, and SMR. In addition, balloon-borne MkIV solar occultation measurements and groundbased Umkehr measurements have been included, as well as two nadir sensors: IASI and SBUV. For each reference dataset, bias determination and precision assessment are performed. Better agreement with reference instruments than for the previous data version, V5R_O3_220 (Laeng et al., 2013), is found: the known high bias around the ozone vmr peak is significantly reduced and the vertical resolution at 35 km has been improved. The agreement with limb and solar occultation reference instruments that have a known small bias vs. ozone sondes is within 7% in the lower and middle stratosphere and 5% in the upper troposphere. Around the ozone vmr peak, the agreement with most of satellite reference instruments is within 5%; this bias is as low as 3% for ACE-FTS, MLS, OSIRIS, POAM and SBUV.

  9. The ro-vibrational `conveyor belt' for all-optical lasing during laser filamentation in Nitrogen

    NASA Astrophysics Data System (ADS)

    Ivanov, Misha; Richter, Maria; Morales, Felipe; Smirnova, Olga

    2016-05-01

    Inducing and controlling lasing in the open air is an intriguing challenge. Recent experiments on laser filamentation in the air have demonstrated generation of population inversion and lasing on the 391 nm line in the nitrogen ion, which corresponds to the transition between its second excited B2Σu+ and the ground X2Σg+ electronic states. Importantly, lasing at this transition appears to be a very general effect, arising during filamentation of virtually any incident radiation, from visible to mid-infrared. We analyze the possible mechanisms that can be responsible for the generation of the population inversion between the B2Σu+ and X2Σg+ states of N2+,focusing on the interplay between tunnel ionization of neutral nitrogen to different electronic states, ultrafast laser driven electronic excitations in the ion, molecular vibrations, laser induced alignment and rotations. We show how the strong laser field creates a ro-vibrational `conveyor belt' carrying the population away from the ground electronic state X2Σg+ and enabling population inversion in B2Σu+ . We show that this mechanism is robust with respect to the incident laser wavelength, and analyze its optimization with respect to the fundamental wavelength and pulse duration.

  10. Condensing polarization mode dispersion using CSRZ-DQPSK modulation in WDM-RoF-PON system

    NASA Astrophysics Data System (ADS)

    Sanofer, P. Fathima; Julus, L. Jerart; Vijayarangan, V.

    2015-06-01

    Differential Quadrature Phase Shift Keying (DQPSK) is considered as an acceptable modulation technique for long-haul high speed communication owing to its ability to diminish the Polarization Mode Dispersion (PMD), non-linear effects and has constant envelope over the communication. The assessment includes Carrier Suppressed Return to Zero (CSRZ) modulation format. The combination of CSRZ and DQPSK techniques would result in a high bit rate with better Bit Error Rate (BER) in Wavelength Division Multiplexing - Passive Optical Network (WDM-PON) setup. The Radio Frequency (RF) signal is obtained finally for wireless service which can be assessed. . The optical communication system is expanded by comprising Polarization Multiplexing (PM) which improves the user scope and the spectral efficiency. The goal is to experimentally analyze the performances of CSRZ-DQPSK modulated non-coherent receiver for wire and RoF (Radio over Fiber) system for wireless service. Also, equal amount of power is provided for both the services. The PMD is reduced both the services. The Proposed system can provide flexible, cost-effective and high bandwidth utilization with reduced BER.

  11. RoPEUS: A New Robust Algorithm for Static Positioning in Ultrasonic Systems

    PubMed Central

    Prieto, José Carlos; Croux, Christophe; Jiménez, Antonio Ramón

    2009-01-01

    A well known problem for precise positioning in real environments is the presence of outliers in the measurement sample. Its importance is even bigger in ultrasound based systems since this technology needs a direct line of sight between emitters and receivers. Standard techniques for outlier detection in range based systems do not usually employ robust algorithms, failing when multiple outliers are present. The direct application of standard robust regression algorithms fails in static positioning (where only the current measurement sample is considered) in real ultrasound based systems mainly due to the limited number of measurements and the geometry effects. This paper presents a new robust algorithm, called RoPEUS, based on MM estimation, that follows a typical two-step strategy: 1) a high breakdown point algorithm to obtain a clean sample, and 2) a refinement algorithm to increase the accuracy of the solution. The main modifications proposed to the standard MM robust algorithm are a built in check of partial solutions in the first step (rejecting bad geometries) and the off-line calculation of the scale of the measurements. The algorithm is tested with real samples obtained with the 3D-LOCUS ultrasound localization system in an ideal environment without obstacles. These measurements are corrupted with typical outlying patterns to numerically evaluate the algorithm performance with respect to the standard parity space algorithm. The algorithm proves to be robust under single or multiple outliers, providing similar accuracy figures in all cases. PMID:22408522

  12. New RO TFC Membranes by Interfacial Polymerization in n-Dodecane with Various co-Solvents

    PubMed Central

    Al-Hobaib, Abdullah Sulaiman; Al-Suhybani, Mohammed Sulaiman; Al-Sheetan, Khalid Mohammed; Mousa, Hasan; Shaik, Mohammed Rafi

    2016-01-01

    The objective of this research is to prepare and characterize a new and highly efficient polyamide TFC RO membrane by interfacial polymerization in dodecane solvent mixed with co-solvents. Three co-solvents were tested namely; acetone, ethyl acetate, and diethyl ether of concentration of 0.5, 1, 2, 3, and 5 wt %. The modified membranes were characterized by SEM, EDX, AFM and contact angle techniques. The results showed that addition of co-solvent results in a decrease in the roughness, pore size and thickness of the produced membranes. However, as the concentration of the co-solvent increases the pore size of the membranes gets larger. Among the three co-solvents tested, acetone was found to result in membranes with the largest pore size and contact angle followed by diethyl ether then ethyl acetate. Measured contact angle increases as the concentration of the co-solvent increases reaching a constant value except for ethyl acetate where it was found to drop. Investigating flux and salt rejection by the formulated membranes showed that higher flux was attained when acetone was used as a co-solvent followed by diethyl ether then ethyl acetate. However, the highest salt rejection was achieved with diethyl ether. PMID:27136591

  13. A European Roadmap for Research in Astrobiology - The AstRoMap Roadmap

    NASA Astrophysics Data System (ADS)

    Gómez, F.; Walter, N.; Horneck, G.; Muller, C.; Rettberg, P.; Capria, M.; Palomba, E.

    2015-10-01

    AstRoMap (Astrobiology Road Mapping activity-www.astromap-eu.org) is a collaborative project which will provide the European Planetary Science Community with a road map in astrobiology. The goals of the project have been: (i) to pose big questions related to astrobiology; and (ii) the identification of experiments, new technology and/or those space missions to be developed in future programs and which could answer those big questions. This collaborative infrastructure includes the organization of expert panels and international workshops in order to discuss about those big questions and the science objectives by the community to be addressed. The main deliverable will be a Roadmap document. The project is steered by a consortium of six European and national research institutes and associations: -­- Centro de Astrobiologica (INTACSIC), Spain -­- European Science Foundation, France -­- Association pour un Réseau Européen d'Exo/Astrobiology (EANA), France -­- B-USOC, Belgium -­- Deutsches Zentrum für Luft- und Raumfahrt (DLR), Germany -­- National Institute for Astrophysics (INAF), ItalyOrigin and evolution of planetary systems -­- Origin of organic compounds in space -­- Rock-water-carbon interactions, organic synthesis, and steps to life -­- Life and habitability on Earth and in Space -­- -­- Biosignatures as facilitating life detection The key topics will focus on a limited number of strategic scientific objectives to be addressed in the next 20 years by European astrobiologists, and suggest research activities for future development.

  14. SCRF spectral mask compliant ultra-wideband signal generation approaches for RoF systems

    NASA Astrophysics Data System (ADS)

    Andrianova, Anna V.; Meshkov, Ivan K.; Sultanov, Albert K.; Vinogradova, Irina L.; Abdrakhmanova, Guzel I.; Grakhova, Elizaveta P.; Ishmiyarov, Arsen A.; Zainullin, Airat R.

    2016-03-01

    Ultra-wideband (UWB) signal generation approach for Radio-over-Fiber (RoF) systems is proposed in the paper. Impulse-radio ultra-wideband (IR-UWB) transmission technology experimental realization comply with State Committee on Radio Frequency (SCRF) regulations is offered in the paper. Three separate IR-UWB signals with carrier frequencies 4,5 GHz, 7 GHz and 9,5 GHz are generated. Such frequencies were chosen because of SCRF spectral mask "windows". The frequencies 4,5 GHz, 7 GHz and 9,5 GHz are the central frequencies of these "windows". To assess the performance of proposed system bit error rate (BER) measurements were taken. UWB signal generation schemes and received IR-UWB signal are shown in the figures. The correlation between BER and received optical power is given in the paper. In the case of UWB signal photonic generation approach the correlation between BER and received optical power for different SMF fiber lengths is given.

  15. A Study of ro-vibrational OH Emission from Herbig Ae/Be Stars

    NASA Astrophysics Data System (ADS)

    Brittain, Sean D.; Adamkovics, Mate; Carr, John S.; Najita, Joan R.

    2016-06-01

    We present a study of ro-vibrational OH and CO emission from 21 disks around Herbig Ae/Be stars. We find that the luminosity of the OH emission is proportional to the luminosity of the CO emission over five orders of magnitude in stellar ultraviolet luminosity. We also find that the profiles of the OH and CO emission lines are similar indicating that they arise from the same radial region of the disk.The CO and OH emission are both correlated with the far ultraviolet (1300-1840Å) luminosity of the stars while the luminosity of the PAH emission is correlated with the longer wavelength ultraviolet (2450-3200Å) luminosity of the stars. Our interpretation of the observations is that the OH and CO are heated by ultraviolet photons in the same region of the disk. We also find that while disk flaring affects the PAH luminosity, it is not a factor in the luminosity of the OH and CO emission. However, transition disks with large inner holes do have systematically lower OH and CO luminosities.

  16. New RO TFC Membranes by Interfacial Polymerization in n-Dodecane with Various co-Solvents.

    PubMed

    Al-Hobaib, Abdullah Sulaiman; Al-Suhybani, Mohammed Sulaiman; Al-Sheetan, Khalid Mohammed; Mousa, Hasan; Shaik, Mohammed Rafi

    2016-01-01

    The objective of this research is to prepare and characterize a new and highly efficient polyamide TFC RO membrane by interfacial polymerization in dodecane solvent mixed with co-solvents. Three co-solvents were tested namely; acetone, ethyl acetate, and diethyl ether of concentration of 0.5, 1, 2, 3, and 5 wt %. The modified membranes were characterized by SEM, EDX, AFM and contact angle techniques. The results showed that addition of co-solvent results in a decrease in the roughness, pore size and thickness of the produced membranes. However, as the concentration of the co-solvent increases the pore size of the membranes gets larger. Among the three co-solvents tested, acetone was found to result in membranes with the largest pore size and contact angle followed by diethyl ether then ethyl acetate. Measured contact angle increases as the concentration of the co-solvent increases reaching a constant value except for ethyl acetate where it was found to drop. Investigating flux and salt rejection by the formulated membranes showed that higher flux was attained when acetone was used as a co-solvent followed by diethyl ether then ethyl acetate. However, the highest salt rejection was achieved with diethyl ether. PMID:27136591

  17. Efficiently Combining Water Reuse and Desalination through Forward Osmosis-Reverse Osmosis (FO-RO) Hybrids: A Critical Review.

    PubMed

    Blandin, Gaetan; Verliefde, Arne R D; Comas, Joaquim; Rodriguez-Roda, Ignasi; Le-Clech, Pierre

    2016-01-01

    Forward osmosis (FO) is a promising membrane technology to combine seawater desalination and water reuse. More specifically, in a FO-reverse osmosis (RO) hybrid process, high quality water recovered from the wastewater stream is used to dilute seawater before RO treatment. As such, lower desalination energy needs and/or water augmentation can be obtained while delivering safe water for direct potable reuse thanks to the double dense membrane barrier protection. Typically, FO-RO hybrid can be a credible alternative to new desalination facilities or to implementation of stand-alone water reuse schemes. However, apart from the societal (public perception of water reuse for potable application) and water management challenges (proximity of wastewater and desalination plants), FO-RO hybrid has to overcome technical limitation such as low FO permeation flux to become economically attractive. Recent developments (i.e., improved FO membranes, use of pressure assisted osmosis, PAO) demonstrated significant improvement in water flux. However, flux improvement is associated with drawbacks, such as increased fouling behaviour, lower rejection of trace organic compounds (TrOCs) in PAO operation, and limitation in FO membrane mechanical resistance, which need to be better considered. To support successful implementation of FO-RO hybrid in the industry, further work is required regarding up-scaling to apprehend full-scale challenges in term of mass transfer limitation, pressure drop, fouling and cleaning strategies on a module scale. In addition, refined economics assessment is expected to integrate fouling and other maintenance costs/savings of the FO/PAO-RO hybrid systems, as well as cost savings from any treatment step avoided in the water recycling. PMID:27376337

  18. Report on the Hemodialysis Reliable Outflow (HeRO) experience in dialysis patients with central venous occlusions

    PubMed Central

    Wallace, Justin R.; Chaer, Rabih A.; Dillavou, Ellen D.

    2014-01-01

    Objective The Hemodialysis Reliable Outflow (HeRO) graft (Hemosphere/CryoLife Inc, Eden Prairie, Minn) has provided an innovative means to obtain hemodialysis access for patients with severe central venous occlusive disease. The outcomes of this novel treatment modality in a difficult population have yet to be clearly established. Methods A retrospective review of HeRO graft placement from June 2010 to January 2012 was performed. Patient hemodialysis access history, clinical complexity, complications, and outcomes were analyzed. Categoric data were described with counts and proportions, and continuous data with means, ranges and, when appropriate, standard deviations. Patency rates were analyzed using life-table analysis, and patency rate comparisons were made with a two-group proportion comparison calculator. Results HeRO graft placement was attempted 21 times in 19 patients (52% women), with 18 of 21 (86%) placed successfully. All but one was placed in the upper extremity. Mean follow-up after successful placement has been 7 months (range, 0–23 months). The primary indication for all HeRO graft placements except one was central vein occlusion(s) and need for arteriovenous access. Patients averaged 2.0 previous (failed) accesses and multiple catheters. Four HeRO grafts (24%), all in women, required ligation and removal for severe steal symptoms in the immediate postoperative period (P < .01 vs men). Three HeROs were placed above fistulas for rescue. All thrombosed <4 months, although the fistulas remained open. An infection rate of 0.5 bacteremic events per 1000 HeRO-days was observed. At a mean follow-up of 7 months, primary patency was 28% and secondary patency was 44%. The observed 12-month primary and secondary patency rates were 11% and 32%, respectively. Secondary patency was maintained in four patients for a mean duration of 10 months (range, 6–18 months), with an average of 4.0 ± 2.2 thrombectomies per catheter. Conclusions HeRO graft placement, when

  19. Transiting exoplanets from the CoRoT space mission. XXI. CoRoT-19b: a low density planet orbiting an old inactive F9V-star

    NASA Astrophysics Data System (ADS)

    Guenther, E. W.; Díaz, R. F.; Gazzano, J.-C.; Mazeh, T.; Rouan, D.; Gibson, N.; Csizmadia, Sz.; Aigrain, S.; Alonso, R.; Almenara, J. M.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bordé, P.; Bouchy, F.; Bruntt, H.; Cabrera, J.; Carone, L.; Carpano, S.; Cavarroc, C.; Deeg, H. J.; Deleuil, M.; Dreizler, S.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Gandolfi, D.; Gillon, M.; Guillot, T.; Hatzes, A.; Havel, M.; Hébrard, G.; Jehin, E.; Jorda, L.; Lammer, H.; Léger, A.; Moutou, C.; Nortmann, L.; Ollivier, M.; Ofir, A.; Pasternacki, Th.; Pätzold, M.; Parviainen, H.; Queloz, D.; Rauer, H.; Samuel, B.; Santerne, A.; Schneider, J.; Tal-Or, L.; Tingley, B.; Weingrill, J.; Wuchterl, G.

    2012-01-01

    Context. Observations of transiting extrasolar planets are of key importance to our understanding of planets because their mass, radius, and mass density can be determined. These measurements indicate that planets of similar mass can have very different radii. For low-density planets, it is generally assumed that they are inflated owing to their proximity to the host-star. To determine the causes of this inflation, it is necessary to obtain a statistically significant sample of planets with precisely measured masses and radii. Aims: The CoRoT space mission allows us to achieve a very high photometric accuracy. By combining CoRoT data with high-precision radial velocity measurements, we derive precise planetary radii and masses. We report the discovery of CoRoT-19b, a gas-giant planet transiting an old, inactive F9V-type star with a period of four days. Methods: After excluding alternative physical configurations mimicking a planetary transit signal, we determine the radius and mass of the planet by combining CoRoT photometry with high-resolution spectroscopy obtained with the echelle spectrographs SOPHIE, HARPS, FIES, and SANDIFORD. To improve the precision of its ephemeris and the epoch, we observed additional transits with the TRAPPIST and Euler telescopes. Using HARPS spectra obtained during the transit, we then determine the projected angle between the spin of the star and the orbit of the planet. Results: We find that the host star of CoRoT-19b is an inactive F9V-type star close to the end of its main-sequence life. The host star has a mass M∗ = 1.21 ± 0.05 M⊙ and radius R∗ = 1.65 ± 0.04 R⊙. The planet has a mass of MP = 1.11 ± 0.06 MJup and radius of RP = 1.29 ± 0.03 RJup. The resulting bulk density is only ρ = 0.71 ± 0.06 g cm-3, which is much lower than that for Jupiter. Conclusions: The exoplanet CoRoT-19b is an example of a giant planet of almost the same mass as Jupiter but a ≈30% larger radius. The CoRoT space mission, launched on

  20. Transiting exoplanets from the CoRoT space mission. XXII. CoRoT-16b: a hot Jupiter with a hint of eccentricity around a faint solar-like star

    NASA Astrophysics Data System (ADS)

    Ollivier, M.; Gillon, M.; Santerne, A.; Wuchterl, G.; Havel, M.; Bruntt, H.; Bordé, P.; Pasternacki, T.; Endl, M.; Gandolfi, D.; Aigrain, S.; Almenara, J. M.; Alonso, R.; Auvergne, M.; Baglin, A.; Barge, P.; Bonomo, A. S.; Bouchy, F.; Cabrera, J.; Carone, L.; Carpano, S.; Cavarroc, C.; Cochran, W. D.; Csizmadia, Sz.; Deeg, H. J.; Deleuil, M.; Diaz, R. F.; Dvorak, R.; Erikson, A.; Ferraz-Mello, S.; Fridlund, M.; Gazzano, J.-C.; Grziwa, S.; Guenther, E.; Guillot, T.; Guterman, P.; Hatzes, A.; Hébrard, G.; Lammer, H.; Léger, A.; Lovis, C.; MacQueen, P. J.; Mayor, M.; Mazeh, T.; Moutou, C.; Ofir, A.; Pätzold, M.; Queloz, D.; Rauer, H.; Rouan, D.; Samuel, B.; Schneider, J.; Tadeu dos Santos, M.; Tal-Or, L.; Tingley, B.; Weingrill, J.

    2012-05-01

    Aims: We report the discovery of CoRoT-16b, a low density hot jupiter that orbits a faint G5V star (mV = 15.63) in 5.3523 ± 0.0002 days with slight eccentricity. A fit of the data with no a priori assumptions on the orbit leads to an eccentricity of 0.33 ± 0.1. We discuss this value and also derive the mass and radius of the planet. Methods: We analyse the photometric transit curve of CoRoT-16 given by the CoRoT satellite, and radial velocity data from the HARPS and HIRES spectrometers. A combined analysis using a Markov chain Monte Carlo algorithm is used to get the system parameters. Results: CoRoT-16b is a 0.535 -0.083/+0.085 MJ, 1.17 -0.14/+0.16 RJ hot Jupiter with a density of 0.44 -0.14/+0.21 g cm-3. Despite its short orbital distance (0.0618 ± 0.0015 AU) and the age of the parent star (6.73 ± 2.8 Gyr), the planet orbit exhibits significantly non-zero eccentricity. This is very uncommon for this type of objects as tidal effects tend to circularise the orbit. This value is discussed taking into account the characteristics of the star and the observation accuracy. The CoRoT space mission, launched on December 27, 2006, has been developed and is operated by the CNES with the contribution of Austria, Belgium, Brasil, ESA, Germany, and Spain.Observations made with the HARPS spectrograph at ESO La Silla Observatory (HARPS programs 083.C-0186 and 184.C-0639) and the HIRES spectrograph at the Keck Observatory (NASA-Keck programs N035Hr, N143Hr and N095Hr).

  1. Selective Retinoic Acid Receptor γ Agonists Promote Repair of Injured Skeletal Muscle in Mouse.

    PubMed

    Di Rocco, Agnese; Uchibe, Kenta; Larmour, Colleen; Berger, Rebecca; Liu, Min; Barton, Elisabeth R; Iwamoto, Masahiro

    2015-09-01

    Retinoic acid signaling regulates several biological events, including myogenesis. We previously found that retinoic acid receptor γ (RARγ) agonist blocks heterotopic ossification, a pathological bone formation that mostly occurs in the skeletal muscle. Interestingly, RARγ agonist also weakened deterioration of muscle architecture adjacent to the heterotopic ossification lesion, suggesting that RARγ agonist may oppose skeletal muscle damage. To test this hypothesis, we generated a critical defect in the tibialis anterior muscle of 7-week-old mice with a cautery, treated them with RARγ agonist or vehicle corn oil, and examined the effects of RARγ agonist on muscle repair. The muscle defects were partially repaired with newly regenerating muscle cells, but also filled with adipose and fibrous scar tissue in both RARγ-treated and control groups. The fibrous or adipose area was smaller in RARγ agonist-treated mice than in the control. In addition, muscle repair was remarkably delayed in RARγ-null mice in both critical defect and cardiotoxin injury models. Furthermore, we found a rapid increase in retinoid signaling in lacerated muscle, as monitored by retinoid signaling reporter mice. Together, our results indicate that endogenous RARγ signaling is involved in muscle repair and that selective RARγ agonists may be beneficial to promote repair in various types of muscle injuries. PMID:26205250

  2. Ascorbic acid enables reversible dopamine receptor /sup 3/H-agonist binding

    SciTech Connect

    Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.

    1981-11-16

    The effects of ascorbic acid on dopaminergic /sup 3/H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the /sup 3/H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total /sup 3/H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable /sup 3/H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable /sup 3/H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of /sup 3/H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific /sup 3/H-agonist binding to dopamine receptors.

  3. Ro-vibrational excitation of an organic molecule (HCN) in protoplanetary disks

    NASA Astrophysics Data System (ADS)

    Bruderer, Simon; Harsono, Daniel; van Dishoeck, Ewine F.

    2015-03-01

    Context. Organic molecules are important constituents of protoplanetary disks. Their ro-vibrational lines observed in the near- and mid-infrared are commonly detected toward T Tauri disks. These lines are the only way to probe the chemistry in the inner few au where terrestrial planets form. To understand this chemistry, accurate molecular abundances have to be determined. This is complicated by excitation effects that include radiative pumping. Most analyses so far have made the assumption of local thermal equilibrium (LTE), which may not be fulfilled because of the high gas densities required to collisionally thermalize the vibrational levels of the molecules. Aims: The non-LTE excitation effects of hydrogen cyanide (HCN) are studied to evaluate (i) how the abundance determination is affected by the LTE assumption; (ii) whether the ro-vibrational excitation is dominated by collisions or radiative pumping; and (iii) which regions of protoplanetary disks are traced by certain vibrational bands. Methods: Starting from estimates for the collisional rate coefficients of HCN, non-LTE slab models of the HCN emission were calculated to study the importance of different excitation mechanisms. Using a new radiative transfer model, the HCN emission from a full two-dimensional disk was then modeled to study the effect of the non-LTE excitation, together with the line formation. We ran models tailored to the T Tauri disk AS 205 (N) where HCN lines in both the 3 μm and 14 μm bands have been observed by VLT-CRIRES and the Spitzer Space Telescope. Results: Reproducing the observed 3 μm/14 μm flux ratios requires very high densities and kinetic temperatures (n> 1014 cm-3 and T> 750 K), if only collisional excitation is accounted for. Radiative pumping can, however, excite the lines easily out to considerable radii ~10 au. Consequently, abundances derived from LTE and non-LTE models do not differ by more than a factor of about 3. Models with both a strongly enhanced abundance

  4. ON THE ASYMMETRY OF THE OH RO-VIBRATIONAL LINES IN HD 100546

    SciTech Connect

    Fedele, D.; Bruderer, S.; Van den Ancker, M. E.; Pascucci, I. E-mail: mvandena@eso.org

    2015-02-10

    We present multi-epoch high-spectral resolution observations with VLT/CRIRES of the OH doublet {sup 2}Π{sub 3/2} P4.5 (1+, 1–) (2.934 μm) toward the protoplanetary disk around HD 100546. The OH doublet is detected at all epochs and is spectrally resolved while nearby H{sub 2}O lines remain undetected. The OH line velocity profile is different in the three data sets: in the first epoch (2012 April, P.A. = 26°) the OH lines are symmetric and line broadening is consistent with the gas being in Keplerian rotation around the star. No OH emission is detected within a radius of 8-11 AU from the star: the line emitting region is similar in size and extent to that of the CO ro-vibrational lines. In the other two epochs (2013 March and 2014 April, P.A. = 90° and 10°, respectively) the OH lines appear asymmetric and fainter compared to 2012 April. We investigate the origin of these line asymmetries which were taken by previous authors as evidence for tidal interaction between a (unseen) massive planet and the disk. We show that the observed asymmetries can be fully explained by a misalignment of the slit of the order of 0.''04-0.''20 with respect to the stellar position. The disk is spatially resolved and the slit misalignment is likely caused by the extended dust emission which is brighter than the stellar photosphere at near-infrared wavelengths which is the wavelength used for the pointing. This can cause the photo-center of HD 100546 to be misaligned with the stellar position at near-infrared wavelengths.

  5. Validation of MIPAS IMK/IAA V5R_O3_224 ozone profiles

    NASA Astrophysics Data System (ADS)

    Laeng, A.; Grabowski, U.; von Clarmann, T.; Stiller, G.; Glatthor, N.; Höpfner, M.; Kellmann, S.; Kiefer, M.; Linden, A.; Lossow, S.; Sofieva, V.; Petropavlovskikh, I.; Hubert, D.; Bathgate, T.; Bernath, P.; Boone, C. D.; Clerbaux, C.; Coheur, P.; Damadeo, R.; Degenstein, D.; Frith, S.; Froidevaux, L.; Gille, J.; Hoppel, K.; McHugh, M.; Kasai, Y.; Lumpe, J.; Rahpoe, N.; Toon, G.; Sano, T.; Suzuki, M.; Tamminen, J.; Urban, J.; Walker, K.; Weber, M.; Zawodny, J.

    2014-11-01

    We present the results of an extensive validation program of the most recent version of ozone vertical profiles retrieved with the IMK/IAA (Institute for Meteorology and Climate Research/Instituto de Astrofísica de Andalucía) MIPAS (Michelson Interferometer for Passive Atmospheric Sounding) research level 2 processor from version 5 spectral level 1 data. The time period covered corresponds to the reduced spectral resolution period of the MIPAS instrument, i.e., January 2005-April 2012. The comparison with satellite instruments includes all post-2005 satellite limb and occultation sensors that have measured the vertical profiles of tropospheric and stratospheric ozone: ACE-FTS, GOMOS, HALOE, HIRDLS, MLS, OSIRIS, POAM, SAGE II, SCIAMACHY, SMILES, and SMR. In addition, balloon-borne MkIV solar occultation measurements and ground-based Umkehr measurements have been included, as well as two nadir sensors: IASI and SBUV. For each reference data set, bias determination and precision assessment are performed. Better agreement with reference instruments than for the previous data version, V5R_O3_220 (Laeng et al., 2014), is found: the known high bias around the ozone vmr (volume mixing ratio) peak is significantly reduced and the vertical resolution at 35 km has been improved. The agreement with limb and solar occultation reference instruments that have a known small bias vs. ozonesondes is within 7% in the lower and middle stratosphere and 5% in the upper troposphere. Around the ozone vmr peak, the agreement with most of the satellite reference instruments is within 5%; this bias is as low as 3% for ACE-FTS, MLS, OSIRIS, POAM and SBUV.

  6. GPS RO sensing of Boundary Layer Height within Southern Ocean Cyclones

    NASA Astrophysics Data System (ADS)

    Schuddeboom, Alex; McDonald, Adrian; Katurji, Marwan; Morgenstern, Olaf; Harvey, Mike

    2016-04-01

    The COSMIC constellation of GPS RO satellites has been used extensively over the previous few years to generate climatologies of boundary layer height (BLH). These satellites use high precision clocks to measure the time it takes for a signal to be transmitted through the atmosphere. From the time measurements, the angle of refraction of the signal can be calculated and then used in turn to calculate atmospheric refractivity. Boundary layer heights can then be determined by identifying sharp gradients in the refractivity profile. The results of this approach have been compared with radiosonde data and show a high level of agreement. By using this technique, we also generated a BLH climatology which was then used to analyse how the height of the boundary layer varies within the specific meteorological context of Southern Ocean cyclones. Analysis of the BLH behaviour over cyclones was primarily based upon generating cyclone composites. This is done by averaging together measurements in a cyclone relative framework to generate a representative cyclone. This technique allows a direct examination of the mean state, however it is also valuable for further analysis such as splitting the composite into regions and analysing the distribution of values over each of these sub-regions. We also investigated the relationship between boundary layer height and surface variables. There is a particularly strong negative relationship between sea ice concentration and boundary layer height. The reasons for this phenomenon are not entirely clear but appear to be at least partially related to changes in the surface sensible heat flux. The effects of other surface variables such as air temperature, sea surface temperature and wind speeds were relatively minor.

  7. Nitrogen transport and deposition during the Rocky Mountain Airborne Nitrogen and Sulfur (RoMANS) study

    NASA Astrophysics Data System (ADS)

    Collett, J. L.; Raja, S.; Taylor, C.; Carrico, C.; Schwandner, F.; Beem, K.; Lee, T.; Sullivan, A.; Day, D.; McMeeking, G.; Kreidenweis, S.; Hand, J.; Schichtel, B.; Malm, W.

    2007-12-01

    A number of deleterious effects have been noted due to increasing deposition of nitrogen compounds in Rocky Mountain National Park (RMNP). The Rocky Mountain Airborne Nitrogen and Sulfur (RoMANS) study was conducted to improve our understanding of the sources and transport of airborne nitrogen and sulfur species within RMNP as well as their deposition pathways. Two field campaigns were conducted, in spring and summer 2006, to characterize pollutant transport and deposition during seasons with historically high nitrogen inputs. Several measurements sites were operated within the park, at locations west and east of the park boundaries, and at locations near the NE, NW, and SE boundaries of the state of Colorado. Measurements at several sites included 24-hour integrated gas concentrations (ammonia, nitric acid, sulfur dioxide), PM2.5 composition, and wet deposition. A core measurement site in the park included more detailed and higher time resolution chemical, optical, and particle size distribution measurements. An overview of study findings will be presented including the composition of collected PM2.5, concentrations of key trace gas species, and observations of wet and dry deposition composition and fluxes. Concentrations of N species in RMNP varied significantly with local and regional transport patterns. High concentrations of nitrate/nitric acid and ammonia/ammonium observed routinely on the eastern plains of Colorado reflect a mixture of urban and agricultural emissions. The highest concentrations of N species in RMNP were generally associated with upslope transport from the east. Nitrogen deposition in RMNP during the spring campaign was dominated by a single, upslope snowstorm. A combination of high pollutant concentrations and heavy precipitation during this upslope event acted to produce N deposition fluxes that far outweighed other spring precipitation events. During the summer study, by contrast, numerous events contributed more equally to total N wet

  8. Ductal epithelial expression of Ro52 correlates with inflammation in salivary glands of patients with primary Sjögren's syndrome

    PubMed Central

    Aqrawi, L A; Kvarnström, M; Brokstad, K A; Jonsson, R; Skarstein, K; Wahren-Herlenius, M

    2014-01-01

    Ro52 is an E3 ubiquitin ligase with a prominent regulatory role in inflammation. The protein is a common target of circulating autoantibodies in rheumatic autoimmune diseases, particularly Sjögren's syndrome (SS). In this study we aimed to investigate the expression of the SS target autoantigen Ro52 in salivary glands of patients with primary Sjögren's syndrome (pSS). Ro52 expression was assessed by immunohistochemical staining of paraffin-embedded and frozen salivary gland biopsies from 28 pSS patients and 19 non-pSS controls from Swedish and Norwegian registries, using anti-human Ro52 monoclonal antibodies. The degree and pattern of staining and inflammation was then evaluated. Furthermore, secreted Ro52 protein was measured in saliva and serum samples from the same individuals through a catch-enzyme-linked immunosorbent assay (ELISA). Ro52 was highly expressed in all the focal infiltrates in pSS patients. Interestingly, a significantly higher degree of Ro52 expression in ductal epithelium was observed in the patients compared to the non-pSS controls (P < 0·03). Moreover, the degree of ductal epithelial expression of Ro52 correlated with the level of inflammation (Spearman's r = 0·48, P < 0·0120). However, no secreted Ro52 protein could be detected in serum and saliva samples of these subjects. Ro52 expression in ductal epithelium coincides with degree of inflammation and is up-regulated in pSS patients. High expression of Ro52 might result in the breakage of tolerance and generation of Ro52 autoantibodies in genetically susceptible individuals. We conclude that the up-regulation of Ro52 in ductal epithelium might be a triggering factor for disease progression in SS. PMID:24673429

  9. Ductal epithelial expression of Ro52 correlates with inflammation in salivary glands of patients with primary Sjögren's syndrome.

    PubMed

    Aqrawi, L A; Kvarnström, M; Brokstad, K A; Jonsson, R; Skarstein, K; Wahren-Herlenius, M

    2014-07-01

    Ro52 is an E3 ubiquitin ligase with a prominent regulatory role in inflammation. The protein is a common target of circulating autoantibodies in rheumatic autoimmune diseases, particularly Sjögren's syndrome (SS). In this study we aimed to investigate the expression of the SS target autoantigen Ro52 in salivary glands of patients with primary Sjögren's syndrome (pSS). Ro52 expression was assessed by immunohistochemical staining of paraffin-embedded and frozen salivary gland biopsies from 28 pSS patients and 19 non-pSS controls from Swedish and Norwegian registries, using anti-human Ro52 monoclonal antibodies. The degree and pattern of staining and inflammation was then evaluated. Furthermore, secreted Ro52 protein was measured in saliva and serum samples from the same individuals through a catch-enzyme-linked immunosorbent assay (ELISA). Ro52 was highly expressed in all the focal infiltrates in pSS patients. Interestingly, a significantly higher degree of Ro52 expression in ductal epithelium was observed in the patients compared to the non-pSS controls (P < 0·03). Moreover, the degree of ductal epithelial expression of Ro52 correlated with the level of inflammation (Spearman's r = 0·48, P < 0·0120). However, no secreted Ro52 protein could be detected in serum and saliva samples of these subjects. Ro52 expression in ductal epithelium coincides with degree of inflammation and is up-regulated in pSS patients. High expression of Ro52 might result in the breakage of tolerance and generation of Ro52 autoantibodies in genetically susceptible individuals. We conclude that the up-regulation of Ro52 in ductal epithelium might be a triggering factor for disease progression in SS. PMID:24673429

  10. Kinetic determinants of agonist action at the recombinant human glycine receptor

    PubMed Central

    Lewis, Trevor M; Schofield, Peter R; McClellan, Annette M L

    2003-01-01

    The amino acids glycine, β-alanine and taurine are all endogenous agonists of the glycine receptor. In this study, a combination of rapid agonist application onto macropatches and steady-state single-channel recordings was used to compare the actions of glycine, β-alanine and taurine upon homomeric α1 human glycine receptors transiently expressed in human embryonic kidney (HEK 293) cells. The 10–90 % rise times determined from rapid application of 100 μm of each agonist were indistinguishable, indicating each agonist has a similar association rate. At saturating concentrations (30 mm) the rise time for glycine (0.26 ms) was 1.8-fold faster than that for β-alanine (0.47 ms) and 3.9-fold faster than that for taurine (1.01 ms), indicating clear differences in the maximum opening rate between agonists. The relaxation following rapid removal of agonist was fitted with a single exponential for β-alanine (3.0 ms) and taurine (2.2 ms), and two exponential components for glycine with a weighted mean time constant of 27.1 ms. This was consistent with differences in dissociation rates estimated from analysis of bursts, with taurine > β-alanine > glycine. Exponential fits to the open period distributions gave time constants that did not differ between agonists and the geometric distribution for the number of openings per burst indicated that all three agonists had a significant component of single-opening bursts. Based upon these data, we propose a kinetic scheme with three independent open states, where the opening rates are dependent upon the activating agonist, while the closing rates are an intrinsic characteristic of the receptor. PMID:12679369

  11. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    SciTech Connect

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  12. Downregulation of (3H)Ro5-4864 binding sites after exposure to peripheral-type benzodiazepines in vitro

    SciTech Connect

    Johnson, M.D.; Wang, J.K.; Morgan, J.I.; Spector, S.

    1986-09-01

    Peripheral-type benzodiazepine (BZD) binding sites undergo a rapid and pronounced downregulation after exposure to these compounds in vitro. Friend erythroleukemia cells were incubated with micromolar concentrations of BZD after which they were washed thoroughly and the binding of the specific peripheral-type BZD radioligand (/sup 3/H)Ro5-4864 was determined. Exposure to the peripheral-type BZD Ro7-3351 decreased the number of (/sup 3/H)Ro5-4864 binding sites from 324 to 41 fmol/10(6) cells with no change in affinity. Downregulation appears to require active cellular processes because it is blocked when exposure to BZD is at 4/sup 0/C rather than at 37/sup 0/C. Furthermore, whereas (/sup 3/H)Ro5-4864 binding is decreased substantially in membrane preparations made from downregulated cells, it is not altered when membrane preparations from control cells are exposed to BZD. The time course of downregulation is quite rapid, as it occurs within minutes. In contrast, the return of sites requires days and there is a close relationship between return of sites and growth of new cells. The ability of BZDs to downregulate correlates more closely with affinity for the peripheral-type site than with biological activity. The ability to undergo downregulation is characteristic of receptors and its occurrence suggests that peripheral-type BZD binding sites are functional receptors.

  13. VizieR Online Data Catalog: Eclipsing binaries in CoRoT-LRc01 field (Cabrera+, 2009)

    NASA Astrophysics Data System (ADS)

    Cabrera, J.; Fridlund, M.; Ollivier, M.; Gandolfi, D.; Csizmadia, Sz.; Alonso, R.; Aigrain, S.; Alapini, A.; Almenara, J.-M.; Barge, P.; Bonomo, A. S.; Borde, P.; Bouchy, F.; Bruntt, H.; Carone, L.; Carpano, S.; Deeg, H. J.; de La, Reza R.; Deleuil, M.; Dvorak, R.; Erikson, A.; Gillon, M.; Gondoin, P.; Guenther, E. W.; Guillot, T.; Hartmann, M.; Hatzes, A.; Hebrard, G.; Jorda, L.; Lammer, H.; Leger, A.; Llebaria, A.; Lovis, C.; Magain, P.; Mayor, M.; Mazeh, T.; Moutou, C.; Ofir, A.; Paetzold, M.; Pepe, F.; Pont, F.; Queloz, D.; Rabus, M.; Rauer, H.; Regulo, C.; Renner, S.; Rouan, D.; Samuel, B.; Santerne, A.; Schneider, J.; Shporer, A.; Stecklum, B.; Tingley, B.; Udry, S.; Wuchterl, G.

    2010-01-01

    The 11408 targets observed by CoRoT were selected using the information gathered in the database Exo-Dat (Deleuil et al. 2009AJ....138..649D; Meunier et al. 2007, ASP Conf., 376, 339), built with dedicated ground based photometric observations in the visible and near IR bands from 2MASS catalog. (3 data files).

  14. Implementation of a GPS-RO data processing system for the KIAPS-LETKF data assimilation system

    NASA Astrophysics Data System (ADS)

    Kwon, H.; Kang, J.-S.; Jo, Y.; Kang, J. H.

    2015-03-01

    The Korea Institute of Atmospheric Prediction Systems (KIAPS) has been developing a new global numerical weather prediction model and an advanced data assimilation system. As part of the KIAPS package for observation processing (KPOP) system for data assimilation, preprocessing, and quality control modules for bending-angle measurements of global positioning system radio occultation (GPS-RO) data have been implemented and examined. The GPS-RO data processing system is composed of several steps for checking observation locations, missing values, physical values for Earth radius of curvature, and geoid undulation. An observation-minus-background check is implemented by use of a one-dimensional observational bending-angle operator, and tangent point drift is also considered in the quality control process. We have tested GPS-RO observations utilized by the Korean Meteorological Administration (KMA) within KPOP, based on both the KMA global model and the National Center for Atmospheric Research Community Atmosphere Model with Spectral Element dynamical core (CAM-SE) as a model background. Background fields from the CAM-SE model are incorporated for the preparation of assimilation experiments with the KIAPS local ensemble transform Kalman filter (LETKF) data assimilation system, which has been successfully implemented to a cubed-sphere model with unstructured quadrilateral meshes. As a result of data processing, the bending-angle departure statistics between observation and background show significant improvement. Also, the first experiment in assimilating GPS-RO bending angle from KPOP within KIAPS-LETKF shows encouraging results.

  15. Implementation of a GPS-RO data processing system for the KIAPS-LETKF data assimilation system

    NASA Astrophysics Data System (ADS)

    Kwon, H.; Kang, J.-S.; Jo, Y.; Kang, J. H.

    2014-11-01

    The Korea Institute of Atmospheric Prediction Systems (KIAPS) has been developing a new global numerical weather prediction model and an advanced data assimilation system. As part of the KIAPS Package for Observation Processing (KPOP) system for data assimilation, preprocessing and quality control modules for bending angle measurements of global positioning system radio occultation (GPS-RO) data have been implemented and examined. GPS-RO data processing system is composed of several steps for checking observation locations, missing values, physical values for Earth radius of curvature, and geoid undulation. An observation-minus-background check is implemented by use of a one-dimensional observational bending angle operator and tangent point drift is also considered in the quality control process. We have tested GPS-RO observations utilized by the Korean Meteorological Administration (KMA) within KPOP, based on both the KMA global model and the National Center for Atmospheric Research (NCAR) Community Atmosphere Model-Spectral Element (CAM-SE) as a model background. Background fields from the CAM-SE model are incorporated for the preparation of assimilation experiments with the KIAPS-LETKF data assimilation system, which has been successfully implemented to a cubed-sphere model with fully unstructured quadrilateral meshes. As a result of data processing, the bending angle departure statistics between observation and background shows significant improvement. Also, the first experiment in assimilating GPS-RO bending angle resulting from KPOP within KIAPS-LETKF shows encouraging results.

  16. Beneficial phosphate recovery from reverse osmosis (RO) concentrate of an integrated membrane system using polymeric ligand exchanger (PLE).

    PubMed

    Kumar, Manish; Badruzzaman, Mohammad; Adham, Samer; Oppenheimer, Joan

    2007-05-01

    Phosphorus (P) discharge to surface water is a major environmental problem. Wastewater treatment is targeted towards removal of this nutrient to prevent degradation of surface water. Integrated membrane systems (IMS) are increasingly being considered for wastewater reclamation, and provide excellent removal of P compounds. However, reverse osmosis (RO), which forms an integral part of these IMSs, concentrates most dissolved substances including P-species such as phosphates in the RO waste stream. In this study, removal of phosphate from this stream using polymeric ligand exchange (PLE) resins was investigated. Further, the possibility of phosphate recovery through struvite (MgNH(4)PO(4).6H(2)O) precipitation was tested. Struvite has been promoted as a slow release fertilizer in recent years. This study demonstrates that PLEs can be successfully used to remove phosphate from RO-concentrate, and to recover more than 85% of the adsorbed phosphorus from the exhausted media and precipitated as a beneficial product (struvite). The approach, presented in this study, suggests advantages of providing economic benefit from a waste product (RO) while avoiding phosphorus discharge to the environment. PMID:17379269

  17. 77 FR 1707 - National Toxicology Program (NTP) Final Process for Preparation of the Report on Carcinogens (RoC)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... October 31, 2011, the NTP released its proposed process for preparation of the RoC (76 FR 67200 and 76 FR..., and presented a revised process at the NTP Board of Scientific Counselors public meeting (76 FR 68461... available on the NTP Web site ( http://ntp.niehs.nih.gov/go/rocprocess ) or by contacting Dr. Ruth Lunn...

  18. Behaviour of RO98pHt polyamide membrane in reverse osmosis and low reverse osmosis conditions for phenol removal.

    PubMed

    Hidalgo, A M; León, G; Gómez, M; Murcia, M D; Gómez, E; Gómez, J L

    2011-10-01

    Phenolic compounds and their derivatives are very common pollutants in wastewaters. Among the methods described for their removal, pressure-driven membrane processes are considered as a reliable alternative. Our research group has previously studied phenol removal in reverse osmosis (RO) conditions and obtained very low rejection percentages. Subsequently, when low reverse osmosis (LRO) conditions were studied, the organic rejection percentages improved. To further our knowledge in this respect, the main objective of this work was to study the behaviour of the polyamide thin-film composite membrane RO98pHt used for phenol removal in RO and LRO conditions. The influence of different operating pressures, phenol feed concentrations and pH on permeate flux and phenol rejection was studied. Low reverse osmosis conditions led to higher phenol rejection percentages in all the assayed conditions, suggesting that other factors related to the molecular characteristics of the organic molecules, such as solubility, acidity and hydrogen bonding capacity, play an important role in the rejection percentage attained. As expected, permeate flux was greater in RO conditions. PMID:22329140

  19. Finest light curve details, physical parameters, and period fluctuations of CoRoT RR Lyrae stars

    NASA Astrophysics Data System (ADS)

    Benkő, J. M.; Szabó, R.; Derekas, A.; Sódor, Á.

    2016-08-01

    The CoRoT satellite supplied the scientific community with a huge data base of variable stars. Among them the RR Lyrae stars have intensively been discussed in numerous papers in the last few years, but the latest runs have not been checked to find RR Lyrae stars up to now. Our main goal was to fill this gap and complete the CoRoT RR Lyrae sample. We found nine unstudied RR Lyrae stars. Seven of them are new discoveries. We identified three new Blazhko stars. The Blazhko effect shows non-strictly repetitive nature for all stars. The frequency spectrum of the Blazhko star CoRoT 104948132 contains second overtone frequency with the highest known period ratio. The harmonic amplitude and phase declines with the harmonic order were studied for non-Blazhko stars. We found a period dependent but similar shape amplitude decline for all stars. We discovered significant random period fluctuation for one of the two oversampled target, CM Ori. After a successful transformation of the CoRoT band parameters to the Johnson V values we estimated the basic physical properties such as mass, luminosity, metallicity. The sample can be divided into two subgroups with respect to the metallicity but otherwise the physical parameters are in the canonical range of RR Lyrae stars.

  20. VizieR Online Data Catalog: Stellar parameters for CoRoT exoplanet field stars (Cortes+, 2015)

    NASA Astrophysics Data System (ADS)

    Cortes, C.; Maciel, S. C.; Vieira, S.; Ferreira Lopes, C. E.; Leao, I. C.; de Oliveira, G. P.; Correia, C.; Canto Martins, B. L.; Catelan, M.; de Medeiros, J. R.

    2016-08-01

    The present stellar sample is composed of 138 stars of spectral types F, G, and K, with visual magnitudes V between 10 to 14, located in two exoplanet fields observed by CoRoT, namely the Galactic center (LRc01: Long Run Center 01) and the Galactic anticenter (LRa01: Long Run Anticenter 01) fields. (4 data files).

  1. Jumping the nuclear envelop barrier: Improving polyplex-mediated gene transfection efficiency by a selective CDK1 inhibitor RO-3306.

    PubMed

    Zhou, Xuefei; Liu, Xiangrui; Zhao, Bingxiang; Liu, Xin; Zhu, Dingcheng; Qiu, Nasha; Zhou, Quan; Piao, Ying; Zhou, Zhuxian; Tang, Jianbin; Shen, Youqing

    2016-07-28

    Successful transfection of plasmid DNA (pDNA) requires intranuclear internalization of pDNA effectively and the nuclear envelope appears to be one of the critical intracellular barriers for polymer mediated pDNA delivery. Polyethylenimine (PEI), as the classic cationic polymer, compact the negatively charged pDNA tightly and make up stable polyplexes. The polyplexes are too large to enter the nuclear through nuclear pores and it is believed that the nuclear envelope breakdown in mitosis could facilitate the nuclear entry of polyplexes. To jump the nuclear envelope barrier, we used a selective and reversible CDK1 inhibitor RO-3306 to control the G2/M transition of the cell cycle and increased the proportion of mitotic cells which have disappeared nuclear envelope during transfection. Herein, we show that RO-3306 remarkably increases the transfection efficiency of PEI polyplexes through enhanced nuclear localization of PEI and pDNA. However, RO-3306 is less effective to the charge-reversal polymer poly[(2-acryloyl)ethyl(p-boronic acid benzyl)diethylammonium bromide] (B-PDEAEA) which responses to cellular stimuli and releases free pDNA in cytoplasm. Our findings not only offer new opportunities for improving non-viral based gene delivery but also provide theoretical support for the rational design of novel functional polymers for gene delivery. We also report current data showing that RO-3306 synergizes TRAIL gene induced apoptosis in cancer cells. PMID:27212103

  2. Pairwise agonist scanning-flow cytometry (PAS-FC) measures inside-out signaling and patient-specific response to combinatorial platelet agonists.

    PubMed

    Jaeger, Daniel T L; Diamond, Scott L

    2013-05-01

    Understanding the response of cells to multiple stimuli is vital for predicting donor specific responses and better understanding the signaling pathways involved. This is of particular importance in platelets because exposure of phosphatidylserine (PS) occurs upon costimulation but not with a single agonist. Here, we describe a multiplexed pairwise agonist scanning-flow cytometry (PAS-FC) method of measuring platelet inside-out responses to all pairs of six platelet agonists (convulxin, SFLLRN, AYPGKF, ADP, U46619, and PGE(2)) used at their EC(50) concentrations. These agonists allowed exploration of platelet signaling downstream of GPVI, PAR-1, PAR-4, P2Y(1), P2Y(12), TP, and IP receptors. The three-color flow cytometry method simultaneously measured integrin α(IIb)β(3) activation with PAC-1 antibody, P-selectin exposure (via α granule release) with anti-P-selectin, and PS exposure with annexin V. These responses were consistent across a healthy male donor pool. In duplicate measurements with each donor, 4 of the 10 donors had a sufficiently unique 45-parameter (15 pairs × 3 colors) phenotype to self-cluster (P < 0.001). This method has the potential for efficiently scanning for patient specific responses across a broad agonist-receptor space. PMID:23662898

  3. Analgesic effectiveness of the narcotic agonist-antagonists

    PubMed Central

    Houde, Raymond W.

    1979-01-01

    1 Two fundamentally different types of narcotic-antogonists have been found to be very effective analgesics with relatively low dependence-producing potentials. 2 These two drug classes can be distinguished as being either morphine-like or nalorphine-like on the basis of their subjective and objective effects after single doses and on chronic administration, and by the character of their abstinence syndromes on abrupt withdrawal or on precipitation by other antagonists. 3 To explain differences in side effects associated with their analgesic actions, the existence of three types of receptors has been postulated: a μ receptor which is believed to be associated with euphoria and other typical morphine-like effects and a kappa (χ) and a sigma (σ) receptor which are believed to be associated with the sedative and psychotomimetic effects, respectively, of the nalorphine-like drugs. 4 The antagonist-analgesics of the morphine-type have the characteristics of being agonists of low intrinsic activity but with high affinity for the μ receptor. Representative analgesics of this type are profadol, propiram and buprenorphine. 5 The antagonist-analgesics of the nalorphine-type are drugs which are believed to have varying degrees of affinity and intrinsic activity at all three receptors, but characteristically seem to act merely as competitive antagonists with no intrinsic activity at the μ receptor. Representative analgesics of this type are pentazocine, nalbuphine and butorphanol. 6 There are considerable differences among the individual drugs of each type in terms of their analgesic and narcotic-antagonistic potencies. However, clear differences in analgesic efficacy among any of the antagonist-analgesics remain to be proved. All give evidence of being capable of relieving pain in nondependent patients in situations in which doses of morphine (or its surrogates) usually used would be effective. 7 The major advantages of the partial agonists of the morphine-type over the

  4. Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists

    PubMed Central

    2014-01-01

    The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels. PMID:25313322

  5. Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists.

    PubMed

    Peukert, Stefan; Hughes, Richard; Nunez, Jill; He, Guo; Yan, Zhao; Jain, Rishi; Llamas, Luis; Luchansky, Sarah; Carlson, Adam; Liang, Guiqing; Kunjathoor, Vidya; Pietropaolo, Mike; Shapiro, Jeffrey; Castellana, Anja; Wu, Xiaoping; Bose, Avirup

    2014-10-01

    The identification of highly potent and orally bioavailable GPR39 agonists is reported. Compound 1, found in a phenotypic screening campaign, was transformed into compound 2 with good activity on both the rat and human GPR39 receptor. This compound was further optimized to improve ligand efficiency and pharmacokinetic properties to yield GPR39 agonists for the potential oral treatment of type 2 diabetes. Thus, compound 3 is the first potent GPR39 agonist (EC50s ≤ 1 nM for human and rat receptor) that is orally bioavailable in mice and robustly induced acute GLP-1 levels. PMID:25313322

  6. Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRβ.

    PubMed

    Kick, Ellen; Martin, Richard; Xie, Yinong; Flatt, Brenton; Schweiger, Edwin; Wang, Tie-Lin; Busch, Brett; Nyman, Michael; Gu, Xiao-Hui; Yan, Grace; Wagner, Brandee; Nanao, Max; Nguyen, Lam; Stout, Thomas; Plonowski, Artur; Schulman, Ira; Ostrowski, Jacek; Kirchgessner, Todd; Wexler, Ruth; Mohan, Raju

    2015-01-15

    A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRβ selectivity. The LXRβ selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2μM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist. PMID:25435151

  7. Paleogeothermal record of the Emeishan mantle plume: evidences from borehole Ro data in the Sichuan basin, SW China

    NASA Astrophysics Data System (ADS)

    Hu, S.

    2013-12-01

    The Emeishan basalt province located in the southwest of China is widely accepted to be a result of the eruption of a mantle plume at the time of middle-late Permian. If it was a mantle plume, the ambient sedimentary rocks must be heated up during the development of the mantle plume and this thermal effect must be recorded by some geothermometers in the country rocks. The vitrinite reflectance (Ro) data as a maximum paleotemperature recorder from boreholes in Sichuan basin was employed to expose the thermal regime related to the proposed Emeishan mantle plume. The Ro profiles from boreholes which drilled close to the Emeishan basalts shows a ';dog-leg' (break) style at the unconformity between the middle and the upper Permian, and the Ro profiles in the lower subsection (pre-middle Permian) shows a significantly higher slopes (gradients) than those in the upper subsection. In contrast, those Ro profiles from boreholes far away from the center of the basalt province have no break at the uncomformity. Based on the chemical kinetic model of Ro, the paleo-temperature gradients for the upper and the lower subsections in different boreholes, as well as the erosion at the unconformity between the middle and the upper Permian, were reconstructed to reveal the variations of the temperature gradients and erosion thickness with geological time and space. Both the thermal regime and the erosion thickness together with their spatial variation (structure) provide strong geothermal evidence for the existence of the Emeishan mantle plume in the middle-late Permian.

  8. Assessment of the Clinical Trainer as a Role Model: A Role Model Apperception Tool (RoMAT)

    PubMed Central

    van Dijk, Nynke; Wieringa-de Waard, Margreet

    2014-01-01

    Purpose Positive role modeling by clinical trainers is important for helping trainees learn professional and competent behavior. The authors developed and validated an instrument to assess clinical trainers as role models: the Role Model Apperception Tool (RoMAT). Method On the basis of a 2011 systematic review of the literature and through consultation with medical education experts and with clinical trainers and trainees, the authors developed 17 attributes characterizing a role model, to be assessed using a Likert scale. In 2012, general practice (GP) trainees, in their first or third year of postgraduate training, who attended a curriculum day at four institutes in different parts of the Netherlands, completed the RoMAT. The authors performed a principal component analysis on the data that were generated, and they tested the instrument’s validity and reliability. Results Of 328 potential GP trainees, 279 (85%) participated. Of these, 202 (72%) were female, and 154 (55%) were first-year trainees. The RoMAT demonstrated both content and convergent validity. Two components were extracted: “Caring Attitude” and “Effectiveness.” Both components had high reliability scores (0.92 and 0.84, respectively). Less experienced trainees scored their trainers significantly higher on the Caring Attitude component. Conclusions The RoMAT proved to be a valid, reliable instrument for assessing clinical trainers’ role-modeling behavior. Both components include an equal number of items addressing personal (Heart), teaching (Head), and clinical (Hands-on) qualities, thus demonstrating that competence in the “3Hs” is a condition for positive role modeling. Educational managers (residency directors) and trainees alike can use the RoMAT. PMID:24556764

  9. Water reuse: >90% water yield in MBR/RO through concentrate recycling and CO2 addition as scaling control.

    PubMed

    Joss, Adriano; Baenninger, Claudia; Foa, Paolo; Koepke, Stephan; Krauss, Martin; McArdell, Christa S; Rottermann, Karin; Wei, Yuansong; Zapata, Ana; Siegrist, Hansruedi

    2011-11-15

    Over 1.5 years continuous piloting of a municipal wastewater plant upgraded with a double membrane system (ca. 0.6 m(3) d(-1) of product water produced) have demonstrated the feasibility of achieving high water quality with a water yield of 90% by combining a membrane bioreactor (MBR) with a submerged ultrafiltration membrane followed by a reverse osmosis membrane (RO). The novelty of the proposed treatment scheme consists of the appropriate conditioning of MBR effluent prior to the RO and in recycling the RO concentrates back to the biological unit. All the 15 pharmaceuticals measured in the influent municipal sewage were retained below 100 ng L(-1), a proposed quality parameter, and mostly below detection limits of 10 ng L(-1). The mass balance of the micropollutants shows that these are either degraded or discharged with the excess concentrate, while only minor quantities were found in the excess sludge. The micropollutant load in the concentrate can be significantly reduced by ozonation. A low treated water salinity (<10 mM inorganic salts; 280 ± 70 μS cm(-1)) also confirms that the resulting product has a high water quality. Solids precipitation and inorganic scaling are effectively mitigated by lowering the pH in the RO feed water with CO(2) conditioning, while the concentrate from the RO is recycled to the biological unit where CO(2) is stripped by aeration. This causes precipitation to occur in the bioreactor bulk, where it is much less of a process issue. SiO(2) is the sole exception. Equilibrium modeling of precipitation reactions confirms the effectiveness of this scaling-mitigation approach for CaCO(3) precipitation, calcium phosphate and sulfate minerals. PMID:21959090

  10. Thromboxane agonist (U46619) potentiates norepinephrine efflux from adrenergic nerves

    SciTech Connect

    Trachte, G.J.

    1986-05-01

    The effect of the synthetic thromboxane/prostaglandin (PG) H2 agonist U46619 on the electrically stimulated rabbit isolated vas deferens was examined to test for thromboxane influences on adrenergic nerves. U46619 effects on force generation, (/sup 3/H) norepinephrine release and norepinephrine-induced contractions were assessed to determine the mechanism of action. U46619 maximally enhanced adrenergic force generation 135 +/- 24% at a concentration of 100 nM. U46619 potentiated maximal contractile effects of exogenously administered norepinephrine 16 +/- 4% and augmented (/sup 3/H)norepinephrine release from electrically stimulated preparations 142 +/- 44%. A competitive thromboxane/PGH2 receptor antagonist, SQ29548, significantly shifted the concentration-response curve for U46619 to the right in a concentration-dependent manner and blocked U46619-induced tritium release. Thus, U46619 appears to potentiate neurotransmitter release by interacting with thromboxane/PGH2 receptors. Because SQ29548 did not prevent the potentiation of norepinephrine contractions by U46619, the postjunctional effect may be independent of thromboxane/PGH2 receptors. We interpret these results to be indicative of both pre- and postjunctional sites of action of U46619. The physiological importance of these thromboxane effects is unknown currently.

  11. Agonistic experience and individual recognition in male Quelea quelea.

    PubMed

    Shawcross, J E; Slater, P J

    1984-01-01

    Male Quelea were moved between groups to assess whether experience of winning or losing in new groups was correlated with their success in competition over food when they were returned to their original groups. No such effect was found. However, differences in time spent feeding after deprivation and in aggressive behaviour were found between groups depending on whether they were made up from high- or low-ranking individuals. In paired encounters there was no evidence that birds threatened unfamiliar individuals more than familiar ones or that they avoided sitting next to them more than familiar birds. This suggests that individual recognition, if it exists at all in these groups, is not important in their agonistic relationships. The rank birds occupied was correlated with beak colour, a probable measure of androgen levels, and with the amount of food consumed after deprivation. The latter result suggests that the same period of deprivation may affect some individuals more than others and this in turn may lead them to compete more for food. PMID:24923828

  12. Agonists and Antagonists of TGF-β Family Ligands.

    PubMed

    Chang, Chenbei

    2016-01-01

    The discovery of the transforming growth factor β (TGF-β) family ligands and the realization that their bioactivities need to be tightly controlled temporally and spatially led to intensive research that has identified a multitude of extracellular modulators of TGF-β family ligands, uncovered their functions in developmental and pathophysiological processes, defined the mechanisms of their activities, and explored potential modulator-based therapeutic applications in treating human diseases. These studies revealed a diverse repertoire of extracellular and membrane-associated molecules that are capable of modulating TGF-β family signals via control of ligand availability, processing, ligand-receptor interaction, and receptor activation. These molecules include not only soluble ligand-binding proteins that were conventionally considered as agonists and antagonists of TGF-β family of growth factors, but also extracellular matrix (ECM) proteins and proteoglycans that can serve as "sink" and control storage and release of both the TGF-β family ligands and their regulators. This extensive network of soluble and ECM modulators helps to ensure dynamic and cell-specific control of TGF-β family signals. This article reviews our knowledge of extracellular modulation of TGF-β growth factors by diverse proteins and their molecular mechanisms to regulate TGF-β family signaling. PMID:27413100

  13. PPARα agonist, fenofibrate, ameliorates age-related renal injury.

    PubMed

    Kim, Eun Nim; Lim, Ji Hee; Kim, Min Young; Kim, Hyung Wook; Park, Cheol Whee; Chang, Yoon Sik; Choi, Bum Soon

    2016-08-01

    The kidney ages quickly compared with other organs. Expression of senescence markers reflects changes in the energy metabolism in the kidney. Two important issues in aging are mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα) is a member of the ligand-activated nuclear receptor superfamily. PPARα plays a major role as a transcription factor that regulates the expression of genes involved in various processes. In this study, 18-month-old male C57BL/6 mice were divided into two groups, the control group (n=7) and the fenofibrate-treated group (n=7) was fed the normal chow plus fenofibrate for 6months. The PPARα agonist, fenofibrate, improved renal function, proteinuria, histological change (glomerulosclerosis and tubular interstitial fibrosis), inflammation, and apoptosis in aging mice. This protective effect against age-related renal injury occurred through the activation of AMPK and SIRT1 signaling. The activation of AMPK and SIRT1 allowed for the concurrent deacetylation and phosphorylation of their target molecules and decreased the kidney's susceptibility to age-related changes. Activation of the AMPK-FOXO3a and AMPK-PGC-1α signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Our results suggest that activation of PPARα and AMPK-SIRT1 signaling may have protective effects against age-related renal injury. Pharmacological targeting of PPARα and AMPK-SIRT1 signaling molecules may prevent or attenuate age-related pathological changes in the kidney. PMID:27130813

  14. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone.

    PubMed

    Watkins, Steven M; Reifsnyder, Peter R; Pan, Huei-ju; German, J Bruce; Leiter, Edward H

    2002-11-01

    Successful therapy for chronic diseases must normalize a targeted aspect of metabolism without disrupting the regulation of other metabolic pathways essential for maintaining health. Use of a limited number of single molecule surrogates for disease, or biomarkers, to monitor the efficacy of a therapy may fail to predict undesirable side effects. In this study, a comprehensive metabolomic assessment of lipid metabolites was employed to determine the specific effects of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone on structural lipid metabolism in a new mouse model of Type 2 diabetes. Dietary supplementation with rosiglitazone (200 mg/kg diet) suppressed Type 2 diabetes in obese (NZO x NON)F1 male mice, but chronic treatment markedly exacerbated hepatic steatosis. The metabolomic data revealed that rosiglitazone i) induced hypolipidemia (by dysregulating liver-plasma lipid exchange), ii) induced de novo fatty acid synthesis, iii) decreased the biosynthesis of lipids within the peroxisome, iv) substantially altered free fatty acid and cardiolipin metabolism in heart, and v) elicited an unusual accumulation of polyunsaturated fatty acids within adipose tissue. These observations suggest that the phenotypes induced by rosiglitazone are mediated by multiple tissue-specific metabolic variables. Because many of the effects of rosiglitazone on tissue metabolism were reflected in the plasma lipid metabolome, metabolomics has excellent potential for developing clinical assessments of metabolic response to drug therapy. PMID:12401879

  15. Therapeutic applications of TRAIL receptor agonists in cancer and beyond.

    PubMed

    Amarante-Mendes, Gustavo P; Griffith, Thomas S

    2015-11-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. PMID:26343199

  16. Minireview: Challenges and opportunities in development of PPAR agonists.

    PubMed

    Wright, Matthew B; Bortolini, Michele; Tadayyon, Moh; Bopst, Martin

    2014-11-01

    The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity. PMID:25148456

  17. Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin-1 receptor in the grey squirrel (Sciurus carolinensis).

    PubMed

    McRobie, Helen R; King, Linda M; Fanutti, Cristina; Symmons, Martyn F; Coussons, Peter J

    2014-06-27

    The melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RΔ24) variant. We demonstrate that the MC1RΔ24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RΔ24. We conclude that the deletion in the MC1RΔ24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R. PMID:24879893

  18. The long-acting β2-adrenoceptor agonist, indacaterol, enhances glucocorticoid receptor-mediated transcription in human airway epithelial cells in a gene- and agonist-dependent manner

    PubMed Central

    Joshi, T; Johnson, M; Newton, R; Giembycz, M A

    2015-01-01

    Background and Purpose Inhaled glucocorticoid (ICS)/long-acting β2-adrenoceptor agonist (LABA) combination therapy is a recommended treatment option for patients with moderate/severe asthma in whom adequate control cannot be achieved by an ICS alone. Previously, we discovered that LABAs can augment dexamethasone-inducible gene expression and proposed that this effect may explain how these two drugs interact to deliver superior clinical benefit. Herein, we extended that observation by analysing, pharmacodynamically, the effect of the LABA, indacaterol, on glucocorticoid receptor (GR)-mediated gene transcription induced by seven ligands with intrinsic activity values that span the spectrum of full agonism to antagonism. Experimental Approach BEAS-2B human airway epithelial cells stably transfected with a 2× glucocorticoid response element luciferase reporter were used to model gene transcription together with an analysis of several glucocorticoid-inducible genes. Key Results Indacaterol augmented glucocorticoid-induced reporter activation in a manner that was positively related to the intrinsic activity of the GR agonist. This effect was demonstrated by an increase in response maxima without a change in GR agonist affinity or efficacy. Indacaterol also enhanced glucocorticoid-inducible gene expression. However, the magnitude of this effect was dependent on both the GR agonist and the gene of interest. Conclusions and Implications These data suggest that indacaterol activates a molecular rheostat, which increases the transcriptional competency of GR in an agonist- and gene-dependent manner without apparently changing the relationship between fractional GR occupancy and response. These findings provide a platform to rationally design ICS/LABA combination therapy that is based on the generation of agonist-dependent gene expression profiles in target and off-target tissues. PMID:25598440

  19. Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow.

    PubMed

    Dore, Kim; Aow, Jonathan; Malinow, Roberto

    2015-11-24

    The NMDA receptor (R) plays important roles in brain physiology and pathology as an ion channel. Here we examine the ion flow-independent coupling of agonist to the NMDAR cytoplasmic domain (cd). We measure FRET between fluorescently tagged cytoplasmic domains of GluN1 subunits of NMDARs expressed in neurons. Different neuronal compartments display varying levels of FRET, consistent with different NMDARcd conformations. Agonist binding drives a rapid and transient ion flow-independent reduction in FRET between GluN1 subunits within individual NMDARs. Intracellular infusion of an antibody targeting the GluN1 cytoplasmic domain blocks agonist-driven FRET changes in the absence of ion flow, supporting agonist-driven movement of the NMDARcd. These studies indicate that extracellular ligand binding to the NMDAR can transmit conformational information into the cell in the absence of ion flow. PMID:26553997

  20. Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.

    PubMed

    Maruyama, Tatsuya; Onda, Kenichi; Hayakawa, Masahiko; Matsui, Tetsuo; Takasu, Toshiyuki; Ohta, Mitsuaki

    2009-06-01

    In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model. PMID:19232786

  1. Potent achiral agonists of the ghrelin (growth hormone secretagogue) receptor. Part I: Lead identification.

    PubMed

    Heightman, Tom D; Scott, Jackie S; Longley, Mark; Bordas, Vincent; Dean, David K; Elliott, Richard; Hutley, Gail; Witherington, Jason; Abberley, Lee; Passingham, Barry; Berlanga, Manuela; de Los Frailes, Maite; Wise, Alan; Powney, Ben; Muir, Alison; McKay, Fiona; Butler, Sharon; Winborn, Kim; Gardner, Christopher; Darton, Jill; Campbell, Colin; Sanger, Gareth

    2007-12-01

    High throughput screening combined with efficient datamining and parallel synthesis led to the discovery of a novel series of indolines showing potent in vitro ghrelin receptor agonist activity and acceleration of gastric emptying in rats. PMID:17942309

  2. Innate immune responses to microbial agonist stimulations in heterophils and monocytes from young commercial turkeys

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The innate immune system recognizes microbial pathogens and pathogen associated molecular patterns and incites inflammatory immune responses to control the infection. Here, we examined functional innate immune responses of turkey heterophils and monocytes to microbial agonist stimulations by measur...

  3. Clinical use of GnRH agonists in canine and feline species.

    PubMed

    Fontaine, E; Fontbonne, A

    2011-04-01

    GnRH (gonadotrophin releasing hormone) is a key hormone of reproductive function in mammals; agonist forms have been largely developed, and data concerning their use in small animal reproduction are now abundant. GnRH agonists act by a two-step mechanism. First, their agonist properties on the pituitary will cause marked LH (luteinizing hormone) and FSH (follicle-stimulating hormone) secretion into the bloodstream, accompanied by an increase in the concentrations of sex steroid hormones. Then, in case of constant administration, GnRH agonists will lead to pituitary desensitization, and FSH and LH levels will collapse. These two effects have been widely documented, and these compounds have many potential benefits in a clinical context, capitalizing both on their stimulating and sterilizing effects. PMID:20964727

  4. Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist.

    PubMed

    Lin, Hsiang-Ru

    2015-01-01

    Lepidozenolide is a sesquiterpenoid isolated from the liverwort Lepidozia fauriana and its possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and hyperglycemia. In this study, whether lepidozenolide may act as a FXR agonist was determined. Indeed, in mammalian one-hybrid and transient transfection reporter assays, lepidozenolide transactivated FXR to modulate promoter action including GAL4, CYP7A1, and PLTP promoters in a dose-dependent manner, while it exhibited slightly less agonistic activity than chenodeoxycholic acid, an endogenous FXR agonist. Through the molecular modeling docking studies lepidozenolide was shown to bind to FXR ligand binding pocket fairly well. All these results indicate that lepidozenolide acts as a FXR agonist. PMID:25315435

  5. Determination of beta-agonists in swine hair by μFIA and chemiluminescence.

    PubMed

    Chen, Xu; Luo, Yong; Shi, Bo; Gao, Zhigang; Du, Yuguang; Liu, Xianming; Zhao, Weijie; Lin, Bingcheng

    2015-04-01

    β-Agonists are a group of illegal feed additives. In this paper, it was found that the light emission produced by the oxidation of luminol by potassium ferricyanide was enhanced by the β-agonists (ractopamine, salbutamol, and terbutaline). Based on chemiluminescence phenomenon, a novel, rapid, and sensitive microflow injection analysis system on a microfluidic glass chip was established for determination of the β-agonists. The chip was fabricated from two glass plates (64 mm × 32 mm) with microchannels of 200 μm width and 100 μm depth. The detection limits were achieved at 2.0 × 10(-8) mol/L of ractopamine, 1.0 × 10(-8) mol/L of terbutaline and 5.0 × 10(-7) mol/L of salbutamol. In this report, our method was applied for determination of the β-agonists in swine hair from three different sources with satisfactory results. PMID:25546131

  6. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system.

    PubMed

    Engel, Abbi L; Holt, Gregory E; Lu, Hailing

    2011-03-01

    Toll-like receptor (TLR) ligation activates both the innate and adaptive immune systems, and plays an important role in antiviral and anti-tumor immunity. Therefore, a significant amount of effort has been devoted to exploit the therapeutic potential of TLR agonists. Depending on the therapeutic purpose, either as adjuvants to vaccine, chemotherapy or standalone therapy, TLR agonists have been administered via different routes. Both preclinical and clinical studies have suggested that the route of administration has significant effects on pharmacokinetics, and that understanding these effects is critical to the success of TLR agonist drug development. This article will summarize the pharmacokinetics of TLR agonists with different administration routes, with an emphasis on clinical studies of TLR ligands in oncologic applications. PMID:21643519

  7. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system

    PubMed Central

    Engel, Abbi L; Holt, Gregory E; Lu, Hailing

    2011-01-01

    Toll-like receptor (TLR) ligation activates both the innate and adaptive immune systems, and plays an important role in antiviral and anti-tumor immunity. Therefore, a significant amount of effort has been devoted to exploit the therapeutic potential of TLR agonists. Depending on the therapeutic purpose, either as adjuvants to vaccine, chemotherapy or standalone therapy, TLR agonists have been administered via different routes. Both preclinical and clinical studies have suggested that the route of administration has significant effects on pharmacokinetics, and that understanding these effects is critical to the success of TLR agonist drug development. This article will summarize the pharmacokinetics of TLR agonists with different administration routes, with an emphasis on clinical studies of TLR ligands in oncologic applications. PMID:21643519

  8. Aryl sulphonyl amides as potent agonists of the growth hormone secretagogue (ghrelin) receptor.

    PubMed

    Witherington, Jason; Abberley, Lee; Bellenie, Benjamin R; Boatman, Rio; Collis, Katharine; Dean, David K; Gaiba, Alessandra; King, N Paul; Shuker, Nicola; Steadman, Jon G A; Takle, Andrew K; Sanger, Gareth; Butler, Sharon; McKay, Fiona; Muir, Alison; Winborn, Kim; Ward, Robert W; Heightman, Tom D

    2009-02-01

    As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists. PMID:19128969

  9. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

    PubMed Central

    Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

    2013-01-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

  10. Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow

    PubMed Central

    Dore, Kim; Aow, Jonathan; Malinow, Roberto

    2015-01-01

    The NMDA receptor (R) plays important roles in brain physiology and pathology as an ion channel. Here we examine the ion flow-independent coupling of agonist to the NMDAR cytoplasmic domain (cd). We measure FRET between fluorescently tagged cytoplasmic domains of GluN1 subunits of NMDARs expressed in neurons. Different neuronal compartments display varying levels of FRET, consistent with different NMDARcd conformations. Agonist binding drives a rapid and transient ion flow-independent reduction in FRET between GluN1 subunits within individual NMDARs. Intracellular infusion of an antibody targeting the GluN1 cytoplasmic domain blocks agonist-driven FRET changes in the absence of ion flow, supporting agonist-driven movement of the NMDARcd. These studies indicate that extracellular ligand binding to the NMDAR can transmit conformational information into the cell in the absence of ion flow. PMID:26553997

  11. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease

    PubMed Central