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Sample records for partial mu-opioid receptor

  1. Mu opioid receptor binding sites in human brain

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    Pilapil, C.; Welner, S.; Magnan, J.; Zamir, N.; Quirion, R.

    1986-01-01

    Our experiments focused on the examination of the distribution of mu opioid receptor binding sites in normal human brain using the highly selective ligand [ 3 H]DAGO, in both membrane binding assay and in vitro receptor autoradiography. Mu opioid binding sites are very discretely distributed in human brain with high densities of sites found in the posterior amygdala, caudate, putamen, hypothalamus and certain cortical areas. Moreover the autoradiographic distribution of [ 3 H]DAGO binding sites clearly reveals the discrete lamination (layers I and III-IV) of mu sites in cortical areas

  2. Quantitative immunolocalization of {mu} opioid receptors: regulation by naltrexone

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    Evans, C.J.; Lam, H.; To, T.; Anton, B. [Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles, CA (United States); Unterwald, E.M. [Department of Psychiatry, New York University Medical Center, New York, NY (United States)

    1998-04-24

    The present study utilized a newly developed quantitative immunohistochemical assay to measure changes in {mu} opioid receptor abundance following chronic administration of the opioid receptor antagonist naltrexone. These data were compared with those obtained from {mu} receptor radioligand binding on adjacent tissue sections, in order to determine whether the characteristic antagonist-induced increase in radioligand binding is due to an increase in the total number of {mu} receptors and/or to an increase in the proportion of receptors that are in an active binding conformation in the absence of a change in the total number of receptors. Adult male Sprague-Dawley rats were administered naltrexone, 7-8 mg/kg per day, or saline continuously for seven days by osmotic minipumps, after which time their brains were processed for immunohistochemistry and receptor autoradiography on adjacent fresh frozen tissue sections. Semiquantitative immunohistochemistry was performed using a radiolabelled secondary antibody for autoradiographic determination and a set of radioactive standards. Results demonstrate an overall concordance between the distribution of {mu} opioid receptors as measured by the two different methods with a few exceptions. Following naltrexone administration, {mu} receptor immunoreactivity was significantly higher in the amygdala, thalamus, hippocampus, and interpeduncular nucleus as compared with the saline-treated control animals. [{sup 3}H]D-Ala{sup 2},N-Me-Phe{sup 4},Gly-ol{sup 5}-enkephalin binding to {mu} opioid receptors was significantly higher in the globus pallidus, amygdala, thalamus, hypothalamus, hippocampus, substantia nigra, ventral tegmental area, central gray, and interpeduncular nucleus of the naltrexone-treated rats.These findings indicate that in some brain regions chronic naltrexone exposure increases the total number of {mu} opioid receptors, while in other regions there is an increase in the percent of active receptors without an

  3. Mu Opioid Receptor Gene: New Point Mutations in Opioid Addicts

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    Amin Dinarvand

    2014-02-01

    Full Text Available Introduction: Association between single-nucleotide polymorphisms (SNPs in mu opioid receptor gene and drug addiction has been shown in various studies. Here, we have evaluated the existence of polymorphisms in exon 3 of this gene in Iranian population and investigated the possible association between these mutations and opioid addiction.  Methods: 79 opioid-dependent subjects (55 males, 24 females and 134 non-addict or control individuals (74 males, 60 females participated in the study. Genomic DNA was extracted from volunteers’ peripheral blood and exon 3 of the mu opioid receptor gene was amplified by polymerase chain reaction (PCR whose products were then sequenced.  Results: Three different heterozygote polymorphisms were observed in 3 male individuals: 759T>C and 877G>A mutations were found in 2 control volunteers and 1043G>C substitution was observed in an opioid-addicted subject. Association between genotype and opioid addiction for each mutation was not statistically significant.  Discussion: It seems that the sample size used in our study is not enough to confirm or reject any association between 759T>C, 877G>A and 1043G>C substitutions in exon 3 of the mu opioid receptor gene and opioid addiction susceptibility in Iranian population.

  4. Mu-opioid receptor knockout mice show diminished food-anticipatory activity

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    Kas, Martien J H; van den Bos, Ruud; Baars, Annemarie M; Lubbers, Marianne; Lesscher, Heidi M B; Hillebrand, Jacquelien J G; Schuller, Alwin G; Pintar, John E; Spruijt, Berry M

    We have previously suggested that during or prior to activation of anticipatory behaviour to a coming reward, mu-opioid receptors are activated. To test this hypothesis schedule induced food-anticipatory activity in mu-opioid receptor knockout mice was measured using running wheels. We hypothesized

  5. Amygdala mu-opioid receptors mediate the motivating influence of cue-triggered reward expectations.

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    Lichtenberg, Nina T; Wassum, Kate M

    2017-02-01

    Environmental reward-predictive stimuli can retrieve from memory a specific reward expectation that allows them to motivate action and guide choice. This process requires the basolateral amygdala (BLA), but little is known about the signaling systems necessary within this structure. Here we examined the role of the neuromodulatory opioid receptor system in the BLA in such cue-directed action using the outcome-specific Pavlovian-to-instrumental transfer (PIT) test in rats. Inactivation of BLA mu-, but not delta-opioid receptors was found to dose-dependently attenuate the ability of a reward-predictive cue to selectively invigorate the performance of actions directed at the same unique predicted reward (i.e. to express outcome-specific PIT). BLA mu-opioid receptor inactivation did not affect the ability of a reward itself to similarly motivate action (outcome-specific reinstatement), suggesting a more selective role for the BLA mu-opioid receptor in the motivating influence of currently unobservable rewarding events. These data reveal a new role for BLA mu-opioid receptor activation in the cued recall of precise reward memories and the use of this information to motivate specific action plans. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  6. The effect of benfotiamine on mu-opioid receptor mediated antinociception in experimental diabetes.

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    Nacitarhan, C; Minareci, E; Sadan, G

    2014-03-01

    Diabetic neuropathy is a prevalent, disabling disorder. Currently, the only treatments available to patients with diabetic neuropathy are glucose control and pain management. B vitamin present neuroprotective effects, which are suggested to be related to their analgesic action in various models of neuropathic pain. According to our literature knowledge there is no report about antinociceptive effects of thiamine as benfotiamine and opioids together in diabetic mice. The purpose of this study was to determine the effects of benfotiamine on the antinociception produced by mu-opioid receptor agonist fentanyl in diabetic mice. The effects of benfotiamine on antinociception produced by fentanyl in diabetic mice were studied in 4 groups. Antinociceptive effect was determined with tail flick, hot plate and formalin test. Our results showed that, mu-opioid agonist fentanyl in benfotiamine applied diabetic group caused more potent antinociceptive effect than in diabetic group without benfotiamine treatment. In brief benfotiamine supplement in diet did not bring out antinociceptive effect itself, but during development of STZ diabetes, benfotiamine replacement increased the antinociceptive effect of fentanyl in mice tail-flick test. This effect is probably due to the replacement of benfotiamine efficiency occurring in diabetes mellitus. Finally, we suppose that oral benfotiamine replacement therapy may be useful to ameliorate analgesic effect of mu-opioid agonists on neuropathic pain in diabetic case. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  7. Human Mu Opioid Receptor (OPRM1A118G) polymorphism is associated with brain mu- opioid receptor binding potential in smokers

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    Ray, R.; Logan, J.; Ray, R.; Ruparel, K.; Newberg, A.; Wileyto, E.P.; Loughead, J.W.; Divgi, C.; Blendy, J.A.; Logan, J.; Zubieta, J.-K.; Lerman, C.

    2011-04-15

    Evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the human MOR gene (OPRM1 A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of OPRM1 A118G genotype on MOR binding potential (BP{sub ND} or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two [{sup 11}C] carfentanil positron emission tomography (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels of MOR BP{sub ND} than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BP{sub ND} difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics.

  8. Human Mu Opioid Receptor (OPRM1A118G) polymorphism is associated with brain mu- opioid receptor binding potential in smokers

    International Nuclear Information System (INIS)

    Ray, R.; Logan, J.; Ruparel, K.; Newberg, A.; Wileyto, E.P.; Loughead, J.W.; Divgi, C.; Blendy, J.A.; Logan, J.; Zubieta, J.-K.; Lerman, C.

    2011-01-01

    Evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the human MOR gene (OPRM1 A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of OPRM1 A118G genotype on MOR binding potential (BP ND or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two [ 11 C] carfentanil positron emission tomography (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels of MOR BP ND than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BP ND difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics.

  9. Expression and purification of functional human mu opioid receptor from E.coli.

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    Yanbin Ma

    Full Text Available N-terminally his-tagged human mu opioid receptor, a G protein-coupled receptor was produced in E.coli employing synthetic codon-usage optimized constructs. The receptor was expressed in inclusion bodies and membrane-inserted in different E.coli strains. By optimizing the expression conditions the expression level for the membrane-integrated receptor was raised to 0.3-0.5 mg per liter of culture. Milligram quantities of receptor could be enriched by affinity chromatography from IPTG induced cultures grown at 18°C. By size exclusion chromatography the protein fraction with the fraction of alpha-helical secondary structure expected for a 7-TM receptor was isolated, by CD-spectroscopy an alpha-helical content of ca. 45% was found for protein solubilised in the detergent Fos-12. Receptor in Fos-12 micelles was shown to bind endomorphin-1 with a K(D of 61 nM. A final yield of 0.17 mg functional protein per liter of culture was obtained.

  10. Cell-Autonomous Regulation of Mu-Opioid Receptor Recycling by Substance P

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    Shanna L. Bowman

    2015-03-01

    Full Text Available How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP, a neuropeptide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R receptor, increases the post-endocytic recycling of the mu-opioid receptor (MOR in trigeminal ganglion (TG neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross-regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeostatic interaction between the pain and analgesic systems.

  11. Chronic ethanol consumption in rats produces opioid antinociceptive tolerance through inhibition of mu opioid receptor endocytosis.

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    Li He

    Full Text Available It is well known that the mu-opioid receptor (MOR plays an important role in the rewarding properties of ethanol. However, it is less clear how chronic ethanol consumption affects MOR signaling. Here, we demonstrate that rats with prolonged voluntary ethanol consumption develop antinociceptive tolerance to opioids. Signaling through the MOR is controlled at many levels, including via the process of endocytosis. Importantly, agonists at the MOR that promote receptor endocytosis, such as the endogenous peptides enkephalin and β-endorphin, show a reduced propensity to promote antinociceptive tolerance than do agonists, like morphine, which do not promote receptor endocytosis. These observations led us to examine whether chronic ethanol consumption produced opioid tolerance by interfering with MOR endocytosis. Indeed, here we show that chronic ethanol consumption inhibits the endocytosis of MOR in response to opioid peptide. This loss of endocytosis was accompanied by a dramatic decrease in G protein coupled receptor kinase 2 (GRK2 protein levels after chronic drinking, suggesting that loss of this component of the trafficking machinery could be a mechanism by which endocytosis is lost. We also found that MOR coupling to G-protein was decreased in ethanol-drinking rats, providing a functional explanation for loss of opioid antinociception. Together, these results suggest that chronic ethanol drinking alters the ability of MOR to endocytose in response to opioid peptides, and consequently, promotes tolerance to the effects of opioids.

  12. Affinity of the enantiomers of. alpha. - and. beta. -cyclazocine for binding to the phencyclidine and. mu. opioid receptors

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    Todd, S.L.; Balster, R.L.; Martin, B.R. (Virginia Commonwealth Univ., Richmond (USA))

    1990-01-01

    The enantiomers in the {alpha} and {beta} series of cyclazocine were evaluated for their ability to bind to phencyclidine (PCP) and {mu}-opioid receptors in order to determine their receptor selectivity. The affinity of (-)-{beta}-cyclazocine for the PCP receptor was 1.5 greater than PCP itself. In contrast, (-)-{alpha}-cyclazocine, (+)-{alpha}-cyclazocine, and (+)-{beta}-cyclazocine were 3-, 5- and 138-fold less potent than PCP, respectively. Scatchard analysis of saturable binding of ({sup 3}H)Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAMGO) also exhibited a homogeneous population of binding sites with an apparent K{sub D} of 1.9 nM and an estimated Bmax of 117 pM. (3H)Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAMGO) binding studies revealed that (-)-{alpha}-cyclazocine (K{sub D} = 0.48 nM) was 31-, 1020- and 12,600-fold more potent than (-)-{beta}-cyclazocine, (+)-{alpha}-cyclazocine and (+)-{beta}-cyclazocine, respectively, for binding to the {mu}-opioid receptor. These data show that, although (-)-{beta}-cyclazocine is a potent PCP receptor ligand consistent with its potent PCP-like discriminative stimulus effects, it shows little selectivity for PCP receptor since it also potently displaces {mu}-opioid binding. However, these cyclazocine isomers, due to their extraordinary degree of stereoselectivity, may be useful in characterizing the structural requirements for benzomorphans having activity at the PCP receptor.

  13. Crystal structure of the[mu]-opioid receptor bound to a morphinan antagonist

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    Manglik, Aashish; Kruse, Andrew C.; Kobilka, Tong Sun; Thian, Foon Sun; Mathiesen, Jesper M.; Sunahara, Roger K.; Pardo, Leonardo; Weis, William I.; Kobilka, Brian K.; Granier, Sébastien (Michigan-Med); (Stanford-MED); (UAB, Spain)

    2012-06-27

    Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled {mu}-opioid receptor ({mu}-OR) in the central nervous system. Here we describe the 2.8 {angstrom} crystal structure of the mouse {mu}-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the {mu}-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

  14. Desensitization and Tolerance of Mu Opioid Receptors on Pontine Kölliker-Fuse Neurons.

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    Levitt, Erica S; Williams, John T

    2018-01-01

    Acute desensitization of mu opioid receptors is thought to be an initial step in the development of tolerance to opioids. Given the resistance of the respiratory system to develop tolerance, desensitization of neurons in the Kölliker-Fuse (KF), a key area in the respiratory circuit, was examined. The activation of G protein-coupled inwardly rectifying potassium current was measured using whole-cell voltage-clamp recordings from KF and locus coeruleus (LC) neurons contained in acute rat brain slices. A saturating concentration of the opioid agonist [Met 5 ]-enkephalin (ME) caused significantly less desensitization in KF neurons compared with LC neurons. In contrast to LC, desensitization in KF neurons was not enhanced by activation of protein kinase C or in slices from morphine-treated rats. Cellular tolerance to ME and morphine was also lacking in KF neurons from morphine-treated rats. The lack of cellular tolerance in KF neurons correlates with the relative lack of tolerance to the respiratory depressant effect of opioids. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  15. Changes in mu-opioid receptor expression and function in the mesolimbic system after long-term access to a palatable diet.

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    Pitman, Kimberley A; Borgland, Stephanie L

    2015-10-01

    The incidence of obesity in both adults and children is rising. In order to develop effective treatments for obesity, it is important to understand how diet can induce changes in the brain that could promote excessive intake of high-calorie foods and alter the efficacy of therapeutic targets. The mu-opioid receptor is involved in regulating the motivation for and hedonic reaction to food. Here, we review the literature examining changes in the expression and function of mu-opioid receptors in the mesolimbic system of rodents after extended access to a high-fat diet. We also review how maternal diet can induce long-term changes in the expression or function of mu-opioid receptors in the mesolimbic system of offspring. Understanding the behavioural and therapeutic implications of these changes requires further study. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Mu opioid receptor availability in people with psychiatric disorders who died by suicide: a case control study

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    Scarr Elizabeth

    2012-08-01

    Full Text Available Abstract Background Mu opioid receptors have previously been shown to be altered in people with affective disorders who died as a result of suicide. We wished to determine whether these changes were more widespread and independent of psychiatric diagnoses. Methods Mu receptor levels were determined using [3 H]DAMGO binding in BA24 from 51 control subjects; 38 people with schizophrenia (12 suicides; 20 people with major depressive disorder (15 suicides; 13 people with bipolar disorder (5 suicides and 9 people who had no history of psychiatric disorders but who died as a result of suicide. Mu receptor levels were further determined in BA9 and caudate-putamen from 38 people with schizophrenia and 20 control subjects using [3 H]DAMGO binding and, in all three regions, using Western blots. Data was analysed using one-way ANOVAs with Bonferroni’s Multiple Comparison Test or, where data either didn’t approximate to a binomial distribution or the sample size was too small to determine distribution, a Kruskal-Wallis test with Dunn’s Multiple Comparison Test. Results [3 H]DAMGO binding density was lower in people who had died as a result of suicide (p3 H]DAMGO binding densities, but not mu protein levels, were significantly decreased in BA9 from people with schizophrenia who died as a result of suicide (p Conclusions Overall these data suggest that mu opioid receptor availability is decreased in the brains of people with schizophrenia who died as a result of suicide, which would be consistent with increased levels of endogenous ligands occupying these receptors.

  17. Binge eating disorder and morbid obesity are associated with lowered mu-opioid receptor availability in the brain.

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    Joutsa, Juho; Karlsson, Henry K; Majuri, Joonas; Nuutila, Pirjo; Helin, Semi; Kaasinen, Valtteri; Nummenmaa, Lauri

    2018-03-09

    Both morbid obesity and binge eating disorder (BED) have previously been linked with aberrant brain opioid function. Behaviorally these two conditions are however different suggesting also differences in neurotransmitter function. Here we directly compared mu-opioid receptor (MOR) availability between morbidly obese and BED subjects. Seven BED and nineteen morbidly obese (non-BED) patients, and thirty matched control subjects underwent positron emission tomography (PET) with MOR-specific ligand [ 11 C]carfentanil. Both subjects with morbid obesity and BED had widespread reduction in [ 11 C]carfentanil binding compared to control subjects. However, there was no significant difference in brain MOR binding between subjects with morbid obesity and BED. Thus, our results indicate that there is common brain opioid abnormality in behaviorally different eating disorders involving obesity. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Mu opioid receptor availability in people with psychiatric disorders who died by suicide: a case control study.

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    Scarr, Elizabeth; Money, Tammie Terese; Pavey, Geoffrey; Neo, Jaclyn; Dean, Brian

    2012-08-28

    Mu opioid receptors have previously been shown to be altered in people with affective disorders who died as a result of suicide. We wished to determine whether these changes were more widespread and independent of psychiatric diagnoses. Mu receptor levels were determined using [3 H]DAMGO binding in BA24 from 51 control subjects; 38 people with schizophrenia (12 suicides); 20 people with major depressive disorder (15 suicides); 13 people with bipolar disorder (5 suicides) and 9 people who had no history of psychiatric disorders but who died as a result of suicide. Mu receptor levels were further determined in BA9 and caudate-putamen from 38 people with schizophrenia and 20 control subjects using [3 H]DAMGO binding and, in all three regions, using Western blots. Data was analysed using one-way ANOVAs with Bonferroni's Multiple Comparison Test or, where data either didn't approximate to a binomial distribution or the sample size was too small to determine distribution, a Kruskal-Wallis test with Dunn's Multiple Comparison Test. [3 H]DAMGO binding density was lower in people who had died as a result of suicide (pendogenous ligands occupying these receptors.

  19. Anti-nociceptive effect of patchouli alcohol: Involving attenuation of cyclooxygenase 2 and modulation of mu-opioid receptor.

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    Yu, Xuan; Wang, Xin-Pei; Yan, Xiao-Jin; Jiang, Jing-Fei; Lei, Fan; Xing, Dong-Ming; Guo, Yue-Ying; Du, Li-Jun

    2017-08-09

    To explore the anti-nociceptive effect of patchouli alcohol (PA), the essential oil isolated from Pogostemon cablin (Blanco) Bent, and determine the mechanism in molecular levels. The acetic acid-induced writhing test and formalin-induced plantar injection test in mice were employed to confifirm the effect in vivo. Intracellular calcium ion was imaged to verify PA on mu-opioid receptor (MOR). Cyclooxygenase 2 (COX2) and MOR of mouse brain were expressed for determination of PA's target. Cellular experiments were carried out to find out COX2 and MOR expression induced by PA. PA significantly reduced latency period of visceral pain and writhing induced by acetic acid saline solution (Peffect of PA. A decrease in the intracellular calcium level (Peffect. PA showed the characters of enhancing the MOR expression and reducing the intracellular calcium ion similar to opioid effect. Both COX2 and MOR are involved in the mechanism of PA's anti-nociceptive effect, and the up-regulation of the receptor expression and the inhibition of intracellular calcium are a new perspective to PA's effect on MOR.

  20. Preparation and biodistribution in mice of ( sup 11 C)carfentanil; A radiopharmaceutical for studying brain. mu. -opioid receptors by positron emission tomography

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    Saji, Hideo; Tsutsumi, Daisuke; Iida, Yasuhiko; Yokoyama, Akira (Kyoto Univ. (Japan). Faculty of Pharmaceutical Science); Magata, Yasuhiro; Konishi, Junji

    1992-02-01

    A potent {mu}-opioid agonist, ({sup 11}C)carfentanil, was prepared by the methylation of carfentanil carboxylic acid with ({sup 11}C)methyl iodide in order to study brain {mu}-opioid receptors by positron emission tomography. Synthesis (including purification) was completed within 25 min and the radiochemical yield was approximately 40%. The radiochemical purity of the product was more than 99% and its specific activity was 3.7-7.4 GBq/{mu}mol. Biodistribution studies performed in mice after intravenous injection showed a high brain uptake and rapid blood clearance, so a high brain/blood ratio of 1.5-1.8 was found from 5 to 30 min. Regional cerebral distribution studies in the mouse showed a significantly higher uptake of ({sup 11}C)carfentanil by the thalamus and striatum than by the cerebellum, with the radioactivity in the striatum disappearing more rapidly than that in the thalamus. Treatment with naloxone significantly reduced the uptake of ({sup 11}C)carfentanil by the thalamus and striatum. These results indicate that ({sup 11}C)carfentanil binds specifically to brain {mu}-opioid receptors. (author).

  1. Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.

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    Tudurí, Eva; Beiroa, Daniel; Stegbauer, Johannes; Fernø, Johan; López, Miguel; Diéguez, Carlos; Nogueiras, Rubén

    2016-11-01

    Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. The influences of reproductive status and acute stress on the levels of phosphorylated mu opioid receptor immunoreactivity in rat hippocampus

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    Keith L. Gonzales

    2011-08-01

    Full Text Available Opioids play a critical role in hippocampally dependent behavior and plasticity. In the hippocampal formation, mu opioid receptors (MOR are prominent in parvalbumin (PARV containing interneurons. Previously we found that gonadal hormones modulate the trafficking of MORs in PARV interneurons. Although sex differences in response to stress are well documented, the point at which opioids, sex and stress interact to influence hippocampal function remains elusive. Thus, we used quantitative immunocytochemistry in combination with light and electron microscopy for the phosphorylated MOR at the SER375 carboxy-terminal residue (pMOR in male and female rats to assess these interactions. In both sexes, pMOR-immunoreactivity (ir was prominent in axons and terminals and in a few neuronal somata and dendrites, some of which contained PARV in the mossy fiber pathway region of the dentate gyrus (DG hilus and CA3 stratum lucidum. In unstressed rats, the levels of pMOR-ir in the DG or CA3 were not affected by sex or estrous cycle stage. However, immediately following 30 minutes of acute immobilization stress (AIS, males had higher levels of pMOR-ir whereas females at proestrus and estrus (high estrogen stages had lower levels of pMOR-ir within the DG. In contrast, the number and types of neuronal profiles with pMOR-ir were not altered by AIS in either males or proestrus females. These data demonstrate that although gonadal steroids do not affect pMOR levels at resting conditions, they are differentially activated both pre- and post-synaptic MORs following stress. These interactions may contribute to the reported sex differences in hippocampally dependent behaviors in stressed animals.

  3. Analgesic tone conferred by constitutively active mu opioid receptors in mice lacking β-arrestin 2

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    Hales Tim G

    2011-04-01

    Full Text Available Abstract Hedonic reward, dependence and addiction are unwanted effects of opioid analgesics, linked to the phasic cycle of μ opioid receptor activation, tolerance and withdrawal. In vitro studies of recombinant G protein coupled receptors (GPCRs over expressed in cell lines reveal an alternative tonic signaling mechanism that is independent of agonist. Such studies demonstrate that constitutive GPCR signaling can be inhibited by inverse agonists but not by neutral antagonists. However, ligand-independent activity has been difficult to examine in vivo, at the systems level, due to relatively low levels of constitutive activity of most GPCRs including μ receptors, often necessitating mutagenesis or pharmacological manipulation to enhance basal signaling. We previously demonstrated that the absence of β-arrestin 2 (β-arr2 augments the constitutive coupling of μ receptors to voltage-activated Ca2+ channels in primary afferent dorsal root ganglion neurons from β-arr2-/- mice. We used this in vitro approach to characterize neutral competitive antagonists and inverse agonists of the constitutively active wild type μ receptors in neurons. We administered these agents to β-arr2-/- mice to explore the role of constitutive μ receptor activity in nociception and hedonic tone. This study demonstrates that the induction of constitutive μ receptor activity in vivo in β-arr2-/- mice prolongs tail withdrawal from noxious heat, a phenomenon that was reversed by inverse agonists, but not by antagonists that lack negative efficacy. By contrast, the aversive effects of inverse agonists were similar in β-arr2-/- and β-arr2+/+ mice, suggesting that hedonic tone was unaffected.

  4. Cell-Autonomous Regulation of Mu-Opioid Receptor Recycling by Substance P

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    Bowman, Shanna L.; Soohoo, Amanda L.; Shiwarski, Daniel J.; Schulz, Stefan; Pradhan, Amynah A.; Puthenveedu, Manojkumar A.

    2015-01-01

    SUMMARY How neurons coordinate and reprogram multiple neurotransmitter signals is an area of broad interest. Here, we show that substance P (SP), a neuropep-tide associated with inflammatory pain, reprograms opioid receptor recycling and signaling. SP, through activation of the neurokinin 1 (NK1R) receptor, increases the post-endocytic recycling of the muopioid receptor (MOR) in trigeminal ganglion (TG) neurons in an agonist-selective manner. SP-mediated protein kinase C (PKC) activation is both required and sufficient for increasing recycling of exogenous and endogenous MOR in TG neurons. The target of this cross-regulation is MOR itself, given that mutation of either of two PKC phosphorylation sites on MOR abolishes the SP-induced increase in recycling and resensitization. Furthermore, SP enhances the resensitization of fentanyl-induced, but not morphine-induced, antinociception in mice. Our results define a physiological pathway that cross-regulates opioid receptor recycling via direct modification of MOR and suggest a mode of homeo-static interaction between the pain and analgesic systems. PMID:25801029

  5. Regulation of ventilation and oxygen consumption by delta- and mu-opioid receptor agonists.

    Science.gov (United States)

    Schaeffer, J I; Haddad, G G

    1985-09-01

    To study the effect of endorphins on metabolic rate and on the relationship between O2 consumption (VO2) and ventilation, we administered enkephalin analogues (relatively selective delta-receptor agonists) and a morphiceptin analogue (a highly selective mu-receptor agonist) intracisternally in nine unanesthetized chronically instrumented adult dogs. Both delta- and mu-agonists decreased VO2 by 40-60%. delta-Agonists induced a dose-dependent decrease in mean instantaneous minute ventilation (VT/TT) associated with periodic breathing. The decrease in VT/TT started and resolved prior to the decrease and returned to baseline of VO2, respectively. In contrast, the mu-agonists induced an increase in VT/TT associated with rapid shallow breathing. Arterial PCO2 increased and arterial PO2 decreased after both delta- and mu-agonists. Low doses of intracisternal naloxone (0.002-2.0 micrograms/kg) reversed the opioid effect on VT/TT but not on VO2; higher doses of naloxone (5-25 micrograms/kg) reversed both. Naloxone administered alone had no effect on VT/TT or VO2. These data suggest that 1) both delta- and mu-agonists induce alveolar hypoventilation despite a decrease in VO2, 2) this hypoventilation results from a decrease in VT/TT after delta-agonists but an increase in dead space ventilation after mu-agonists, and 3) endorphins do not modulate ventilation and metabolic rate tonically, but we speculate that they may do so in response to stressful stimulation.

  6. Identification in the mu-opioid receptor of cysteine residues responsible for inactivation of ligand binding by thiol alkylating and reducing agents.

    Science.gov (United States)

    Gaibelet, G; Capeyrou, R; Dietrich, G; Emorine, L J

    1997-05-19

    Inactivation by thiol reducing and alkylating agents of ligand binding to the human mu-opioid receptor was examined. Dithiothreitol reduced the number of [3H]diprenorphine binding sites. Replacement by seryl residues of either C142 or C219 in extracellular loops 1 and 2 of the mu receptor resulted in a complete loss of opioid binding. A disulfide bound linking C142 to C219 may thus be essential to maintain a functional conformation of the receptor. We also demonstrated that inactivation of ligand binding upon alkylation by N-ethylmaleimide occurred at two sites. Alteration of the more sensitive (IC50 = 20 microM) did not modify antagonists binding but decreased agonist affinity almost 10-fold. Modification of the less reactive site (IC50 = 2 mM) decreased the number of both agonist and antagonist binding sites. The alkylation site of higher sensitivity to N-ethylmaleimide was shown by mutagenesis experiments to be constituted of both C81 and C332 in transmembrane domains 1 and 7 of the mu-opioid receptor.

  7. Internalisation of the mu-opioid receptor by endomorphin-1 and leu-enkephalin is dependant on aromatic amino acid residues.

    Science.gov (United States)

    Del Borgo, Mark P; Blanchfield, Joanne T; Toth, Istvan

    2008-04-15

    The opioid receptor system in the central nervous system controls a number of physiological processes, most notably pain. However, most opioids currently available have a variety of side-effects as well as exhibiting tolerance. Tolerance is most likely to be a complex phenomenon, however, the role of receptor internalisation is thought to play a crucial role. In this study, we examined the role of aromaticity in ligand-mediated receptor internalisation of the mu-opioid receptor (MOPR). These studies show that the amount of receptor internalisation may be dependant on the amphiphilicity of the ligand. Specifically, deletion of the C-terminus aromatic residues of endomorphin 1, particularly tryptophan reduces receptor-mediated internalisation whilst the addition of tryptophan within the enkephalin sequence increases receptor internalisation and decreases tolerance.

  8. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to "Biased Opioids"?

    Science.gov (United States)

    Root-Bernstein, Robert; Turke, Miah; Subhramanyam, Udaya K Tiruttani; Churchill, Beth; Labahn, Joerg

    2018-01-17

    Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists.

  9. Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogs activate two mu opioid receptor subtypes that modulate antinociception and catalepsy in the rat.

    Science.gov (United States)

    Negri, L; Erspamer, G F; Severini, C; Potenza, R L; Melchiorri, P; Erspamer, V

    1992-08-01

    Three naturally occurring dermorphin-like peptides from the skin of the frog Phyllomedusa bicolor, the related carboxyl-terminal amides, and some substituted analogs were synthesized, their binding profiles to opioid receptors were determined, and their biological activities were studied in isolated organ preparations and intact animals. The opioid binding profile revealed a very high selectivity of these peptides for mu sites and suggested the existence of two receptor subtypes, of high and low affinity. The peptides tested acted as potent mu opioid agonists on isolated organ preparations. They were several times more active in inhibiting electrically evoked contractions in guinea pig ileum than in mouse vas deferens. When injected into the lateral brain ventricle or peritoneum of rats, the high-affinity-site-preferring ligand, [Lys7-NH2]dermorphin, behaved as a potent analgesic agent. By contrast, the low-affinity-site-preferring ligand, [Trp4,Asn7-NH2]dermorphin, produced a weak antinociception but an intense catalepsy.

  10. The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT in human lung cancer.

    Directory of Open Access Journals (Sweden)

    Frances E Lennon

    Full Text Available Recent epidemiologic studies implying differences in cancer recurrence based on anesthetic regimens raise the possibility that the mu opioid receptor (MOR can influence cancer progression. Based on our previous observations that overexpression of MOR in human non-small cell lung cancer (NSCLC cells increased tumor growth and metastasis, this study examined whether MOR regulates growth factor receptor signaling and epithelial mesenchymal transition (EMT in human NSCLC cells. We utilized specific siRNA, shRNA, chemical inhibitors and overexpression vectors in human H358 NSCLC cells that were either untreated or treated with various concentrations of DAMGO, morphine, fentanyl, EGF or IGF. Cell function assays, immunoblot and immunoprecipitation assays were then performed. Our results indicate MOR regulates opioid and growth factor-induced EGF receptor signaling (Src, Gab-1, PI3K, Akt and STAT3 activation which is crucial for consequent human NSCLC cell proliferation and migration. In addition, human NSCLC cells treated with opioids, growth factors or MOR overexpression exhibited an increase in snail, slug and vimentin and decrease ZO-1 and claudin-1 protein levels, results consistent with an EMT phenotype. Further, these effects were reversed with silencing (shRNA or chemical inhibition of MOR, Src, Gab-1, PI3K, Akt and STAT3 (p<0.05. Our data suggest a possible direct effect of MOR on opioid and growth factor-signaling and consequent proliferation, migration and EMT transition during lung cancer progression. Such an effect provides a plausible explanation for the epidemiologic findings.

  11. Sex and age-dependent effects of a maternal junk food diet on the mu-opioid receptor in rat offspring.

    Science.gov (United States)

    Gugusheff, Jessica R; Bae, Sung Eun; Rao, Alexandra; Clarke, Iain J; Poston, Lucilla; Taylor, Paul D; Coen, Clive W; Muhlhausler, Beverly S

    2016-03-15

    Perinatal junk food exposure increases the preference for palatable diets in juvenile and adult rat offspring. Previous studies have implicated reduced sensitivity of the opioid pathway in the programming of food preferences; however it is not known when during development these changes in opioid signalling first emerge. This study aimed to determine the impact of a maternal junk food (JF) diet on mu-opioid receptor (MuR) expression and ligand binding in two key regions of the reward pathway, the nucleus accumbens (NAc) and the ventral tegmental area (VTA) in rats during the early suckling (postnatal day (PND) 1 and 7) and late suckling/early post-weaning (PND 21 and 28) periods. Female rats were fed either a JF or a control diet for two weeks prior to mating and throughout pregnancy and lactation. MuR expression in the VTA was significantly reduced in female JF offspring on PND 21 and 28 (by 32% and 57% respectively, Pjunk food exposure on MuR mRNA expression or binding were detected at these time points in male offspring. These findings provide evidence that the opioid signalling system is a target of developmental programming by the end of the third postnatal week in females, but not in males. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Antinociceptive action of DBO 17 and DBO 11 in mice: two 3,8 diazabicyclo (3.2.1.) octane derivates with selective mu opioid receptor affinity.

    Science.gov (United States)

    Fadda, P; Barlocco, D; Tronci, S; Cignarella, G; Fratta, W

    1997-11-01

    Two 3,8 diazabicyclo (3.2.1.) octane derivates, namely DBO 17 and DBO 11, were studied for the opioid-like activity. In the rat brain membrane preparation binding studies, DBO 17 and DBO 11 showed a high affinity and selectivity for the mu opioid receptor (Ki's: 5.1 and 25 nM, respectively). DBO 17 and DBO 11 inhibited the nociceptive response in the hot-plate test of mice with ED50 values of 0.16 mg/kg and 0.44 mg/kg, respectively. The antinociceptive action of both DBO 17 and DBO 11 was blocked by naloxone. Tolerance to the antinociceptive action of DBO 17 and DBO 11 was present after 13 and 7 days of repeated treatment, respectively. Both DBO 17 and DBO 11 were ineffective in morphine-tolerant mice and vice versa. Chronic treatments (three times daily for seven consecutive days) of DBO 17 and DBO 11 induced a naloxone-precipitated withdrawal syndrome in DBO 17 treated mice similar to that in morphine treated mice, whereas in DBO 11 treated mice abstinence signs were virtually absent. These results indicate an interesting pharmacological profile that suggests these compounds as possible new candidates for the clinical treatment of pain.

  13. Acute inflammation induces segmental, bilateral, supraspinally mediated opioid release in the rat spinal cord, as measured by mu-opioid receptor internalization.

    Science.gov (United States)

    Chen, W; Marvizón, J C G

    2009-06-16

    The objective of this study was to measure opioid release in the spinal cord during acute and long-term inflammation using mu-opioid receptor (MOR) internalization. In particular, we determined whether opioid release occurs in the segments receiving the noxious signals or in the entire spinal cord, and whether it involves supraspinal signals. Internalization of neurokinin 1 receptors (NK1Rs) was measured to track the intensity of the noxious stimulus. Rats received peptidase inhibitors intrathecally to protect opioids from degradation. Acute inflammation of the hind paw with formalin induced moderate MOR internalization in the L5 segment bilaterally, whereas NK1R internalization occurred only ipsilaterally. MOR internalization was restricted to the lumbar spinal cord, regardless of whether the peptidase inhibitors were injected in a lumbar or thoracic site. Formalin-induced MOR internalization was substantially reduced by isoflurane anesthesia. It was also markedly reduced by a lidocaine block of the cervical-thoracic spinal cord (which did not affect the evoked NK1R internalization) indicating that spinal opioid release is mediated supraspinally. In the absence of peptidase inhibitors, formalin and hind paw clamp induced a small amount of MOR internalization, which was significantly higher than in controls. To study spinal opioid release during chronic inflammation, we injected complete Freund's adjuvant (CFA) in the hind paw and peptidase inhibitors intrathecally. Two days later, no MOR or NK1R internalization was detected. Furthermore, CFA inflammation decreased MOR internalization induced by clamping the inflamed hind paw. These results show that acute inflammation, but not chronic inflammation, induces segmental opioid release in the spinal cord that involves supraspinal signals.

  14. Mu-opioid receptor inhibition decreases voluntary wheel running in a dopamine-dependent manner in rats bred for high voluntary running.

    Science.gov (United States)

    Ruegsegger, Gregory N; Brown, Jacob D; Kovarik, M Cathleen; Miller, Dennis K; Booth, Frank W

    2016-12-17

    The mesolimbic dopamine and opioid systems are postulated to influence the central control of physical activity motivation. We utilized selectively bred rats for high (HVR) or low (LVR) voluntary running behavior to examine (1) inherent differences in mu-opioid receptor (Oprm1) expression and function in the nucleus accumbens (NAc), (2) if dopamine-related mRNAs, wheel-running, and food intake are differently influenced by intraperitoneal (i.p.) naltrexone injection in HVR and LVR rats, and (3) if dopamine is required for naltrexone-induced changes in running and feeding behavior in HVR rats. Oprm1 mRNA and protein expression were greater in the NAc of HVR rats, and application of the Oprm1 agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) to dissociated NAc neurons produced greater depolarizing responses in neurons from HVR versus LVR rats. Naltrexone injection dose-dependently decreased wheel running and food intake in HVR, but not LVR, rats. Naltrexone (20mg/kg) decreased tyrosine hydroxylase mRNA in the ventral tegmental area and Fos and Drd5 mRNA in NAc shell of HVR, but not LVR, rats. Additionally, lesion of dopaminergic neurons in the NAc with 6-hydroxydopamine (6-OHDA) ablated the decrease in running, but not food intake, in HVR rats following i.p. naltrexone administration. Collectively, these data suggest the higher levels of running observed in HVR rats, compared to LVR rats, are mediated, in part, by increased mesolimbic opioidergic signaling that requires downstream dopaminergic activity to influence voluntary running, but not food intake. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Increased serum IL-6 level time-dependently regulates hyperalgesia and spinal mu opioid receptor expression during CFA-induced arthritis.

    Science.gov (United States)

    Tekieh, E; Zaringhalam, Jalal; Manaheji, H; Maghsoudi, N; Alani, B; Zardooz, H

    2011-01-01

    Interleukin (IL)-6 is known to cause pro- and anti-inflammatory effects during different stages of inflammation. Recent therapeutic investigations have focused on treatment of various inflammatory disorders with anti-cytokine substances. As a result, the aim of this study was to further elucidate the influence of IL-6 in hyperalgesia and edema during different stages of Complete Freund's Adjuvant (CFA)-induced arthritis (AA) in male Wistar rats. AA was induced by a single subcutaneous injection of CFA into the rats' hindpaw. Anti-IL-6 was administered either daily or weekly during the 21 days of study. Spinal mu opioid receptor (mOR) expression was detected by Western blotting. Daily and weekly treatment with an anti-IL-6 antibody significantly decreased paw edema in the AA group compared to the AA control group. Additionally, daily and weekly anti-IL-6 administration significantly reduced hyperalgesia on day 7 in the AA group compared to the AA control group; however, there were significant increases in hyperalgesia in the antibody-treated group on days 14 and 21 compared to the AA control group. IL-6 antibody-induced increases in hyperalgesia on the 14 th and 21 st days after CFA injection correlated with a time-dependent, significant reduction in spinal mOR expression during anti-IL-6 treatment. Our study confirmed the important time-dependent relationship between serum IL-6 levels and hyperalgesia during AA. These results suggest that the stages of inflammation in AA must be considered for anti-hyperalgesic and anti-inflammatory interventions via anti-IL-6 antibody treatment.

  16. Constitutive cannabinoid 1 and mu opioid receptor activity in the ventral tegmental area: occurrence, function and therapeutic relevance

    NARCIS (Netherlands)

    Meye, F.J.

    2012-01-01

    Cannabinoid 1 receptors (CB1Rs) play a crucial role in regulating systems dedicated to processing rewards and emotions. It was known that in artificial systems, CB1Rs can exhibit activity that is independent of the typical agonist-driven form. However, it remained largely unclear whether this

  17. The Effect of the [mu]-Opioid Receptor Antagonist Naloxone on Extinction of Conditioned Fear in the Developing Rat

    Science.gov (United States)

    Kim, Jee Hyun; Richardson, Rick

    2009-01-01

    Several recent studies report that neurotransmitters that are critically involved in extinction in adult rats are not important for extinction in young rats. Specifically, pretest injection of the [gamma]-aminobutryic acid (GABA) receptor inverse agonist FG7142 has no effect on extinction in postnatal day (P)17 rats, although it reverses…

  18. 14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity.

    Science.gov (United States)

    Zádor, Ferenc; Balogh, Mihály; Váradi, András; Zádori, Zoltán S; Király, Kornél; Szűcs, Edina; Varga, Bence; Lázár, Bernadette; Hosztafi, Sándor; Riba, Pál; Benyhe, Sándor; Fürst, Susanna; Al-Khrasani, Mahmoud

    2017-11-05

    14-O-methyl (14-O-Me) group in morphine-6-O-sulfate (M6SU) or oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-O-MeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal transit in in vivo. The potency and efficacy of test compound were measured by [ 35 S]GTPγS binding, isolated mouse vas deferens (MVD) and rat vas deferens (RVD) assays. The affinity of 14-O-MeM for opioid receptors was assessed by radioligand binding and MVD assays. The antinociceptive and gastrointestinal effects of the novel compound were evaluated in the rat tail-flick test and charcoal meal test, respectively. Morphine, DAMGO, Ile 5,6 deltorphin II, deltorphin II and U-69593 were used as reference compounds. 14-O-MeM showed higher efficacy (E max ) and potency (EC 50 ) than morphine in MVD, RVD or [ 35 S]GTPγS binding. In addition, 14-O-MeM compared to morphine showed higher affinity for μ-opioid receptor (MOR). In vivo, in rat tail-flick test 14-O-MeM proved to be stronger antinociceptive agent than morphine after peripheral or central administration. Additionally, both compounds inhibited the gastrointestinal peristalsis. However, when the antinociceptive and antitransit doses for each test compound are compared, 14-O-MeM proved to have slightly more favorable pharmacological profile. Our results affirm that 14-O-MeM, an opioid of high efficacy and affinity for MOR can be considered as a novel analgesic agent of potential clinical value. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Immunohistochemical localization of mu opioid receptor in the marginal division with comparison to patches in the neostriatum of the rat brain

    Directory of Open Access Journals (Sweden)

    Wu Bingyi

    2011-06-01

    Full Text Available Abstract Background Mu opioid receptor (MOR, which plays key roles in analgesia and also has effects on learning and memory, was reported to distribute abundantly in the patches of the neostriatum. The marginal division (MrD of the neostriatum, which located at the caudomedial border of the neostriatum, was found to stain for enkephalin and substance P immunoreactivities and this region was found to be involved in learning and memory in our previous study. However, whether MOR also exists in the MrD has not yet been determined. Methods In this study, we used western blot analysis and immunoperoxidase histochemical methods with glucose oxidase-DAB-nickel staining to investigate the expression of MOR in the MrD by comparison to the patches in the neostriatum. Results The results from western blot analyses revealed that the antibody to MOR detected a 53 kDa protein band, which corresponded directly to the molecular weight of MOR. Immunohistochemical results showed that punctate MOR-immunoreacted fibers were observed in the "patch" areas in the rostrodorsal part of the neostriatum but these previous studies showed neither labelled neuronal cell bodies, nor were they shown in the caudal part of the neostriatum. Dorsoventrally oriented dark MOR-immunoreactive nerve fibers with individual labelled fusiform cell bodies were firstly observed in the band at the caudomedial border, the MrD, of the neostriatum. The location of the MOR-immunoreactivity was in the caudomedial border of the neostriatum. The morphology of the labelled fusiform neuronal somatas and the dorsoventrally oriented MOR-immunoreacted fibers in the MrD was distinct from the punctate MOR-immunoreactive diffuse mosaic-patterned patches in the neostriatum. Conclusions The results indicated that MOR was expressed in the MrD as well as in patches in the neostriatum of the rat brain, but with different morphological characteristics. The punctate MOR-immunoreactive and diffuse mosaic

  20. General, kappa, delta and mu opioid receptor antagonists mediate feeding elicited by the GABA-B agonist baclofen in the ventral tegmental area and nucleus accumbens shell in rats: reciprocal and regional interactions.

    Science.gov (United States)

    Miner, Patricia; Shimonova, Lyudmila; Khaimov, Arthur; Borukhova, Yaffa; Ilyayeva, Ester; Ranaldi, Robert; Bodnar, Richard J

    2012-03-14

    Food intake is significantly increased following administration of agonists of GABA and opioid receptors into the nucleus accumbens shell (NACs) and ventral tegmental area (VTA). GABA-A or GABA-B receptor antagonist pretreatment within the VTA or NACs differentially affects mu-opioid agonist-induced feeding elicited from the same site. Correspondingly, general or selective opioid receptor antagonist pretreatment within the VTA or NACs differentially affects GABA agonist-induced feeding elicited from the same site. Regional interactions have been evaluated in feeding studies by administering antagonists in one site prior to agonist administration in a second site. Thus, opioid antagonist-opioid agonist and GABA antagonist-GABA agonist feeding interactions have been identified between the VTA and NACs. However, pretreatment with GABA-A or GABA-B receptor antagonists in the VTA failed to affect mu opioid agonist-induced feeding elicited from the NACs, and correspondingly, these antagonists administered in the NACs failed to affect mu opioid-induced feeding elicited from the VTA. To evaluate whether regional and reciprocal VTA and NACs feeding interactions occur for opioid receptor modulation of GABA agonist-mediated feeding, the present study examined whether feeding elicited by the GABA-B agonist, baclofen microinjected into the NACs was dose-dependently blocked by pretreatment with general (naltrexone: NTX), mu (beta-funaltrexamine: BFNA), kappa (nor-binaltorphamine: NBNI) or delta (naltrindole: NTI) opioid antagonists in the VTA, and correspondingly, whether VTA baclofen-induced feeding was dose-dependently blocked by NACs pretreatment with NTX, BFNA, NBNI or NTI in rats. Bilateral pairs of cannulae aimed at the VTA and NACs were stereotaxically implanted in rats, and their food intakes were assessed following vehicle and baclofen (200 ng) in each site. Baclofen produced similar magnitudes of increased food intake following VTA and NACs treatment. Baclofen

  1. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”?

    Science.gov (United States)

    Turke, Miah; Subhramanyam, Udaya K. Tiruttani; Churchill, Beth; Labahn, Joerg

    2018-01-01

    Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR) were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists. PMID:29342106

  2. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”?

    Directory of Open Access Journals (Sweden)

    Robert Root-Bernstein

    2018-01-01

    Full Text Available Extensive evidence demonstrates functional interactions between the adrenergic and opioid systems in a diversity of tissues and organs. While some effects are due to receptor and second messenger cross-talk, recent research has revealed an extracellular, allosteric opioid binding site on adrenergic receptors that enhances adrenergic activity and its duration. The present research addresses whether opioid receptors may have an equivalent extracellular, allosteric adrenergic binding site that has similar enhancing effects on opioid binding. Comparison of adrenergic and opioid receptor sequences revealed that these receptors share very significant regions of similarity, particularly in some of the extracellular and transmembrane regions associated with adrenergic binding in the adrenergic receptors. Five of these shared regions from the mu opioid receptor (muOPR were synthesized as peptides and tested for binding to adrenergic, opioid and control compounds using ultraviolet spectroscopy. Adrenergic compounds bound to several of these muOPR peptides with low micromolar affinity while acetylcholine, histamine and various adrenergic antagonists did not. Similar studies were then conducted with purified, intact muOPR with similar results. Combinations of epinephrine with methionine enkephalin or morphine increased the binding of both by about half a log unit. These results suggest that muOPR may be allosterically enhanced by adrenergic agonists.

  3. Detection and Quantization of the Expression of Two mu-Opioid Receptor Splice Variants mRNA (hMOR-1A and hMOR-1O in Peripheral Blood Lymphocytes of Long-Term Abstinent Former Opioid Addicts

    Directory of Open Access Journals (Sweden)

    N Vousooghi, Pharm

    2012-05-01

    Full Text Available

    Background and Objectives

    The mu-Opioid receptor (MOR exerts a critical role on effects of opiodis. The objective of this study is to find a peripheral bio-marker in addiction studies through quantization of the expression of two MOR splice variants mRNA (hMOR-1A and hMOR-1O in peripheral blood lymphocytes (PBLs of long-term abstinent former opioids addicts.

    Methods

    In this case-control study, case and control people were male and divided in two groups: people who gave up addiction to opioids (case and healthy individuals without history of addiction (control. The mRNA expression in PBLs of participants was detected and measured by real-time Polymerase Chain Reaction (PCR using SYBR Green Dye.

    Results

    The hMOR-1A mRNA expression in PBLs of abstinent group was significantly reduced and reached to 0.33 of the control group (p<0.001. Similar results were obtained for the other splice variant with the mRNA expression of hMOR-1O in PBLs of abstinent group reaching to 0.38 of that of the control group (p < 0.001.

    Conclusion

    mRNA expression deficiency of two mu-opioid receptor splice variants, hMOR-1A and nMOR-1O, seams to be a risk factor making individuals vulnerable to drug addiction. Based on this analysis measuring the amount of mRNA expression of these two splice variants in PBLs can serve as a peripheral bio-marker for detecting people at risk.

  4. Correlation of stable elevations in striatal mu-opioid receptor availability in detoxified alcoholic patients with alcohol craving: a positron emission tomography study using carbon 11-labeled carfentanil.

    Science.gov (United States)

    Heinz, Andreas; Reimold, Matthias; Wrase, Jana; Hermann, Derik; Croissant, Bernhard; Mundle, Götz; Dohmen, Bernhard M; Braus, Dieter F; Braus, Dieter H; Schumann, Gunter; Machulla, Hans-Jürgen; Bares, Roland; Mann, Karl

    2005-01-01

    The pleasant effects of food and alcohol intake are partially mediated by mu-opiate receptors in the ventral striatum, a central area of the brain reward system. Blockade of mu-opiate receptors with naltrexone reduces the relapse risk among some but not all alcoholic individuals. To test the hypothesis that alcohol craving is pronounced among alcoholic individuals with a high availability of mu-opiate receptors in the brain reward system. Patients and comparison sample. The availability of central mu-opiate receptors was measured in vivo with positron emission tomography (PET) and the radioligand carbon 11-labeled carfentanil in the ventral striatum and compared with the severity of alcohol craving as assessed by the Obsessive Compulsive Drinking Scale (OCDS). Hospitalized care. Volunteer sample of 25 male alcohol-dependent inpatients assessed after detoxification of whom 12 underwent PET again 5 weeks later. Control group of 10 healthy men. After 1 to 3 weeks of abstinence, the availability of mu-opiate receptors in the ventral striatum, including the nucleus accumbens, was significantly elevated in alcoholic patients compared with healthy controls and remained elevated when 12 alcoholic patients had these levels measured 5 weeks later (P<.05 corrected for multiple testing). Higher availability of mu-opiate receptors in this brain area correlated significantly with the intensity of alcohol craving as assessed by the OCDS. Abstinent alcoholic patients displayed an increase in mu-opiate receptors in the ventral striatum, including the nucleus accumbens, which correlated with the severity of alcohol craving. These findings point to a neuronal correlate of alcohol urges.

  5. BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

    Directory of Open Access Journals (Sweden)

    Kelsey Moore

    2016-11-01

    Full Text Available Blood oxygen level dependent (BOLD imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (µ opioid receptor knock-outs (MuKO in response to oxycodone (OXY. Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high µ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala and hypothalamus, and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex and prelimbic cortex. Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala and preoptic areas. This result indicates that most effects of OXY on positive BOLD are mediated by the µ opioid receptor (on-target effects. OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122 and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum, and in some case intensified (hippocampus. Negative BOLD analysis therefore shows activation and deactivation events in the absence of the µ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects. Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY

  6. /sup 3/H)-(H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) ((/sup 3/H)CTOP), a potent and highly selective peptide for mu opioid receptors in rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Hawkins, K.N.; Knapp, R.J.; Lui, G.K.; Gulya, K.; Kazmierski, W.; Wan, Y.P.; Pelton, J.T.; Hruby, V.J.; Yamamura, H.I.

    1989-01-01

    The cyclic, conformationally restricted octapeptide (3H)-(H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) ((3H)CTOP) was synthesized and its binding to mu opioid receptors was characterized in rat brain membrane preparations. Association rates (k+1) of 1.25 x 10(8) M-1 min-1 and 2.49 x 10(8) M-1 min-1 at 25 and 37 degrees C, respectively, were obtained, whereas dissociation rates (k-1) at the same temperatures were 1.93 x 10(-2) min-1 and 1.03 x 10(-1) min-1 at 25 and 37 degrees C, respectively. Saturation isotherms of (3H)CTOP binding to rat brain membranes gave apparent Kd values of 0.16 and 0.41 nM at 25 and 37 degrees C, respectively. Maximal number of binding sites in rat brain membranes were found to be 94 and 81 fmol/mg of protein at 25 and 37 degrees C, respectively. (3H)CTOP binding over a concentration range of 0.1 to 10 nM was best fit by a one site model consistent with binding to a single site. The general effect of different metal ions and guanyl-5'-yl-imidodiphosphate on (3H)CTOP binding was to reduce its affinity. High concentrations (100 mM) of sodium also produced a reduction of the apparent mu receptor density. Utilizing the delta opioid receptor specific peptide (3H)-(D-Pen2,D-Pen5)enkephalin, CTOP appeared to be about 2000-fold more specific for mu vs. delta opioid receptor than naloxone. Specific (3H)CTOP binding was inhibited by a large number of opioid or opiate ligands.

  7. Dermorphin-related peptides from the skin of Phyllomedusa bicolor and their amidated analogs activate two mu opioid receptor subtypes that modulate antinociception and catalepsy in the rat.

    OpenAIRE

    Negri, L; Erspamer, G F; Severini, C; Potenza, R L; Melchiorri, P; Erspamer, V

    1992-01-01

    Three naturally occurring dermorphin-like peptides from the skin of the frog Phyllomedusa bicolor, the related carboxyl-terminal amides, and some substituted analogs were synthesized, their binding profiles to opioid receptors were determined, and their biological activities were studied in isolated organ preparations and intact animals. The opioid binding profile revealed a very high selectivity of these peptides for mu sites and suggested the existence of two receptor subtypes, of high and ...

  8. Knockdown of ventral tegmental area mu-opioid receptors in rats prevents effects of social defeat stress: Implications for amphetamine cross-sensitization, social avoidance, weight regulation and expression of brain-derived neurotrophic factor

    Science.gov (United States)

    Johnston, Caitlin E.; Herschel, Daniel; Lasek, Amy W.; Hammer, Ronald P.; Nikulina, Ella M.

    2014-01-01

    Social defeat stress causes social avoidance and long-lasting cross-sensitization to psychostimulants, both of which are associated with increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). Moreover, social stress upregulates VTA mu-opioid receptor (MOR) mRNA. In the VTA, MOR activation inhibits GABA neurons to disinhibit VTA dopamine neurons, thus providing a role for VTA MORs in the regulation of psychostimulant sensitization. The present study determined the effect of lentivirus-mediated MOR knockdown in the VTA on the consequences of intermittent social defeat stress, a salient and profound stressor in humans and rodents. Social stress exposure induced social avoidance and attenuated weight gain in animals with non-manipulated VTA MORs, but both these effects were prevented by VTA MOR knockdown. Rats with non-manipulated VTA MOR expression exhibited cross-sensitization to amphetamine challenge (1.0 mg/kg, i.p.), evidenced by a significant augmentation of locomotion. By contrast, knockdown of VTA MORs prevented stress-induced cross-sensitization without blunting the locomotor-activating effects of amphetamine. At the time point corresponding to amphetamine challenge, immunohistochemical analysis was performed to examine the effect of stress on VTA BDNF expression. Prior stress exposure increased VTA BDNF expression in rats with non-manipulated VTA MOR expression, while VTA MOR knockdown prevented stress-induced expression of VTA BDNF. Taken together, these results suggest that upregulation of VTA MOR is necessary for the behavioral and biochemical changes induced by social defeat stress. Elucidating VTA MOR regulation of stress effects on the mesolimbic system may provide new therapeutic targets for treating stress-induced vulnerability to substance abuse. PMID:25446676

  9. Synthesis, modelling, and mu-opioid receptor affinity of N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicycl.

    Science.gov (United States)

    Pinna, G A; Murineddu, G; Curzu, M M; Villa, S; Vianello, P; Borea, P A; Gessi, S; Toma, L; Colombo, D; Cignarella, G

    2000-08-01

    A series of N-3-arylpropenyl-N-9-propionyl-3,9-diazabicyclo[3.3.1]nonanes (1a-g) and of reverted N-3-propionyl-N-9-arylpropenyl isomers (2a-g), as homologues of the previously reported analgesic 3,8-diazabicyclo[3.2.1]octanes (I-II), were synthesized and evaluated for the binding affinity towards opioid receptor subtypes mu, delta and kappa. Compounds 1a-g and 2a-g exhibited a strong selective mu-affinity with Ki values in the nanomolar range, which favourably compared with those of I and II. In addition, contrary to the trend observed for DBO-I, II, the mu-affinity of series 2 is markedly higher than that of the isomeric series 1. This aspect was discussed on the basis of the conformational studies performed on DBN which allowed hypotheses on the mode of interaction of these compounds with the mu receptor.

  10. ERK1/2 activation in rat ventral tegmental area by the mu-opioid agonist fentanyl : An in vitro study

    NARCIS (Netherlands)

    Lesscher, HMB; Burbach, JPH; Van Ree, JM; Gerrits, MAFM

    2003-01-01

    Opioid receptors in the ventral tegmental area, predominantly the mu-opioid receptors, have been suggested to modulate reinforcement sensitivity for both opioid and non-opioid drugs of abuse. The present study was conducted to study signal transduction proteins, which may mediate the functioning of

  11. Delta/mu opioid receptor interactions in operant conditioning assays of pain-depressed responding and drug-induced rate suppression: assessment of therapeutic index in male Sprague Dawley rats.

    Science.gov (United States)

    Cone, Katherine; Lanpher, Janell; Kinens, Abigail; Richard, Philomena; Couture, Sarah; Brackin, Rebecca; Payne, Emily; Harrington, Kylee; Rice, Kenner C; Stevenson, Glenn W

    2018-05-01

    Although delta/mu receptor interactions vary as a function of behavioral endpoint, there have been no assessments of these interactions using assays of pain-depressed responding. This is the first report of delta/mu interactions using an assay of pain-depressed behavior. A mult-cycle FR10 operant schedule was utilized in the presence of (nociception) and in the absence of (rate suppression) a lactic acid inflammatory pain-like manipulation. SNC80 and methadone were used as selective/high efficacy delta and mu agonists, respectively. Both SNC80 and methadone alone produced a dose-dependent restoration of pain-depressed responding and dose-dependent response rate suppression. Three fixed ratio mixtures, based on the relative potencies of the drugs in the nociception assay, also produced dose-dependent antinociception and sedation. Isobolographic analysis indicated that all three mixtures produced supra-additive antinociceptive effects and simply additive sedation effects. The therapeutic index (TI) inversely varied as a function of amount of SNC80 in the mixture, such that lower amounts of SNC80 produced a higher TI, and larger amounts produced a lower TI. Compared to literature using standard pain-elicited assays, the orderly relationship between SNC80 and TI reported here may be a unique function of assessing pain-depressed behavior.

  12. Opioid regulation of mu receptor internalisation: relevance to the development of tolerance and dependence.

    Science.gov (United States)

    Lopez-Gimenez, Juan F; Milligan, Graeme

    2010-11-01

    Internalisation of the mu opioid receptor from the surface of cells is generally achieved by receptor occupancy with agonist ligands of high efficacy. However, in many situations the potent analgesic morphine fails to promote internalisation effectively and whether there is a direct link between this and the propensity for the sustained use of morphine to result in both tolerance and dependence has been studied intensely. Although frequently described as a partial agonist, this characteristic appears insufficient to explain the poor capacity of morphine to promote internalisation of the mu opioid receptor. Experiments performed using both transfected cell systems and ex vivo/in vivo models have provided evidence that when morphine can promote internalisation of the mu receptor there is a decrease in the development of tolerance and dependence. Although aspects of this model are controversial, such observations suggest a number of approaches to further enhance the use of morphine as an analgesic.

  13. A Potential Role for mu-Opioids in Mediating the Positive Effects of Gratitude.

    Science.gov (United States)

    Henning, Max; Fox, Glenn R; Kaplan, Jonas; Damasio, Hanna; Damasio, Antonio

    2017-01-01

    Gratitude is a complex emotional feeling associated with universally desirable positive effects in personal, social, and physiological domains. Why or how gratitude achieves these functional outcomes is not clear. Toward the goal of identifying its' underlying physiological processes, we recently investigated the neural correlates of gratitude. In our study, participants were exposed to gratitude-inducing stimuli, and rated each according to how much gratitude it provoked. As expected, self-reported gratitude intensity correlated with brain activity in distinct regions of the medial pre-frontal cortex associated with social reward and moral cognition. Here we draw from our data and existing literature to offer a theoretical foundation for the physiological correlates of gratitude. We propose that mu-opioid signaling (1) accompanies the mental experience of gratitude, and (2) may account for the positive effects of gratitude on social relationships, subjective wellbeing, and physiological health.

  14. Atypical Opioid Mechanisms of Control of Injury-Induced Cutaneous Pain by Delta Receptors

    Science.gov (United States)

    2016-07-01

    treat, and current opioids (i.e. mu opioid receptor agonists such as morphine) cause unacceptable side effects including addiction . Injuries suffered...treat, and current opioids that act on mu opioid receptors such as morphine generate significant side effects including addiction . War-related...al., J Neurosci Methods, 1994), starting with 0.1 g and ending with 2.0 g filament as cutoff value. As shown in Figure 2, our preliminary experiments

  15. Wheel running reduces high-fat diet intake, preference and mu-opioid agonist stimulated intake

    Science.gov (United States)

    Liang, Nu-Chu; Bello, Nicholas T.; Moran, Timothy H.

    2015-01-01

    The ranges of mechanisms by which exercise affects energy balance remain unclear. One potential mechanism may be that exercise reduces intake and preference for highly palatable, energy dense fatty foods. The current study used a rodent wheel running model to determine whether and how physical activity affects HF diet intake/preference and reward signaling. Experiment 1 examined whether wheel running affected the ability of intracerebroventricular (ICV) µ opioid receptor agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO) to increase HF diet intake. Experiment 2 examined the effects of wheel running on the intake of and preference for a previously preferred HF diet. We also assessed the effects of wheel running and diet choice on mesolimbic dopaminergic and opioidergic gene expression. Experiment 1 revealed that wheel running decreased the ability of ICV DAMGO administration to stimulate HF diet intake. Experiment 2 showed that wheel running suppressed weight gain and reduced intake and preference for a previously preferred HF diet. Furthermore, the mesolimbic gene expression profile of wheel running rats was different from that of their sedentary paired-fed controls but similar to that of sedentary rats with large HF diet consumption. These data suggest that alterations in preference for palatable, energy dense foods play a role in the effects of exercise on energy homeostasis. The gene expression results also suggest that the hedonic effects of exercise may substitute for food reward to limit food intake and suppress weight gain. PMID:25668514

  16. Examining the role of mu opioid receptor endocytosis in the beneficial and side-effects of prolonged opioid use: From a symposium on new concepts in mu-opioid pharmacology

    OpenAIRE

    Whistler, Jennifer L.

    2012-01-01

    Opioid drugs remain the gold standard for the treatment of severe pain, both acute/post-surgical and chronic. However, the utility of opioid drugs for the treatment of chronic pain is compromised by the development of analgesic tolerance which, in turn, leads to dose-escalation and increased likelihood of dangerous side effects, including dependence. Consequently, there remains resistance among clinicians and the general population to using opiates for pain management because of risk of “addi...

  17. Nicotine receptor partial agonists for smoking cessation

    Directory of Open Access Journals (Sweden)

    Kate Cahill

    Full Text Available BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist and reducing smoking satisfaction (acting as an antagonist. OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist' in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialized register was in December 2011. We also searched online clinical trials registers. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up. The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs, using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: Two recent cytisine trials (937 people

  18. Nicotine receptor partial agonists for smoking cessation.

    Science.gov (United States)

    Cahill, Kate; Stead, Lindsay F; Lancaster, Tim

    2012-04-18

    Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including cytisine, dianicline and varenicline for smoking cessation. We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, PsycINFO and Web of Science using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in December 2011. We also searched online clinical trials registers. We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow-up.The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model. Two recent cytisine trials (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled RR of

  19. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels

    2015-01-01

    to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...... antagonists have been essential in defining the tonic current but both remaining issues concerning the GABAARs involved and the therapeutic possibilities of modulating tonic inhibition underline the need for GABAAR antagonists with improved selectivity....

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

    Energy Technology Data Exchange (ETDEWEB)

    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. (GSKPA)

    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.

  1. Studies of the Mu-Opioid Receptor/G-protein Complex Affinity Co-Purified and Membrane Preparations from 7315c Cells

    Science.gov (United States)

    1989-06-09

    drugs. This assay was terminated by glass fiber rapid filtration as described above. Phospholipid Vesicle Formation and Reconstituted Ligand Binding...m 1!:~1!: COCO CD ~~~ ...... I I I a o a .......... 0 a ... 0 ~ ɛ 0 = = = 00 co .. N a a a a . .. . ~ (wnwJiitw %) 9MIONI8

  2. Dual growth of adolescent smoking and drinking: Evidence for an interaction between the mu-opioid receptor (OPRM1) A118G polymorphism and sex

    NARCIS (Netherlands)

    Kleinjan, M.; Poelen, E.A.P.; Engels, R.C.M.E.; Verhagen, M.

    2013-01-01

    Smoking and alcohol use often co-occur during adolescence, but little is known about the codevelopment of these substances. In the search for etiological factors that help to explain the development of adolescent substance use patterns, studies have revealed substantial heritability for both alcohol

  3. Autoradiographic localization of mu and delta opioid receptors in the mesocorticolimbic dopamine system

    Energy Technology Data Exchange (ETDEWEB)

    Dilts, R.P. Jr.

    1989-01-01

    In vitro autoradiographic techniques were coupled with selective chemical lesions of the A10 dopamine cells and intrinsic perikarya of the region to delineate the anatomical localization of mu and delta opioid receptors, as well as, neurotensin receptors. Mu opioid receptors were labeled with {sup 125}I-DAGO. Delta receptors were labeled with {sup 125}I-DPDPE. Neurotensin receptors were labeled with {sup 125}I-NT3. Unilateral lesions of the dopamine perikarya were produced by injections of 6-OHDA administered in the ventral mesencephalon. Unilateral lesions of intrinsic perikarya were induced by injections of quinolinic acid in to the A10 dopamine cell region. Unilateral lesions produced with 6-OHDA resulted in the loss of neurotensin receptors in the A10 region and within the terminal fields. Mu opioid receptors were unaffected by this treatment, but delta opioid receptors increased in the contralateral striatum and nucleus accumbens following 6-OHDA administration. Quinolinic acid produced a reduction of mu opioid receptors within the A10 region with a concomitant reduction in neurotensin receptors in both the cell body region and terminal fields. These results are consistent with a variety of biochemical and behavioral data which suggest the indirect modulation of dopamine transmission by the opioids. In contrast these results strongly indicate a direct modulation of the mesolimbic dopamine system by neurotensin.

  4. Dopamine D4 receptor counteracts morphine-induced changes in M opioid receptor signaling in the striosomes of the rat caudate putamen.

    OpenAIRE

    Rivera, Alicia; Valderrama-Carvajal, Alejandra; Roales-Buján, Ruth; Suárez-Boomgaard, Diana; Medina-Luque, José; Shumilov, Kirill; De-la-Calle-Martin, Adelaida

    2015-01-01

    Morphine is one of the most potent analgesic drugs used to relieve moderate to severe pain. After long-term use of morphine, neuroadaptive changes in the brain promotes tolerance, which result in a reduced sensitivity to most of its effects with attenuation of analgesic efficacy, and dependence, revealed by drug craving and physical or psychological manifestations of drug withdrawal. The mu opioid receptor (MOR) is critical, not only in mediating morphine analgesia, but also in addictive beha...

  5. Ivy and neurogliaform interneurons are a major target of μ opioid receptor modulation

    OpenAIRE

    Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

    2011-01-01

    Mu opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform ...

  6. Atypical Opioid Mechanisms of Control of Injury-Induced Cutaneous Pain by Delta Receptors

    Science.gov (United States)

    2017-07-01

    i.e. mu opioid receptor agonists such as morphine) cause unacceptable side effects including addiction . Injuries suffered most frequently by active...slides. The slides were then processed for fluorescent in situ hybridization with RNAscope technology (ACD Biosystems) to detect Oprd1 mRNA, as...tissue as done in Bardoni et al., Neuron, 2014) and negative controls (no probe). Controls indicated that the technology and reagents work as expected

  7. Partial agonists and subunit selectivity at NMDA receptors

    DEFF Research Database (Denmark)

    Risgaard, Rune; Hansen, Kasper Bø; Clausen, Rasmus Prætorius

    2010-01-01

    Subunit-selective ligands for glutamate receptors remains an area of interest as glutamate is the major excitatory neurotransmitter in the brain and involved in a number of diseased states in the central nervous system (CNS). Few subtype-selective ligands are known, especially among the N...

  8. μ Opioid Receptor Expression after Morphine Administration Is Regulated by miR-212/132 Cluster.

    Directory of Open Access Journals (Sweden)

    Adrian Garcia-Concejo

    Full Text Available Since their discovery, miRNAs have emerged as a promising therapeutical approach in the treatment of several diseases, as demonstrated by miR-212 and its relation to addiction. Here we prove that the miR-212/132 cluster can be regulated by morphine, through the activation of mu opioid receptor (Oprm1. The molecular pathways triggered after morphine administration also induce changes in the levels of expression of oprm1. In addition, miR-212/132 cluster is actively repressing the expression of mu opioid receptor by targeting a sequence in the 3' UTR of its mRNA. These findings suggest that this cluster is closely related to opioid signaling, and function as a post-transcriptional regulator, modulating morphine response in a dose dependent manner. The regulation of miR-212/132 cluster expression is mediated by MAP kinase pathway, CaMKII-CaMKIV and PKA, through the phosphorylation of CREB. Moreover, the regulation of both oprm1 and of the cluster promoter is mediated by MeCP2, acting as a transcriptional repressor on methylated DNA after prolonged morphine administration. This mechanism explains the molecular signaling triggered by morphine as well as the regulation of the expression of the mu opioid receptor mediated by morphine and the implication of miR-212/132 in these processes.

  9. Partial Agonism of Taurine at Gamma-Containing Native and Recombinant GABAA Receptors

    Science.gov (United States)

    Kletke, Olaf; Gisselmann, Guenter; May, Andrea; Hatt, Hanns; A. Sergeeva, Olga

    2013-01-01

    Taurine is a semi-essential sulfonic acid found at high concentrations in plasma and mammalian tissues which regulates osmolarity, ion channel activity and glucose homeostasis. The structural requirements of GABAA-receptors (GABAAR) gated by taurine are not yet known. We determined taurine potency and efficacy relative to GABA at different types of recombinant GABAAR occurring in central histaminergic neurons of the mouse hypothalamic tuberomamillary nucleus (TMN) which controls arousal. At binary α1/2β1/3 receptors taurine was as efficient as GABA, whereas incorporation of the γ1/2 subunit reduced taurine efficacy to 60–90% of GABA. The mutation γ2F77I, which abolishes zolpidem potentiation, significantly reduced taurine efficacy at recombinant and native receptors compared to the wild type controls. As taurine was a full- or super- agonist at recombinant αxβ1δ-GABAAR, we generated a chimeric γ2 subunit carrying the δ subunit motif around F77 (MTVFLH). At α1/2β1γ2(MTVFLH) receptors taurine became a super-agonist, similar to δ-containing ternary receptors, but remained a partial agonist at β3-containing receptors. In conclusion, using site-directed mutagenesis we found structural determinants of taurine’s partial agonism at γ-containing GABAA receptors. Our study sheds new light on the β1 subunit conferring the widest range of taurine-efficacies modifying GABAAR function under (patho)physiological conditions. PMID:23637894

  10. Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia.

    Science.gov (United States)

    Kołaczkowski, Marcin; Marcinkowska, Monika; Bucki, Adam; Śniecikowska, Joanna; Pawłowski, Maciej; Kazek, Grzegorz; Siwek, Agata; Jastrzębska-Więsek, Magdalena; Partyka, Anna; Wasik, Anna; Wesołowska, Anna; Mierzejewski, Paweł; Bienkowski, Przemyslaw

    2015-03-06

    We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  11. Heterologous expression of a deuterated membrane-integrated receptor and partial deuteration in methylotrophic yeasts

    International Nuclear Information System (INIS)

    Massou, S.; Puech, V.; Talmont, F.; Demange, P.; Lindley, N.D.; Tropis, M.; Milon, A.

    1999-01-01

    Methylotrophic yeast has previously been shown to be an excellent system for the cost-effective production of perdeuterated biomass and for the heterologous expression of membrane receptors. A protocol for the expression of 85% deuterated, functional human μ-opiate receptor was established. For partially deuterated biomass, deuteration level and distribution were determined for fatty acids, amino acids and carbohydrates. It was shown that prior to biosynthesis of lipids and amino acids (and of carbohydrates, to a lower extent), exchange occurs between water and methanol hydrogen atoms, so that 80%-90% randomly deuterated biomass and over-expressed proteins may be obtained using only deuterated water

  12. Outcomes of breast cancer patients with triple negative receptor status treated with accelerated partial breast irradiation.

    Science.gov (United States)

    Wilkinson, J Ben; Reid, Robert E; Shaitelman, Simona F; Chen, Peter Y; Mitchell, Christine K; Wallace, Michelle F; Marvin, Kimberly S; Grills, Inga S; Margolis, Jeffrey M; Vicini, Frank A

    2011-11-01

    Triple negative receptor status (TNRS) of patients undergoing breast-conserving therapy treated with whole-breast irradiation has been associated with increased distant metastasis and decreased disease-free and overall survival. This paper reports the outcomes of TNRS patients treated with accelerated partial breast irradiation (APBI). We studied 455 patients who received APBI at our institution, using interstitial, intracavitary, and three-dimensional conformal radiation therapy. TNRS was assigned if a patient tested negative for all three (ER [estrogen receptor], PR [progesterone receptor], and HER2/neu) receptors. Of 202 patients with all receptor results available, 20 patients were designated TNRS, and 182 patients had at least one receptor positive (RP). We analyzed ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), distant metastasis (DM), and overall survival (OS). Mean follow-up was 4.1 years for the TNRS group and 5.1 years for the RP cohort (p = 0.11). TNRS patients had a higher histologic grade (59% TNRS vs. 13% RP; p 0.52). OS for the RP cohort was 93% at 5 years (p > 0.28). In our patient population, TNRS conferred a clinical outcome similar to that of patients with RP disease treated with APBI. Further investigation with larger patient populations and longer follow-up periods is warranted to confirm that APBI is a safe and effective treatment for patients with localized TNRS breast cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Outcomes of Breast Cancer Patients With Triple Negative Receptor Status Treated With Accelerated Partial Breast Irradiation

    International Nuclear Information System (INIS)

    Wilkinson, J. Ben; Reid, Robert E.; Shaitelman, Simona F.; Chen, Peter Y.; Mitchell, Christine K.; Wallace, Michelle F.; Marvin, Kimberly S.; Grills, Inga S.; Margolis, Jeffrey M.; Vicini, Frank A.

    2011-01-01

    Purpose: Triple negative receptor status (TNRS) of patients undergoing breast-conserving therapy treated with whole-breast irradiation has been associated with increased distant metastasis and decreased disease-free and overall survival. This paper reports the outcomes of TNRS patients treated with accelerated partial breast irradiation (APBI). Methods and Materials: We studied 455 patients who received APBI at our institution, using interstitial, intracavitary, and three-dimensional conformal radiation therapy. TNRS was assigned if a patient tested negative for all three (ER [estrogen receptor], PR [progesterone receptor], and HER2/neu) receptors. Of 202 patients with all receptor results available, 20 patients were designated TNRS, and 182 patients had at least one receptor positive (RP). We analyzed ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), distant metastasis (DM), and overall survival (OS). Results: Mean follow-up was 4.1 years for the TNRS group and 5.1 years for the RP cohort (p = 0.11). TNRS patients had a higher histologic grade (59% TNRS vs. 13% RP; p 0.52). OS for the RP cohort was 93% at 5 years (p > 0.28). Conclusions: In our patient population, TNRS conferred a clinical outcome similar to that of patients with RP disease treated with APBI. Further investigation with larger patient populations and longer follow-up periods is warranted to confirm that APBI is a safe and effective treatment for patients with localized TNRS breast cancer.

  14. Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation

    NARCIS (Netherlands)

    H.T. Brüggenwirth (Hennie); A.L.M. Boehmer (Annemie); S. Ramnarain; M.C. Verleun-Mooijman; D.P.E. Satijn (David); J. Trapman (Jan); J.A. Grootegoed (Anton); A.O. Brinkmann (Albert)

    1997-01-01

    textabstractIn the coding part and the intron-exon boundaries of the androgen-receptor gene of a patient with partial androgen insensitivity, no mutation was found. The androgen receptor of this patient displayed normal ligand-binding parameters and migrated as a

  15. The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat

    NARCIS (Netherlands)

    Bosman, D. K.; van den Buijs, C. A.; de Haan, J. G.; Maas, M. A.; Chamuleau, R. A.

    1991-01-01

    Two benzodiazepine-receptor partial inverse agonists (Ro 15-4513, Ro 15-3505) and one benzodiazepine-receptor antagonist (flumazenil) were administered to rats with hepatic encephalopathy due to acute liver ischemia. Significant improvement (P less than 0.002) of both the clinical grade of hepatic

  16. HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in a rat model of bone cancer pain by restoring μ-opioid receptor in spinal cord.

    Science.gov (United States)

    Hou, Xinran; Weng, Yingqi; Ouyang, Bihan; Ding, Zhuofeng; Song, Zongbin; Zou, Wangyuan; Huang, Changsheng; Guo, Qulian

    2017-08-15

    Bone cancer pain (BCP) is a common complication with inadequate management in patients suffering from advanced cancer. Histone deacetylase inhibitors showed significant analgesic effect in multiple inflammatory and neuropathic pain models, but their effect in bone cancer pain has never been explored. In this study, we utilized a BCP rat model with intra-tibial inoculation of Walker 256 mammary gland carcinoma cells, which developed progressive mechanical hypersensitivity but not thermal hypersensitivity. Intrathecal application of trichostatin A (TSA), a classic pan-HDAC inhibitor, ameliorated tactile hypersensitivity and enhanced the analgesic effect of morphine in BCP rats. The analgesic effect of TSA was blocked by co-administration of CTAP, a specific MOR antagonist, confirming the involvement of mu-opioid receptor (MOR). A reduction of MOR expression was observed in the lumbar spinal cord of BCP rats and TSA treatment was able to partially reverse it. In vitro study in PC12 cells also demonstrated the dose-dependent enhancement of MOR expression by TSA treatment. Taking all into consideration, we could draw the conclusion that HDAC inhibitor TSA ameliorates mechanical hypersensitivity and potentiates analgesic effect of morphine in BCP rats, probably by restoring MOR expression in spinal cord. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Partial androgen insensitivity syndrome due to somatic mosaicism of the androgen receptor.

    Science.gov (United States)

    Batista, Rafael Loch; Rodrigues, Andresa De Santi; Machado, Aline Zamboni; Nishi, Mirian Yumie; Cunha, Flávia Siqueira; Silva, Rosana Barbosa; Costa, Elaine M F; Mendonca, Berenice B; Domenice, Sorahia

    2018-01-26

    Androgen insensitivity syndrome (AIS) is the most frequent etiology of 46,XY disorders of sex development (DSDs), and it is an X-linked disorder caused by mutations in the androgen receptor (AR) gene. AIS patients present a broad phenotypic spectrum and individuals with a partial phenotype present with different degrees of undervirilized external genitalia. There are more than 500 different AR gene allelic variants reported to be linked to AIS, but the presence of somatic mosaicisms has been rarely identified. In the presence of a wild-type AR gene, a significant degree of spontaneous virilization at puberty can be observed, and it could influence the gender assignment, genetic counseling and the clinical and psychological management of these patients and the psychosexual outcomes of these patients are not known. In this study, we report two patients with AR allelic variants in heterozygous (c.382G>T and c.1769-1G>C) causing a partial AIS (PAIS) phenotype. The first patient was raised as female and she had undergone a gonadectomy at puberty. In both patients there was congruency between gender of rearing and gender identity and gender role. Somatic mosaicism is rare in AIS and nonsense AR variant allelic can cause partial AIS phenotype in this situation. Despite the risk of virilization and prenatal androgen exposure, the gender identity and gender role was concordant with sex of rearing in both cases. A better testosterone response can be expected in male individuals and this should be considered in the clinical management.

  18. Partial least squares based gene expression analysis in estrogen receptor positive and negative breast tumors.

    Science.gov (United States)

    Ma, W; Zhang, T-F; Lu, P; Lu, S H

    2014-01-01

    Breast cancer is categorized into two broad groups: estrogen receptor positive (ER+) and ER negative (ER-) groups. Previous study proposed that under trastuzumab-based neoadjuvant chemotherapy, tumor initiating cell (TIC) featured ER- tumors response better than ER+ tumors. Exploration of the molecular difference of these two groups may help developing new therapeutic strategies, especially for ER- patients. With gene expression profile from the Gene Expression Omnibus (GEO) database, we performed partial least squares (PLS) based analysis, which is more sensitive than common variance/regression analysis. We acquired 512 differentially expressed genes. Four pathways were found to be enriched with differentially expressed genes, involving immune system, metabolism and genetic information processing process. Network analysis identified five hub genes with degrees higher than 10, including APP, ESR1, SMAD3, HDAC2, and PRKAA1. Our findings provide new understanding for the molecular difference between TIC featured ER- and ER+ breast tumors with the hope offer supports for therapeutic studies.

  19. NMDA receptor modulation by dextromethorphan and acute stress selectively alters electroencephalographic indicators of partial report processing.

    Science.gov (United States)

    Weckesser, Lisa J; Enge, Sören; Riedel, Philipp; Kirschbaum, Clemens; Miller, Robert

    2017-10-01

    Proceeding from a biophysical network model, the present study hypothesized that glutamatergic neurotransmission across the NMDA receptor (NMDAR) plays a key role in visual perception and its modulation by acute stress. To investigate these hypotheses, behavioral and electroencephalographic (EEG) indicators of partial report task processing were assessed in twenty-four healthy young men who randomly received a non-competitive NMDAR antagonist (0.8 mg/kg dextromethorphan, DXM) or a placebo, and concurrently accomplished a stress-induction (MAST) or control protocol in three consecutive sessions. Saliva samples served to quantify cortisol responses to the MAST, whereas a passive auditory oddball paradigm was implemented to verify the impact of DXM on the EEG-derived mismatch negativity component (MMN). DXM administration significantly increased MMN amplitudes but not salivary cortisol concentrations. By contrast, concurrent MAST exposure significantly reduced MMN latencies but also increased cortisol concentrations. With regard to EEG indicators, DXM administration reduced visually "evoked" (30Hz to 50Hz) and "induced" occipital gamma-band activity (70Hz to 100Hz), which was partly compensated by additional MAST exposure. However, neither the interventions nor EEG activity were significantly associated with behavioral partial report sensitivities. In summary, the present data suggest that glutamatergic neurotransmission across the NMDAR is only one among many determinants of intact visual perception. Accordingly, therapeutic doses of DXM and their inhibitory modulation by stress probably yield more pronounced electroencephalographic as compared with behavioural effects. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  20. An N-methyl-D-aspartate receptor mediated large, low-frequency, spontaneous excitatory postsynaptic current in neonatal rat spinal dorsal horn neurons.

    Science.gov (United States)

    Thomson, L M; Zeng, J; Terman, G W

    2006-09-01

    Examples of spontaneous oscillating neural activity contributing to both pathological and physiological states are abundant throughout the CNS. Here we report a spontaneous oscillating intermittent synaptic current located in lamina I of the neonatal rat spinal cord dorsal horn. The spontaneous oscillating intermittent synaptic current is characterized by its large amplitude, slow decay time, and low-frequency. We demonstrate that post-synaptic N-methyl-D-aspartate receptors (NMDARs) mediate the spontaneous oscillating intermittent synaptic current, as it is inhibited by magnesium, bath-applied d-2-amino-5-phosphonovalerate (APV), or intracellular MK-801. The NR2B subunit of the NMDAR appears important to this phenomenon, as the NR2B subunit selective NMDAR antagonist, alpha-(4-hydroxphenyl)-beta-methyl-4-benzyl-1-piperidineethanol tartrate (ifenprodil), also partially inhibited the spontaneous oscillating intermittent synaptic current. Inhibition of spontaneous glutamate release by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Gly5] enkephalin-ol (DAMGO) inhibited the spontaneous oscillating intermittent synaptic current frequency. Marked inhibition of spontaneous oscillating intermittent synaptic current frequency by tetrodotoxin (TTX), but not post-synaptic N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314), suggests that the glutamate release important to the spontaneous oscillating intermittent synaptic current is dependent on active neural processes. Conversely, increasing dorsal horn synaptic glutamate release by GABAA or glycine inhibition increased spontaneous oscillating intermittent synaptic current frequency. Moreover, inhibiting glutamate transporters with threo-beta-benzyloxyaspartic acid (DL-TBOA) increased spontaneous oscillating intermittent synaptic current frequency and decay time. A possible functional role of this spontaneous NMDAR

  1. The long-term outcome of boys with partial androgen insensitivity syndrome and a mutation in the androgen receptor gene

    NARCIS (Netherlands)

    Lucas-Herald, A.; S. Bertelloni (Silvano); A. Juul (Anders); J. Bryce (Jillian); Jiang, J.; M. Rodie (Martina); R. Sinnott (Richard); Boroujerdi, M.; Lindhardt Johansen, M.; O. Hiort (Olaf); P-M. Holterhus (Paul-Martin); M.L. Cools (Martine); Guaragna-Filho, G.; Guerra-Junior, G.; N. Weintrob (Naomi); S.E. Hannema (Sabine); S.L.S. Drop (Stenvert); T. Guran (Tulay); F. Darendeliler (Feyza); A. Nordenström (Anna); I.A. Hughes (Ieuan A.); Acerini, C.; Tadokoro-Cuccaro, R.; S.F. Ahmed (Faisal)

    2016-01-01

    textabstractBackground: In boys with suspected partial androgen insensitivity syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the androgen receptor gene (AR) is lacking. Objective: To assess the clinical characteristics and long-term

  2. Small heterodimer partner overexpression partially protects against liver tumor development in farnesoid X receptor knockout mice

    International Nuclear Information System (INIS)

    Li, Guodong; Kong, Bo; Zhu, Yan; Zhan, Le; Williams, Jessica A.; Tawfik, Ossama; Kassel, Karen M.; Luyendyk, James P.; Wang, Li; Guo, Grace L.

    2013-01-01

    Farnesoid X receptor (FXR, Nr1h4) and small heterodimer partner (SHP, Nr0b2) are nuclear receptors that are critical to liver homeostasis. Induction of SHP serves as a major mechanism of FXR in suppressing gene expression. Both FXR −/− and SHP −/− mice develop spontaneous hepatocellular carcinoma (HCC). SHP is one of the most strongly induced genes by FXR in the liver and is a tumor suppressor, therefore, we hypothesized that deficiency of SHP contributes to HCC development in the livers of FXR −/− mice and therefore, increased SHP expression in FXR −/− mice reduces liver tumorigenesis. To test this hypothesis, we generated FXR −/− mice with overexpression of SHP in hepatocytes (FXR −/− /SHP Tg ) and determined the contribution of SHP in HCC development in FXR −/− mice. Hepatocyte-specific SHP overexpression did not affect liver tumor incidence or size in FXR −/− mice. However, SHP overexpression led to a lower grade of dysplasia, reduced indicator cell proliferation and increased apoptosis. All tumor-bearing mice had increased serum bile acid levels and IL-6 levels, which was associated with activation of hepatic STAT3. In conclusion, SHP partially protects FXR −/− mice from HCC formation by reducing tumor malignancy. However, disrupted bile acid homeostasis by FXR deficiency leads to inflammation and injury, which ultimately results in uncontrolled cell proliferation and tumorigenesis in the liver. - Highlights: • SHP does not prevent HCC incidence nor size in FXR KO mice but reduces malignancy. • Increased SHP promotes apoptosis. • Bile acids and inflammation maybe critical for HCC formation with FXR deficiency

  3. Agonists and partial agonists of rhodopsin: retinal polyene methylation affects receptor activation.

    Science.gov (United States)

    Vogel, Reiner; Lüdeke, Steffen; Siebert, Friedrich; Sakmar, Thomas P; Hirshfeld, Amiram; Sheves, Mordechai

    2006-02-14

    Using Fourier transform infrared (FTIR) difference spectroscopy, we have studied the impact of sites and extent of methylation of the retinal polyene with respect to position and thermodynamic parameters of the conformational equilibrium between the Meta I and Meta II photoproducts of rhodopsin. Deletion of methyl groups to form 9-demethyl and 13-demethyl analogues, as well as addition of a methyl group at C10 or C12, shifted the Meta I/Meta II equilibrium toward Meta I, such that the retinal analogues behaved like partial agonists. This equilibrium shift resulted from an apparent reduction of the entropy gain of the transition of up to 65%, which was only partially offset by a concomitant reduction of the enthalpy increase. The analogues produced Meta II photoproducts with relatively small alterations, while their Meta I states were significantly altered, which accounted for the aberrant transitions to Meta II. Addition of a methyl group at C14 influenced the thermodynamic parameters but had little impact on the position of the Meta I/Meta II equilibrium. Neutralization of the residue 134 in the E134Q opsin mutant increased the Meta II content of the 13-demethyl analogue, but not of the 9-demethyl analogue, indicating a severe impairment of the allosteric coupling between the conserved cytoplasmic ERY motif involved in proton uptake and the Schiff base/Glu 113 microdomain in the 9-demethyl analogue. The 9-methyl group appears therefore essential for the correct positioning of retinal to link protonation of the cytoplasmic motif with protonation of Glu 113 during receptor activation.

  4. Exploring the binding energy profiles of full agonists, partial agonists, and antagonists of the α7 nicotinic acetylcholine receptor.

    Science.gov (United States)

    Tabassum, Nargis; Ma, Qianyun; Wu, Guanzhao; Jiang, Tao; Yu, Rilei

    2017-09-01

    Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are important drug targets for the treatment of neurological diseases. However, the precise determinants of the binding efficacies of ligands for these receptors are unclear. Therefore, in this study, the binding energy profiles of various ligands (full agonists, partial agonists, and antagonists) were quantified by docking those ligands with structural ensembles of the α7 nAChR exhibiting different degrees of C-loop closure. This approximate treatment of interactions suggested that full agonists, partial agonists, and antagonists of the α7 nAChR possess distinctive binding energy profiles. Results from docking revealed that ligand binding efficacy may be related to the capacity of the ligand to stabilize conformational states with a closed C loop.

  5. Effects of BMS-902483, an α7 nicotinic acetylcholine receptor partial agonist, on cognition and sensory gating in relation to receptor occupancy in rodents.

    Science.gov (United States)

    Pieschl, Rick L; Miller, Regina; Jones, Kelli M; Post-Munson, Debra J; Chen, Ping; Newberry, Kimberly; Benitex, Yulia; Molski, Thaddeus; Morgan, Daniel; McDonald, Ivar M; Macor, John E; Olson, Richard E; Asaka, Yukiko; Digavalli, Siva; Easton, Amy; Herrington, James; Westphal, Ryan S; Lodge, Nicholas J; Zaczek, Robert; Bristow, Linda J; Li, Yu-Wen

    2017-07-15

    The α7 nicotinic acetylcholine receptor is thought to play an important role in human cognition. Here we describe the in vivo effects of BMS-902483, a selective potent α7 nicotinic acetylcholine receptor partial agonist, in relationship to α7 nicotinic acetylcholine receptor occupancy. BMS-902483 has low nanomolar affinity for rat and human α7 nicotinic acetylcholine receptors and elicits currents in cells expressing human or rat α7 nicotinic acetylcholine receptors that are about 60% of the maximal acetylcholine response. BMS-902483 improved 24h novel object recognition memory in mice with a minimal effective dose (MED) of 0.1mg/kg and reversed MK-801-induced deficits in a rat attentional set-shifting model of executive function with an MED of 3mg/kg. Enhancement of novel object recognition was blocked by the silent α7 nicotinic acetylcholine receptor agonist, NS6740, demonstrating that activity of BMS-902483 was mediated by α7 nicotinic acetylcholine receptors. BMS-902483 also reversed ketamine-induced deficits in auditory gating in rats, and enhanced ex vivo hippocampal long-term potentiation examined 24h after dosing in mice. Results from an ex vivo brain homogenate binding assay showed that α7 receptor occupancy ranged from 64% (novel object recognition) to ~90% (set shift and gating) at the MED for behavioral and sensory processing effects of BMS-902483. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. The μ-opioid receptor gene and smoking initiation and nicotine dependence

    Directory of Open Access Journals (Sweden)

    Kendler Kenneth S

    2006-08-01

    Full Text Available Abstract The gene encoding the mu-opioid receptor (OPRM1 is reported to be associated with a range of substance dependence. Experiments in knockout mice indicate that the mu-opioid receptor may mediate reinforcing effects of nicotine. In humans, opioid antagonist naltrexone may reduce the reinforcing effects of tobacco smoking. Additionally, the OPRM1 gene is located in a region showing linkage to nicotine dependence. The OPRM1 is thus a plausible candidate gene for smoking behavior. To investigate whether OPRM1 contributes to the susceptibility of smoking initiation and nicotine dependence, we genotyped 11 SNPs in the gene for 688 Caucasian subjects of lifetime smokers and nonsmokers. Three SNPs showed nominal significance for smoking initiation and one reached significance for nicotine dependence. The global test for three-marker (rs9479757-rs2075572-rs10485057 haplotypes was significant for smoking initiation (p = 0.0022. The same three-marker haplotype test was marginal (p = 0.0514 for nicotine dependence. These results suggest that OPRM1 may be involved in smoking initiation and nicotine dependence.

  7. Varenicline: a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist approved for smoking cessation.

    Science.gov (United States)

    Lam, Sum; Patel, Priti N

    2007-01-01

    Tobacco smoking remains a significant health problem in the United States. It has been associated with staggering morbidity and mortality, specifically due to malignancies and cardiovascular disease. Smoking cessation can be difficult and frequently requires pharmacologic interventions in addition to nonpharmacologic measures. Previously available agents are nicotine replacement products and bupropion, which increased quit rates by about 2-fold compared with placebo. Varenicline is the first drug in a new class known as the selective alpha4beta2 nicotinic receptor partial agonists. In several randomized, double-blind, 52-week clinical trials involving healthy chronic smokers, varenicline demonstrated superiority to placebo and bupropion in terms of efficacy measures. Additionally, it improved tobacco withdrawal symptoms and reinforcing effects of smoking in relapsed patients. Patients should start therapy in combination with tobacco cessation counseling 1 week before quit date and continue the regimen for 12 weeks. The dose of varenicline should be titrated to minimize nausea. The recommended dosage is 0.5 mg once daily (QD) on days 1-3; titrate to 0.5 mg twice daily (BID) on days 4-7; and 1 mg BID starting on day 8. An additional 12-week maintenance therapy may be considered for those who achieve abstinence. The most common side effects are nausea (30%), insomnia (18%), headache (15%), abnormal dreams (13%), constipation (8%), and abdominal pain (7%). Overall, varenicline is a breakthrough in the management of tobacco addiction and has demonstrated good efficacy in motivated quitters. It also provides an option for smokers who cannot tolerate other pharmacologic interventions.

  8. A DFT approach to discriminate the antagonist and partial agonist activity of ligands binding to the NMDA receptor

    Science.gov (United States)

    Haslak, Zeynep Pinar; Bozkurt, Esra; Dutagaci, Bercem; De Proft, Frank; Aviyente, Viktorya; De Vleeschouwer, Freija

    2018-02-01

    The activation of N-methyl-D-aspartate receptors is found to be intimately associated with neurodegenerative diseases which make them promising therapeutic targets. Despite the significantly increasing multidisciplinary interests centred on this ionotropic channel, design of new ligands with intended functional activity remains a great challenge. In this article, a computational study based on density functional theory is presented to understand the structural factors of ligands determining their function as antagonists and partial agonists. With this aim, the GluN1 subunit is chosen as being one of the essential components in the activation mechanism, and quantum chemical calculations are implemented for 30 antagonists and 30 partial agonists known to bind to this subunit with different binding affinities. Several quantum chemical descriptors are investigated which might unlock the difference between antagonists and partial agonists.

  9. Partial separation of platelet and placental adenosine receptors from adenosine A2-like binding protein

    International Nuclear Information System (INIS)

    Zolnierowicz, S.; Work, C.; Hutchison, K.; Fox, I.H.

    1990-01-01

    The ubiquitous adenosine A2-like binding protein obscures the binding properties of adenosine receptors assayed with 5'-N-[ 3 H]ethylcarboxamidoadenosine [( 3 H]NECA). To solve this problem, we developed a rapid and simple method to separate adenosine receptors from the adenosine A2-like binding protein. Human platelet and placental membranes were solubilized with 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. The soluble platelet extract was precipitated with polyethylene glycol and the fraction enriched in adenosine receptors was isolated from the precipitate by differential centrifugation. The adenosine A2-like binding protein was removed from the soluble placental extract with hydroxylapatite and adenosine receptors were precipitated with polyethylene glycol. The specificity of the [ 3 H]NECA binding is typical of an adenosine A2 receptor for platelets and an adenosine A1 receptor for placenta. This method leads to enrichment of adenosine A2 receptors for platelets and adenosine A1 receptors for placenta. This provides a useful preparation technique for pharmacologic studies of adenosine receptors

  10. Partial neuromuscular blockade in humans enhances muscle blood flow during exercise independently of muscle oxygen uptake and acetylcholine receptor blockade

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Krustrup, Peter; Iaia, F Marcello

    2009-01-01

    This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one-legged k......This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one...... conductance during exercise, events that are not associated with either acetylcholine or an increased oxygen demand. The results do not support an essential role for acetylcholine, released form the neuromuscular junction, in exercise hyperaemia or for the enhanced blood flow during neuromuscular blockade....... The enhanced exercise hyperemia during partial neuromuscular blockade may be related to a greater recruitment of fast-twitch muscle fibres. Key words: blood flow, neuromuscular blockade, exercise, skeletal muscle....

  11. The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa.

    Science.gov (United States)

    Frank, Guido K W; Shott, Megan E; Hagman, Jennifer O; Schiel, Marissa A; DeGuzman, Marisa C; Rossi, Brogan

    2017-04-01

    Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience-based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine-related reward circuits are hypersensitive and could provide a treatment target. Here, we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program. The results show that aripiprazole treatment was associated with greater increase in body mass index (BMI) during treatment. The use of dopamine receptor agonists may support treatment success in anorexia nervosa and should be further investigated. © 2017 Wiley Periodicals, Inc.

  12. Reduced GABAA receptor density contralateral to a potentially epileptogenic MRI abnormality in a patient with complex partial seizures

    International Nuclear Information System (INIS)

    Kuwert, T.; Stodieck, S.R.G.; Puskas, C.; Diehl, B.; Puskas, Z.; Schuierer, G.; Vollet, B.; Schober, O.

    1996-01-01

    Imaging cerebral GABA A receptor density (GRD) with single-photon emission tomography (SPET) and iodine-123 iomazenil is highly accurate in lateralizing epileptogenic foci in patients with complex partial seizures of temporal origin. Limited knowledge exists on how iomazenil SPET compares with magnetic resonance imaging (MRI) in this regard. We present a patient with complex partial seizures in whom MRI had identified an arachnoid cyst anterior to the tip of the left temporal lobe. Contralaterally to this structural abnormality, interictal electroencephalography (EEG) performed after sleep deprivation disclosed an intermittent frontotemporal dysrhythmic focus with slow and sharp waves. On iomazenil SPET images GRD was significantly reduced in the right temporal lobe and thus contralaterally to the MRI abnormality, but ipsilaterally to the pathological EEG findings. These data suggest that iomazenil SPET may significantly contribute to the presurgical evaluation of epileptic patients even when MRI identifies potentialy epileptogenic structural lesions. (orig.)

  13. Receptor binding properties and antinociceptive effects of chimeric peptides consisting of a micro-opioid receptor agonist and an ORL1 receptor antagonist.

    Science.gov (United States)

    Kawano, Susumu; Ito, Risa; Nishiyama, Miharu; Kubo, Mai; Matsushima, Tomoko; Minamisawa, Motoko; Ambo, Akihiro; Sasaki, Yusuke

    2007-07-01

    Receptor binding properties and antinociceptive activities of chimeric peptides linked by spacers were investigated. The peptides consisted of the micro-opioid receptor ligand dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) or its analog YRFB (Tyr-D-Arg-Phe-betaAla-NH(2)) linked to the ORL1 receptor ligand Ac-Arg-Tyr-Tyr-Arg-Ile-Lys-NH(2) (Ac-RYYRIK-NH(2)). All chimeric peptides were found to possess high receptor binding affinities for both micro-opioid and ORL1 receptors in mouse brain membranes although their binding affinities for both receptors in spinal membranes were significantly lower. Among them, chimeric peptide 2, which consists of dermorphin and Ac-RYYRIK-NH(2) connected by a long spacer, had the highest binding affinity towards both receptors. In the tail-flick test following intrathecal (i.t.) administration to mice, all chimeric peptides showed potent and dose-dependent antinociceptive activities with an ED(50) of 1.34-4.51 (pmol/mouse), nearly comparable to dermorphin alone (ED(50); 1.08 pmol/mouse). In contrast to their micro-opioid receptor binding profiles, intracerebroventricular (i.c.v.) administration of the chimeric peptides resulted in much less potent antinociceptive activity (ED(50) 5.55-100peptides, and the regulation of mu-opioid receptor-mediated antinociception in brain. The present chimeric peptides may be useful as pharmacological tools for studies on micro-opioid receptor/ORL1 receptor heterodimers.

  14. Partial functional complementation between human and mouse cytomegalovirus chemokine receptor homologues

    DEFF Research Database (Denmark)

    Farrell, Helen E; Abraham, Alexander M; Cardin, Rhonda D

    2011-01-01

    The human cytomegalovirus (CMV) proteins US28 and UL33 are homologous to chemokine receptors (CKRs). Knockout of the mouse CMV M33 protein (UL33 homologue) results in substantial attenuation of salivary gland infection/replication and reduced efficiency of reactivation from tissue explants. M33-m...

  15. Cloning and structural analysis of partial acetylcholine receptor subunit genes from the parasitic nematode Teladorsagia circumcincta

    NARCIS (Netherlands)

    Walker, J.; Hoekstra, R.; Roos, M. H.; Wiley, L. J.; Weiss, A. S.; Sangster, N. C.; Tait, A.

    2001-01-01

    Nematode nicotinic acetylcholine receptors (nAChRs) are the sites of action for the anthelmintic drug levamisole. Recent findings indicate that the molecular mechanism of levamisole resistance may involve changes in the number and/or functions of target nAChRs. Accordingly, we have used an RT-PCR

  16. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR γ activators and pan-PPAR partial agonists.

    Directory of Open Access Journals (Sweden)

    Marcelo Vizoná Liberato

    Full Text Available Thiazolidinediones (TZDs act through peroxisome proliferator activated receptor (PPAR γ to increase insulin sensitivity in type 2 diabetes (T2DM, but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD and found that the ligand binding pocket (LBP is occupied by bacterial medium chain fatty acids (MCFAs. We verified that MCFAs (C8-C10 bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5, linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products.

  17. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists.

    Science.gov (United States)

    Moskal, Joseph R; Burch, Ronald; Burgdorf, Jeffrey S; Kroes, Roger A; Stanton, Patric K; Disterhoft, John F; Leander, J David

    2014-02-01

    The N-methyl-d-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an N-methyl-d-aspartate receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressant activity without psychotomimetic side effects. The authors review the mechanism of action of GLYX-13 that was investigated in preclinical studies and evaluated in clinical studies. Specifically, the authors review its pharmacology, pharmacokinetics, and drug safety that were demonstrated in clinical studies. NMDAR full antagonists can produce rapid antidepressant effects in treatment-resistant subjects; however, they are often accompanied by psychotomimetic effects that make chronic use outside of a clinical trial inpatient setting problematic. GLYX-13 appears to exert its antidepressant effects in the frontal cortex via NMDAR-triggered synaptic plasticity. Understanding the mechanistic underpinning of GLYX-13's antidepressant action should provide both novel insights into the role of the glutamatergic system in depression and identify new targets for therapeutic development.

  18. Partial agonism through a zinc-Ion switch constructed between transmembrane domains III and VII in the tachykinin NK(1) receptor

    DEFF Research Database (Denmark)

    Holst, B; Elling, C E; Schwartz, T W

    2000-01-01

    switch located exactly one helical turn below the two previously identified interaction points for Substance P in, respectively, TM-III and -VII. The metal-ion chelator, phenantroline, which in the beta(2)-adrenergic receptor increased both the potency and the agonistic efficacy of Zn(2+) or Cu(2......Partly due to lack of detailed knowledge of the molecular recognition of ligands the structural basis for partial versus full agonism is not known. In the beta(2)-adrenergic receptor the agonist binding site has previously been structurally and functionally exchanged with an activating metal....... In contrast to the similarly mutated beta(2)-adrenergic receptor, signal transduction-i.e., inositol phosphate turnover-could be stimulated by both Zn(2+) and by the natural agonist, Substance P in the mutated NK(1) receptor. The metal-ion acted as a 25% partial agonist through binding to the bidentate zinc...

  19. The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia.

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    Linda J Bristow

    Full Text Available The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R-N-(6-(1H-imidazol-1-yl-4-pyrimidinyl-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043, in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat and 0.29 micromolar (human. BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM. BMS-933043 treatment i improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc, ii reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc and set shift performance in rats (1-10 mg/kg, po and iii reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po. BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc and mismatch negativity (0.03-3 mg/kg, sc in rats treated with S(+ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.

  20. Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3

    Directory of Open Access Journals (Sweden)

    Cao Henian

    2006-01-01

    Full Text Available Abstract Background Familial partial lipodystrophy (Dunnigan type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367 results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition. Methods We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol. Results The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable. Conclusion Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-γ deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.

  1. Dianicline, a novel α4β2 nicotinic acetylcholine receptor partial agonist, for smoking cessation: a randomized placebo-controlled clinical trial

    DEFF Research Database (Denmark)

    Tonstad, Serena; Holme, Ingar; Tønnesen, Philip

    2011-01-01

    Dianicline is a α4β2 nicotinic acetylcholine receptor partial agonist, a class of drugs that includes varenicline and cytisine. Varenicline is efficacious for smoking cessation, while cytisine has not been studied systematically. The efficacy of dianicline has not been previously tested in an ade......Dianicline is a α4β2 nicotinic acetylcholine receptor partial agonist, a class of drugs that includes varenicline and cytisine. Varenicline is efficacious for smoking cessation, while cytisine has not been studied systematically. The efficacy of dianicline has not been previously tested...

  2. Memory retrieval in response to partial cues requires NMDA receptor-dependent neurotransmission in the medial prefrontal cortex.

    Science.gov (United States)

    Jo, Yong Sang; Choi, June-Seek

    2014-03-01

    The medial prefrontal cortex (mPFC) has been suggested to play a crucial role in retrieving detailed contextual information about a previous learning episode in response to a single retrieval cue. However, few studies investigated the neurochemical mechanisms that mediate the prefrontal retrieval process. In the current study, we examined whether N-methyl-D-aspartate receptors (NMDARs) in the mPFC were necessary for retrieval of a well-learned spatial location on the basis of partial or degraded spatial cues. Rats were initially trained to find a hidden platform in the Morris water maze using four extramaze cues in the surrounding environment. Their retrieval performance was subsequently tested under different cue conditions. Infusions of DL-2-amino-5-phosphonovaleric acid (APV), a NMDAR antagonist, significantly disrupted memory retrieval when three of the original cues were removed. By contrast, APV injections into the mPFC did not affect animals' retrieval performance when the original cues were presented or when three novels landmarks were added alongside the original cues. These results indicate that prefrontal NMDARs are required for memory retrieval when allocentric spatial information is degraded. NMDAR-dependent neurotransmission in the mPFC may facilitate an active retrieval process to reactivate complete contextual representations associated with partial retrieval cues. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex

    Directory of Open Access Journals (Sweden)

    Tariq Waseem Chohan

    2014-09-01

    Full Text Available Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1 and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET and wild-type (WT mice using [3H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV and the dentate gyrus (DG of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex.

  4. Genetic Analysis Using Partial Sequencing of Melanocortin 4 Receptor (MC4R Gene in Bligon Goat

    Directory of Open Access Journals (Sweden)

    Latifah Latifah

    2017-08-01

    Full Text Available Melanocortin 4 Receptor gene is involved in sympathetic nerve activity, adrenal and thyroid functions, and media for leptin in regulating energy balance and homeostasis. The aim of this research was to perform genetic analysis of MC4R gene sequences from Bligon goats. Fourty blood samples of Bligon does were used for DNA extraction. The primers were designed after alignment of 12 DNA sequences of MC4R gene from goat, sheep, and cattle. The primers were constructed on the Capra hircus MC4R gene sequence from GenBank (accession No. NM_001285591. Two DNA polymorphisms of MC4R were revealed in exon region (g.998 A/G and g.1079 C/T. The SNP g.998 A/G was a non-synonymous polymorphism i.e., changing of amino acid from methionine (Met to isoleucine (Ile. The SNP g.1079 C/T was a synonymous polymorphism. Restriction enzyme mapping on Bligon goat MC4R gene revealed three restriction enzymes (RsaI (GT’AC, Acc651 (G’GTAC_C, and KpnI (G_GTAC’C, which can recognize the SNP at g.1079 C/T. The restriction enzymes may be used for genotyping of the gene target using PCR-RFLP method in the future research.

  5. Interleukin-1 receptor antagonist modulates the early phase of liver regeneration after partial hepatectomy in mice.

    Directory of Open Access Journals (Sweden)

    Antonino Sgroi

    Full Text Available BACKGROUND: Cytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration. METHODS: We performed 70%-hepatectomy in wild type (WT mice, IL-1ra knock-out (KO mice and in WT mice treated by anakinra. We analyzed liver regeneration at regular intervals by measuring the blood levels of cytokines, the hepatocyte proliferation by bromodeoxyuridin (BrdU incorporation, proliferating cell nuclear antigen (PCNA and Cyclin D1 expression. The effect of anakinra on hepatocyte proliferation was also tested in vitro using human hepatocytes. RESULTS: At 24h and at 48 h after hepatectomy, IL-1ra KO mice had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-1β and MCP-1 and a reduced and delayed hepatocyte proliferation measured by BrdU incorporation, PCNA and Cyclin D1 protein levels, when compared to WT mice. IGFBP-1 and C/EBPβ expression was significantly decreased in IL-1ra KO compared to WT mice. WT mice treated with anakinra showed significantly decreased levels of IL-6 and significantly higher hepatocyte proliferation at 24h compared to untreated WT mice. In vitro, primary human hepatocytes treated with anakinra showed significantly higher proliferation at 24h compared to hepatocytes without treatment. CONCLUSION: IL1ra modulates the early phase of liver regeneration by decreasing the inflammatory stress and accelerating the entry of hepatocytes in proliferation. IL1ra might be a therapeutic target to improve hepatocyte proliferation.

  6. The truncated metabolite GLP-2 (3-33) interacts with the GLP-2 receptor as a partial agonist.

    Science.gov (United States)

    Thulesen, Jesper; Knudsen, Lotte Bjerre; Hartmann, Bolette; Hastrup, Sven; Kissow, Hannelouise; Jeppesen, Palle Bekker; Ørskov, Cathrine; Holst, Jens Juul; Poulsen, Steen Seier

    2002-01-15

    The therapeutic potential of the intestinotrophic mediator glucagon-like peptide-2 (1-33) [GLP-2 (1-33)] has increased interest in the pharmacokinetics of the peptide. This study was undertaken to investigate whether the primary degradation product GLP-2 (3-33) interacts with the GLP-2 receptor. Functional (cAMP) and binding in vitro studies were carried out in cells expressing the transfected human GLP-2 receptor. Furthermore, a biologic response of GLP-2 (3-33) was tested in vivo. Mice were allocated to groups treated for 10 days (twice daily) with: (1) 5 microg GLP-2 (1-33), (2) 25 microg GLP-2 (3-33), (3) 5 microg GLP-2 (1-33)+100 microg GLP-2 (3-33), or (4) 5 microg GLP-2 (1-33)+500 microg GLP-2 (3-33). The intestine was investigated for growth changes. GLP-2 (3-33) bound to the GLP-2 receptor with a binding affinity of 7.5% of that of GLP-2 (1-33). cAMP accumulation was stimulated with an efficacy of 15% and a potency more than two orders of magnitude lower than that of GLP-2 (1-33). Increasing doses of GLP-2 (3-33) (10(-7)-10(-5) M) caused a shift to the right in the dose-response curve of GLP-2 (1-33). Treatment of mice with either GLP-2 (1-33) or (3-33) induced significant growth responses in both the small and large intestines, but the response induced by GLP-2 (3-33) was much smaller. Co-administration of 500 microg of GLP-2 (3-33) and 5 microg GLP-2 (1-33) resulted in a growth response that was smaller than that of 5 microg GLP-2 (1-33) alone. Consistent with the observed in vivo activities, our functional studies and binding data indicate that GLP-2 (3-33) acts as a partial agonist with potential competitive antagonistic properties on the GLP-2 receptor.

  7. Localized infusions of the partial alpha 7 nicotinic receptor agonist SSR180711 evoke rapid and transient increases in prefrontal glutamate release

    DEFF Research Database (Denmark)

    Bortz, D M; Mikkelsen, J D; Bruno, J P

    2013-01-01

    The ability of local infusions of the alpha 7 nicotinic acetycholine receptor (α7 nAChR) partial agonist SSR180711 to evoke glutamate release in prefrontal cortex was determined in awake rats using a microelectrode array. Infusions of SSR180711 produced dose-dependent increases in glutamate levels...

  8. Familial partial lipodystrophy phenotype resulting from a single-base mutation in deoxyribonucleic acid-binding domain of peroxisome proliferator-activated receptor-gamma

    NARCIS (Netherlands)

    Monajemi, Houshang; Zhang, Lin; Li, Gang; Jeninga, Ellen H.; Cao, Henian; Maas, Mario; Brouwer, C. B.; Kalkhoven, Eric; Stroes, Erik; Hegele, Robert A.; Leff, Todd

    2007-01-01

    CONTEXT: Familial partial lipodystrophy (FPLD) results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in PPARG, encoding peroxisome proliferator-activated receptor-gamma (PPARgamma). The LMNA form is called FPLD2 (MIM 151660) and the PPARG form is called FPLD3 (MIM

  9. Opioid receptors in midbrain dopaminergic regions of the rat. 1. Mu receptor autoradiography

    International Nuclear Information System (INIS)

    German, D.C.; Speciale, S.G.; Manaye, K.F.; Sadeq, M.

    1993-01-01

    Several lines of evidence indicate that an interaction exists between opioid peptides and midbrain dopaminergic neurons. The purpose of this study was to map and quantify the density of the mu opioid receptor subtype relative to the location of the dopaminergic (DA) neurons in the retrorubral field (nucleus A8), substantia nigra (nucleus A9), and ventral tegmental area and related nuclei (nucleus A10) in the rat. Sections through the rostral-caudal extent of the midbrain were stained with an antibody against tyrosine hydroxylase, as a DA cell marker, and comparable sections were processed for in vitro receptor autoradiography using the mu-selective ligand, 3 H-Tyr-D-Ala-N-MePhe-Gyl-ol enkephalin. In the nucleus A8 region, there were low levels of mu binding. In the rostral portion of nucleus A9, there was prominent mu binding both in the ventral pars compacta, which contains numerous DA neurons, and in regions that correspond to the location of the DA dendrites which project ventrally into the underlying substantia nigra pars reticulata. In the caudal portion of nucleus A9, mu binding was greatest in the substantia nigra pars reticulata, but also in the same region that contains DA neurons. In nucleus A10, mu receptor densities differed depending upon the nucleus A10 subdivision, and the rostral-caudal position in the nucleus. Low receptor densities were observed in rostral portions of the ventral tegmental area and interfascicular nucleus, and there was negligible binding in the parabrachial pigmented nucleus and paranigral nucleus at the level of the interpeduncular nucleus; all regions where there are high densities of DA somata. Mu binding was relatively high in the central linear nucleus, and in the dorsal and medial divisions of the medial terminal nucleus of the accessory optic system, which has been shown to contain DA dendrites. These data indicate that mu opioid receptors are located in certain regions occupied by all three midbrain DA nuclei, but in a

  10. Partial agonism at the α7 nicotinic acetylcholine receptor improves attention, impulsive action and vigilance in low attentive rats.

    Science.gov (United States)

    Hayward, Andrew; Adamson, Lisa; Neill, Joanna C

    2017-04-01

    Inattention is a disabling symptom in conditions such as schizophrenia and attention deficit/hyperactivity disorder. Nicotine can improve attention and vigilance, but is unsuitable for clinical use due to abuse liability. Genetic knockout of the α7 nicotinic acetylcholine receptor (nAChR) induces attention deficits therefore selective agonism may improve attention, without the abuse liability associated with nicotine. The α7 nAChR partial agonist encenicline (formerly EVP-6124) enhances memory in rodents and humans. Here we investigate, for the first time, efficacy of encenicline to improve attention and vigilance in animals behaviourally grouped for low attentive traits in the 5 choice-continuous performance task (5C-CPT). Female Lister Hooded rats were trained to perform the 5C-CPT with a variable stimulus duration (SD). Animals were then grouped based on performance into upper and lower quartiles of d' (vigilance) and accuracy (selective attention), producing high-attentive (HA) and low-attentive (LA) groups. LA animals showed an increase in selective attention and vigilance at 0.3mg/kg encenicline, a reduction in impulsive action (probability of false alarms) and increase in vigilance following 1mg/kg at 0.75sSD. At 1mg/kg, HA animals had reduced selective attention at 0.75sSD and reduced vigilance at 0.75 and 1.25sSD. Improvement of attention, vigilance and impulsive action in LA animals demonstrates that encenicline has pro-attentive properties dependent on baseline levels of performance. Our work suggests that α7 nAChR partial agonism may improve attention particularly in conditions with low attention. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  11. Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP.

    Directory of Open Access Journals (Sweden)

    Hua Bai

    Full Text Available Mutations of the insulin/IGF signaling (IIS pathway extend Drosophila lifespan. Based on genetic epistasis analyses, this longevity assurance is attributed to downstream effects of the FOXO transcription factor. However, as reported FOXO accounts for only a portion of the observed longevity benefit, suggesting there are additional outputs of IIS to mediate aging. One candidate is target of rapamycin complex 1 (TORC1. Reduced TORC1 activity is reported to slow aging, whereas reduced IIS is reported to repress TORC1 activity. The eukaryotic translation initiation factor 4E binding protein (4E-BP is repressed by TORC1, and activated 4E-BP is reported to increase Drosophila lifespan. Here we use genetic epistasis analyses to test whether longevity assurance mutants of chico, the Drosophila insulin receptor substrate homolog, require Drosophila d4eBP to slow aging. In chico heterozygotes, which are robustly long-lived, d4eBP is required but not sufficient to slow aging. Remarkably, d4eBP is not required or sufficient for chico homozygotes to extend longevity. Likewise, chico heterozygote females partially require d4eBP to preserve age-dependent locomotion, and both chico genotypes require d4eBP to improve stress-resistance. Reproduction and most measures of growth affected by either chico genotype are always independent of d4eBP. In females, chico heterozygotes paradoxically produce more rather than less phosphorylated 4E-BP (p4E-BP. Altered IRS function within the IIS pathway of Drosophila appears to have partial, conditional capacity to regulate aging through an unconventional interaction with 4E-BP.

  12. Satiety and the role of μ-opioid receptors in the portal vein.

    Science.gov (United States)

    De Vadder, Filipe; Gautier-Stein, Amandine; Mithieux, Gilles

    2013-12-01

    Mu-opioid receptors (MORs) are known to influence food intake at the brain level, through their involvement in the food reward system. MOR agonists stimulate food intake. On the other hand, MOR antagonists suppress food intake. MORs are also active in peripheral organs, especially in the small intestine where they control the gut motility. Recently, an indirect role in the control of food intake was ascribed to MORs in the extrinsic gastrointestinal neural system. MORs present in the neurons of the portal vein walls sense blood peptides released from the digestion of dietary protein. These peptides behave as MOR antagonists. Their MOR antagonist action initiates a gut-brain circuitry resulting in the induction of intestinal gluconeogenesis, a function controlling food intake. Thus, periportal MORs are a key mechanistic link in the satiety effect of protein-enriched diets. Copyright © 2013 Elsevier Ltd. All rights reserved.

  13. EVP-6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors.

    Science.gov (United States)

    Prickaerts, Jos; van Goethem, Nick P; Chesworth, Richard; Shapiro, Gideon; Boess, Frank G; Methfessel, Christoph; Reneerkens, Olga A H; Flood, Dorothy G; Hilt, Dana; Gawryl, Maria; Bertrand, Sonia; Bertrand, Daniel; König, Gerhard

    2012-02-01

    EVP-6124, (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, is a novel partial agonist of α7 neuronal nicotinic acetylcholine receptors (nAChRs) that was evaluated here in vitro and in vivo. In binding and functional experiments, EVP-6124 showed selectivity for α7 nAChRs and did not activate or inhibit heteromeric α4β2 nAChRs. EVP-6124 had good brain penetration and an adequate exposure time. EVP-6124 (0.3 mg/kg, p.o.) significantly restored memory function in scopolamine-treated rats (0.1 mg/kg, i.p.) in an object recognition task (ORT). Although donepezil at 0.1 mg/kg, p.o. or EVP-6124 at 0.03 mg/kg, p.o. did not improve memory in this task, co-administration of these sub-efficacious doses fully restored memory. In a natural forgetting test, an ORT with a 24 h retention time, EVP-6124 improved memory at 0.3 mg/kg, p.o. This improvement was blocked by the selective α7 nAChR antagonist methyllycaconitine (0.3 mg/kg, i.p. or 10 μg, i.c.v.). In co-application experiments of EVP-6124 with acetylcholine, sustained exposure to EVP-6124 in functional investigations in oocytes caused desensitization at concentrations greater than 3 nM, while lower concentrations (0.3-1 nM) caused an increase in the acetylcholine-evoked response. These actions were interpreted as representing a co-agonist activity of EVP-6124 with acetylcholine on α7 nAChRs. The concentrations of EVP-6124 that resulted in physiological potentiation were consistent with the free drug concentrations in brain that improved memory performance in the ORT. These data suggest that the selective partial agonist EVP-6124 improves memory performance by potentiating the acetylcholine response of α7 nAChRs and support new therapeutic strategies for the treatment of cognitive impairment. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

  14. VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.

    Science.gov (United States)

    Nickols, Hilary Highfield; Yuh, Joannes P; Gregory, Karen J; Morrison, Ryan D; Bates, Brittney S; Stauffer, Shaun R; Emmitte, Kyle A; Bubser, Michael; Peng, Weimin; Nedelcovych, Michael T; Thompson, Analisa; Lv, Xiaohui; Xiang, Zixiu; Daniels, J Scott; Niswender, Colleen M; Lindsley, Craig W; Jones, Carrie K; Conn, P Jeffrey

    2016-01-01

    Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [(3)H]inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy-efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models. Copyright © 2015 by The American Society for Pharmacology and

  15. Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI).

    Science.gov (United States)

    Dunbar, Geoffrey C; Inglis, Fraser; Kuchibhatla, Ramana; Sharma, Tonmoy; Tomlinson, Mark; Wamsley, James

    2007-03-01

    Cognitive decline seen in the normal elderly is associated with selective loss of neuronal nicotinic acetylcholine receptors (nAChRs). Nicotine given either by inhalation or transdermally helps cognition, but unacceptable side effects limit its utility. The present study assessed the safety, tolerability and effect on cognition of ispronicline, a highly selective partial agonist at the 4beta2 nAChR, in elderly subjects (n =76) with age associated memory impairment (AAMI). This double-blind, placebo-controlled cross-over study explored ascending oral doses of ispronicline in the range 50-150 mg given as a single morning dose for a period of 3 weeks. Pharmacokinetics (PK) were assessed, as well as cognitive function measured by means of the Cognitive Drug Research (CDR) computerized test battery. Ispronicline had a favourable safety profile and was well tolerated at doses below 150 mg. No effect of clinical importance was seen on biochemistry, haematology, urine analysis, vital signs, electrocardiogram (ECG) or Holter monitoring. The most frequent drug induced adverse event was light-headedness (dizziness). A beneficial effect was seen on cognition across the dose range. This was most marked at 50 mg on factors measuring attention and episodic memory. PK analysis indicated a plasma Cmax range of 5-25/35 ng/ml ispronicline was associated with the most beneficial effect. These early results demonstrate ispronicline was well tolerated and did not display the side effects typical of nicotine. Ispronicline also had a beneficial effect on cognition in subjects with AAMI. This was seen most strongly in a Cmax range that had been predicted from pre-clinical animal studies.

  16. Insight into partial agonism by observing multiple equilibria for ligand-bound and Gs-mimetic nanobody-bound β1-adrenergic receptor.

    Science.gov (United States)

    Solt, Andras S; Bostock, Mark J; Shrestha, Binesh; Kumar, Prashant; Warne, Tony; Tate, Christopher G; Nietlispach, Daniel

    2017-11-27

    A complex conformational energy landscape determines G-protein-coupled receptor (GPCR) signalling via intracellular binding partners (IBPs), e.g., G s and β-arrestin. Using 13 C methyl methionine NMR for the β 1 -adrenergic receptor, we identify ligand efficacy-dependent equilibria between an inactive and pre-active state and, in complex with G s -mimetic nanobody, between more and less active ternary complexes. Formation of a basal activity complex through ligand-free nanobody-receptor interaction reveals structural differences on the cytoplasmic receptor side compared to the full agonist-bound nanobody-coupled form, suggesting that ligand-induced variations in G-protein interaction underpin partial agonism. Significant differences in receptor dynamics are observed ranging from rigid nanobody-coupled states to extensive μs-to-ms timescale dynamics when bound to a full agonist. We suggest that the mobility of the full agonist-bound form primes the GPCR to couple to IBPs. On formation of the ternary complex, ligand efficacy determines the quality of the interaction between the rigidified receptor and an IBP and consequently the signalling level.

  17. The effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear.

    Science.gov (United States)

    Handford, Charlotte E; Tan, Shawn; Lawrence, Andrew J; Kim, Jee Hyun

    2014-09-01

    The metabotropic glutamate receptor 5 (mGlu5) and N-methyl-D-aspartate (NMDA) receptor are critical for processes underlying synaptic plasticity, such as long-term potentiation. mGlu5 signaling increases neuronal excitability and potentiates NMDA receptor currents in the amygdala and the hippocampus. The present study examined the involvement of mGlu5 in the acquisition and consolidation of conditioned fear to a tone and context in mice, and explored the functional relationship between mGlu5 and NMDA receptors in this regard. Experiment 1 showed that systemic administration of the mGlu5 negative allosteric modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) prior to conditioning significantly attenuated cue-elicited freezing during fear conditioning, which suggests that mGlu5 is necessary for the formation of a tone-shock association. This effect was dose-related (Experiment 2) and not due to any effects of MTEP on shock sensitivity or state-dependency (Experiment 3). Post-conditioning injection of MTEP had no effects (Experiment 4). Although post-conditioning injection of the NMDA receptor partial agonist D-cycloserine (DCS) alone facilitated consolidation of conditioned fear (Experiment 6), it was not able to rescue the acquisition deficit caused by MTEP (Experiment 5). Taken together, these findings indicate a crucial role for mGlu5 signaling in acquisition and NMDA receptor signaling in consolidation of conditioned fear.

  18. Effect of partial volume correction on muscarinic cholinergic receptor imaging with single-photon emission tomography in patients with temporal lobe epilepsy

    International Nuclear Information System (INIS)

    Weckesser, M.; Ziemons, K.; Griessmeier, M.; Sonnenberg, F.; Langen, K.J.; Mueller-Gaertner, H.W.; Hufnagel, A.; Elger, C.E.; Hacklaender, T.; Holschbach, M.

    1997-01-01

    Animal experiments and preliminary results in humans have indicated alterations of hippocampal muscarinic acetylcholine receptors (mAChR) in temporal lobe epilepsy. Patients with temporal lobe epilepsy often present with a reduction in hippocampal volume. The aim of this study was to investigate the influence of hippocampal atrophy on the quantification of mAChR with single photon emission tomography (SPET) in patients with temporal lobe epilepsy. Cerebral uptake of the muscarinic cholinergic antagonist [ 123 I]4-iododexetimide (IDex) was investigated by SPET in patients suffering from temporal lobe epilepsy of unilateral (n=6) or predominantly unilateral (n=1) onset. Regions of interest were drawn on co-registered magnetic resonance images. Hippocampal volume was determined in these regions and was used to correct the SPET results for partial volume effects. A ratio of hippocampal IDex binding on the affected side to that on the unaffected side was used to detect changes in muscarinic cholinergic receptor density. Before partial volume correction a decrease in hippocampal IDex binding on the focus side was found in each patient. After partial volume no convincing differences remained. Our results indicate that the reduction in hippocampal IDex binding in patients with epilepsy is due to a decrease in hippocampal volume rather than to a decrease in receptor concentration. (orig.). With 2 figs., 2 tabs

  19. 5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function.

    Science.gov (United States)

    Wang, Xin; Dergacheva, Olga; Kamendi, Harriet; Gorini, Christopher; Mendelowitz, David

    2007-08-01

    Opioids evoke respiratory depression, bradycardia, and reduced respiratory sinus arrhythmia, whereas serotonin (5-HT) agonists stimulate respiration and cardiorespiratory interactions. This study tested whether serotonin agonists can prevent the inhibitory effects of opioids on cardiorespiratory function. Spontaneous and rhythmic inspiratory-related activity and gamma-aminobutyric acid (GABA) neurotransmission to premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus were recorded simultaneously in an in vitro thick slice preparation. The mu-opioid agonist fentanyl inhibited respiratory frequency. The 5-hydroxytryptamine 1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin increased respiratory frequency by itself and also prevented the fentanyl-induced respiratory depression. The 5-hydroxytryptamine 4alpha agonist BIMU-8 did not by itself change inspiratory activity but prevented the mu-opioid-mediated respiratory depression. Both spontaneous and inspiratory-evoked GABAergic neurotransmission to cardiac vagal neurons were inhibited by fentanyl. 8-Hydroxy-2-(di-n-propylamino)tetralin inhibited spontaneous but not inspiratory-evoked GABAergic activity to parasympathetic cardiac neurons. However, 8-hydroxy-2-(di-n-propylamino)tetralin differentially altered the opioid-mediated depression of inspiratory-evoked GABAergic activity but did not change the opioid-induced reduction in spontaneous GABAergic neurotransmission. In contrast, BIMU-8 did not alter GABAergic neurotransmission to cardiac vagal neurons by itself but prevented the fentanyl depression of both spontaneous and inspiratory-elicited GABAergic neurotransmission to cardiac vagal neurons. In the presence of tetrodotoxin, the inhibition of GABAergic inhibitory postsynaptic currents with fentanyl is prevented by coapplication of BIMU-8, indicating that BIMU-8 acts at presynaptic GABAergic terminals to prevent fentanyl-induced depression. These results suggest that activation of 5

  20. Dopamine D4 Receptor Counteracts Morphine-Induced Changes in µ Opioid Receptor Signaling in the Striosomes of the Rat Caudate Putamen

    Directory of Open Access Journals (Sweden)

    Diana Suárez-Boomgaard

    2014-01-01

    Full Text Available The mu opioid receptor (MOR is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [35S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D4 receptor (D4R agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to Gi/0 protein, the present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine.

  1. The effect of partial agonist of serotonin-1A receptor on cognitive functions in animal model of schizophrenia

    OpenAIRE

    Antošová, Eliška

    2011-01-01

    Serotoin is a neurotransmitter participating in regulation of many physiologic fuctions. Main serotogenous neurons can be found in nukleus raphe of the brain stem. Nucleus raphe inervates many areas of the brain including the cerebal cortex and hipocampus. These structures are important for controling of higher cognitive functions. 5HT1A receptor is one of many subtypes of serotonin receptors and its activation inhibits iniciating of the action potencials. 5HT1A receptor is expressed presynap...

  2. PET and SPECT in medically non-refractory complex partial seizures. Temporal asymmetries of glucose consumption, Benzodiazepine receptor density

    International Nuclear Information System (INIS)

    Matheja, P.; Kuwert, T.; Wolf, K.; Schober, O.; Stodieck, S.R.G.; Diehl, B.; Ringelstein, E.B.; Schuierer, G.

    1998-01-01

    Aim: In contrast to medically refractory complex partial seizures (CPS), only limited knowledge exists on cerebral perfusion and metabolism in medically non-refractory CPS. The aim of this study was to investigate the frequency of temporal asymmetries in regional cerebral glucose consumption (rCMRGlc), regional cerebral blood flow (rCBF), and regional cerebral benzodiazepine receptor density (BRD) in this group of patients. Methods: The study included 49 patients with medically non-refractory cryptogenic CPS (age: 36.0±16.1 years). rCMRGlc was studied with F-18-FDG-PET (FDG), rCBF with Tc-99m-ECD-SPECT (ECD), and BRD with I-123-iomazenil-SPECT (IMZ). All studies were performed interictally and within four weeks in each patient. Duration of epilepsy ranged from 0.1 to 42 years (median 4.0 years). SPECT was performed with the triple-headed SPECT camera Multispect 3, PET with the PET camera ECAT EXACT 47. Using linear profiles, glucose consumption, as well as uptake of ECD and IMZ, were measured in four temporal regions of interest (ROIs), and asymmetry indices were calculated (ASY). The results were compared to 95% confidence intervals determined in control subjects. Results: Thirty-five of the 49 (71%) patients had at least one significantly elevated ASY; temporal rCMRGlc was asymmetrical in 41% of the patients, temporal BRD in 29%, and temporal rCBF in 24%. One patient had an asymmetry of all three variables, two of temporal rCMRGlc and BRD, three of temporal rCMRGlc and rCBF, and another four of rCBF and BRD. Fourteen patients had an isolated temporal asymmetry in rCMRGlc, seven in BRD, and four in rCBF. A discrepancy in lateralization between the three modalities was not observed. Conclusion: The majority of patients with medically non-refractory CPS have focal abnormalities of blood flow and metabolism in their temporal lobe. In this group of patients, FDG-PET demonstrates abnormalities with the highest frequency of the three modalities studied, followed by IMZ

  3. GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity

    Directory of Open Access Journals (Sweden)

    Allison Doyle Brackley

    2016-09-01

    Full Text Available Opioids remain the standard for analgesic care; however, adverse effects of systemic treatments contraindicate long-term administration. While most clinical opioids target mu opioid receptors (MOR, those that target the delta class (DOR also demonstrate analgesic efficacy. Furthermore, peripherally restrictive opioids represent an attractive direction for analgesia. However, opioid receptors including DOR are analgesically incompetent in the absence of inflammation. Here, we report that G protein-coupled receptor kinase 2 (GRK2 naively associates with plasma membrane DOR in peripheral sensory neurons to inhibit analgesic agonist efficacy. This interaction prevents optimal Gβ subunit association with the receptor, thereby reducing DOR activity. Importantly, bradykinin stimulates GRK2 movement away from DOR and onto Raf kinase inhibitory protein (RKIP. protein kinase C (PKC-dependent RKIP phosphorylation induces GRK2 sequestration, restoring DOR functionality in sensory neurons. Together, these results expand the known function of GRK2, identifying a non-internalizing role to maintain peripheral DOR in an analgesically incompetent state.

  4. Naloxone-sensitive, haloperidol-sensitive, [3H](+)SKF-10047-binding protein partially purified from rat liver and rat brain membranes: an opioid/sigma receptor?

    Science.gov (United States)

    Tsao, L I; Su, T P

    1997-02-01

    A naloxone-sensitive, haloperidol-sensitive, [3H](+)SKF-10047-binding protein was partially purified from rat liver and rat brain membranes in an affinity chromatography originally designed to purify sigma receptors. Detergent-solubilized extracts from membranes were adsorbed to Sephadex G-25 resin containing an affinity ligand for sigma receptors: N-(2- 3,4-dichlorophenyl]ethyl)-N-(6-aminohexyl)-(2-[1-pyrrolidinyl]) ethylamine (DAPE). After eluting the resin with haloperidol, a protein that bound [3H](+)SKF-10047 was detected in the eluates. However, the protein was not the sigma receptor. [3H](+)SKF-10047 binding to the protein was inhibited by the following compounds in the order of decreasing potency: (+)pentazocine > (-) pentazocine > (+/-)cyclazocine > (-)morphine > (-)naloxone > haloperidol > (+)SKF-10047 > DADLE > (-)SKF-10047. Further, the prototypic sigma receptor ligands, such as 1,3-di-o-tolylguanidine (DTG), (+)3-PPP, and progesterone, bound poorly to the protein. Tryptic digestion and heat treatment of the affinity-purified protein abolished radioligand binding. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE) of the partially-purified protein from the liver revealed a major diffuse band with a molecular mass of 31 kDa, a polypeptide of 65 kDa, and another polypeptide of > 97 kDa. This study demonstrates the existence of a novel protein in the rat liver and rat brain which binds opioids, benzomorphans, and haloperidol with namomolar affinity. The protein resembles the opioid/sigma receptor originally proposed by Martin et al. [(1976): J. Pharmacol. Exp. Ther., 197:517-532.]. A high degree of purification of this protein has been achieved in the present study.

  5. A phase 2a multicenter, double-blind, placebo-controlled, crossover trial to investigate the efficacy, safety, and toleration of CP-866,087 (a high-affinity mu-opioid receptor antagonist) in premenopausal women diagnosed with female sexual arousal disorder (FSAD)

    DEFF Research Database (Denmark)

    Orri, Miguel; Abraham, Lucy; Giraldi, Annamaria

    2013-01-01

    Female sexual arousal disorder (FSAD) is a condition that can affect women of all ages and have a significant negative impact on emotional well-being.......Female sexual arousal disorder (FSAD) is a condition that can affect women of all ages and have a significant negative impact on emotional well-being....

  6. Revealing vilazodone's binding mechanism underlying its partial agonism to the 5-HT1A receptor in the treatment of major depressive disorder.

    Science.gov (United States)

    Zheng, Guoxun; Xue, Weiwei; Yang, Fengyuan; Zhang, Yang; Chen, Yuzong; Yao, Xiaojun; Zhu, Feng

    2017-11-01

    It has been estimated that major depressive disorder (MDD) will become the second largest global burden among all diseases by 2030. Various types of drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and serotonin receptor partial agonist/reuptake inhibitors (SPARIs), have been approved and become the primary or first-line medications prescribed for MDD. SPARI was expected to demonstrate more enhanced drug efficacy and a rapid onset of action as compared to SSRI and SNRI. As one of the most famous SPARIs, vilazodone was approved by the FDA for the treatment of MDD. Because of the great clinical importance of vilazodone, its binding mechanism underlying its partial agonism to the 5-HT 1A receptor (5-HT 1A R) could provide valuable information to SPARIs' drug-like properties. However, this mechanism has not been reported to date; consequently, the rational design of new efficacious SPARI-based MDD drugs is severely hampered. To explore the molecular mechanism of vilazodone, an integrated computational strategy was adopted in this study to reveal its binding mechanism and prospective structural feature at the agonist binding site of 5-HT 1A R. As a result, 22 residues of this receptor were identified as hotspots, consistently favoring the binding of vilazodone and its analogues, and a common binding mechanism underlying their partial agonism to 5-HT 1A R was, therefore, discovered. Moreover, three main interaction features between vilazodone and 5-HT 1A R have been revealed and schematically summarized. In summary, this newly identified binding mechanism will provide valuable information for medicinal chemists working in the field of rational design of novel SPARIs for MDD treatment.

  7. Synthesis of iodine-123 labelled analogues of the partial agonist (S)-and (R)-bretazenil for the study of CNS benzodiazepine receptors using SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Katsifis, Andrew; Mattner, Filomena; McPhee, Meredith; Kassiou, Michael; Najdovski, Ljubco; Dikic, Branko [Australian Nuclear Science and Technology Organisation, Radiopharmaceutical Div., Menai, Sydney, NSW (Australia)

    1996-09-01

    The (S) and (R)-[{sup 123}I]iodinated analogues of the benzodiazepine receptor partial agonist bretazenil have been synthesized for study of the central benzodiazepine receptor using SPECT, (S)- and (R)-[{sup 123}I]iodobretazenil were prepared from the appropriate tin precursors by electrophilic iododestannylation with Na[{sup 123}I] in the presence of Chloramine-T. The products were purified by semi-preparative reverse-phase HPLC with radiochemical yields of 80% in a total synthesis time of 50 minutes. The specific activity was determined to be greater than 2500 Ci/mmol. The radiochemical and chemical purity assessed by radio-TLC and HPLC were found to be 98%. The enantiomeric purity of the (S) and (R) isomers were greater than 97% as assessed by analytical chiral HPLC analysis. (author).

  8. Oxygen partial pressure modulates 67-kDa laminin receptor expression, leading to altered activity of the green tea polyphenol, EGCG.

    Science.gov (United States)

    Tsukamoto, Shuntaro; Yamashita, Shuya; Kim, Yoon Hee; Kumazoe, Motofumi; Huang, Yuhui; Yamada, Koji; Tachibana, Hirofumi

    2012-09-21

    (-)-Epigallocatechin-3-O-gallate (EGCG) exhibits anti-tumor activity mediated via the 67-kDa laminin receptor (67LR). In this study, we found that 67LR protein levels are reduced by exposure to low O(2) levels (5%), without affecting the expression of HIF-1α. We also found that EGCG-induced anti-cancer activity is abrogated under low O(2) levels (5%) in various cancer cells. Notably, treatment with the proteasome inhibitor, prevented down-regulation of 67LR and restored sensitivity to EGCG under 5% O(2). In summary, 67LR expression is highly sensitive to O(2) partial pressure, and the activity of EGCG can be regulated in cancer cells by O(2) partial pressure. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  9. Reduced GABA{sub A} receptor density contralateral to a potentially epileptogenic MRI abnormality in a patient with complex partial seizures

    Energy Technology Data Exchange (ETDEWEB)

    Kuwert, T. [Dept. of Nuclear Medicine, Muenster Univ. (Germany); Stodieck, S.R.G. [Dept. of Neurology, Muenster Univ. (Germany); Puskas, C. [Dept. of Nuclear Medicine, Muenster Univ. (Germany); Diehl, B. [Dept. of Neurology, Muenster Univ. (Germany); Puskas, Z. [Inst. of Clinical Radiology, Muenster Univ. (Germany); Schuierer, G. [Inst. of Clinical Radiology, Muenster Univ. (Germany); Vollet, B. [Dept. of Nuclear Medicine, Muenster Univ. (Germany); Schober, O. [Dept. of Nuclear Medicine, Muenster Univ. (Germany)

    1996-01-01

    Imaging cerebral GABA{sub A} receptor density (GRD) with single-photon emission tomography (SPET) and iodine-123 iomazenil is highly accurate in lateralizing epileptogenic foci in patients with complex partial seizures of temporal origin. Limited knowledge exists on how iomazenil SPET compares with magnetic resonance imaging (MRI) in this regard. We present a patient with complex partial seizures in whom MRI had identified an arachnoid cyst anterior to the tip of the left temporal lobe. Contralaterally to this structural abnormality, interictal electroencephalography (EEG) performed after sleep deprivation disclosed an intermittent frontotemporal dysrhythmic focus with slow and sharp waves. On iomazenil SPET images GRD was significantly reduced in the right temporal lobe and thus contralaterally to the MRI abnormality, but ipsilaterally to the pathological EEG findings. These data suggest that iomazenil SPET may significantly contribute to the presurgical evaluation of epileptic patients even when MRI identifies potentialy epileptogenic structural lesions. (orig.)

  10. Affinity purification and partial characterization of the zonulin/zonula occludens toxin (Zot) receptor from human brain.

    Science.gov (United States)

    Lu, R; Wang, W; Uzzau, S; Vigorito, R; Zielke, H R; Fasano, A

    2000-01-01

    The intercellular tight junctions (TJs) of endothelial cells represent the limiting structure for the permeability of the blood-brain barrier (BBB). Although the BBB has been recognized as being the interface between the bloodstream and the brain, little is known about its regulation. Zonulin and its prokaryotic analogue, zonula occludens toxin (Zot) elaborated by Vibrio cholerae, both modulate intercellular TJs by binding to a specific surface receptor with subsequent activation of an intracellular signaling pathway involving phospholipase C and protein kinase C activation and actin polymerization. Affinity column purification revealed that human brain plasma membrane preparations contain two Zot binding proteins of approximately 55 and approximately 45 kDa. Structural and kinetic studies, including saturation and competitive assays, identified the 55-kDa protein as tubulin, whereas the 45-kDa protein represents the zonulin/Zot receptor. Biochemical characterization provided evidence that this receptor is a glycoprotein containing multiple sialic acid residues. Comparison of the N-terminal sequence of the zonulin/Zot receptor with other protein sequences by BLAST analysis revealed a striking similarity with MRP-8, a 14-kDa member of the S-100 family of calcium binding proteins. The discovery and characterization of this receptor from human brain may significantly contribute to our knowledge on the pathophysiological regulation of the BBB.

  11. An investigation into the receptor-regulating effects of the acute administration of opioid agonists and an antagonist on beta adrenergic receptors in the rat cerebral cortex

    International Nuclear Information System (INIS)

    Roper, I.

    1987-01-01

    Past and current research indicated that biochemical deviations which might be involved in the etiology and pathophysiology of depression, included abnormalities or imbalances in the noradrenergic, serotonergic, hormonal and possibly in the endogenous opioid, dopaminergic, histaminergic, cholinergic and trace amine systems. In order to investigate a possible link between the noradrenergic system and opioids, it was decided to test the acute effects of opioid administration on cortical beta adrenoceptor numbers and affinity. As these receptors have been most consistently downregulated by antidepressant treatment, they may be involved in the mechanism of antidepressant action of these agents. It was decided to investigate beta adrenoceptor-regulatory effects of opioid treatment. Naloxone was tested alone, with a view to suppressing any possible endogenous opioid influences upon beta receptor status and revealing an effect which would possibly be the opposite of that brought about by the administration of opioid agonists. Naloxone was administered together with morphine to demonstrate that any beta receptor up- or downregulation which might be measured, had indeed been opioid-receptor mediated. It was found that the acute administration of four different mu opioid agonists, naloxone and naloxone plus morphine, did not cause any statistically significant alterations in cortical beta adrenergic receptor numbers or affinity in the rat. A radioactive ligand, the beta adrenoceptor-labelling compound referred to as DHA (L-dihydroalprenolol HCI) was used in this study

  12. Identification, purification and partial characterisation of an oligonucleotide receptor in membranes of HepG2 cells

    OpenAIRE

    Diesbach, Philippe de; Berens, Catherine; N’Kuli, Francisca; Monsigny, Michel; Sonveaux, Etienne; Wattiez, Ruddy; Courtoy, Pierre J.

    2000-01-01

    The low and unpredictable uptake and cytosolic transfer of oligonucleotides (ODN) is a major reason for their limited benefit. Improving the ODN potential for therapy and research requires a better understanding of their receptor-mediated endocytosis. We have undertaken to identify a membrane ODN receptor on HepG2 cells by ligand blotting of cell extracts with [(125)I]ODN and by photolabelling of living cells with a [(125)I]ODN-benzophenone conjugate. A major band at 66 kDa was identified by ...

  13. Molecular docking study of Papaver alkaloids to some alkaloid receptors

    Directory of Open Access Journals (Sweden)

    A. Nofallah

    2017-11-01

    Full Text Available Background and objectives: More than 40 different alkaloids have been obtained from opium the most important of which are morphine, codeine, papaverine, noscapine and tabaine. Opioid alkaloids produce analgesia by affecting areas of the brain that have peptides with pharmacological pseudo-opioid properties. These alkaloids show important effects on some intracellular peptides like mu, delta, and kappa receptors. Therefore, studying the effects of these alkaloids on different receptors is essential. Methods: Molecular docking is a well-known method in exploring the protein-ligand interactions. In this research, five important alkaloids were docked to crystal structure of human mu opioid receptor (4DKL, human delta opioid receptor (4EJ4 and human kappa opioid receptor (4DJH which were retrieved from protein databank. The 3D-structures of alkaloids were drawn by chembiooffice2010 and minimized with hyperchem package and submitted to molecular docking utilizing autodock-vina. Flexibility of the proteins was considered. The docking studies were performed to compare the affinity of these five alkaloids to the mentioned receptors. Results: We computationally docked each alkaloid compound onto each receptor structure and estimated their binding affinity based on dock scores. Dock score is a criteria including binding energy which utilized here for prediction and comparison of the binding affinities. Binding interactions of the docked alkaloids in receptor pockets were also visually inspected and compared. Conclusion: In this approach, using docking study as a computational method provided a valuable insight of opioid receptor pocket structures which would be essential to design more efficient drugs in pain managements and addiction treatments.

  14. Effect of tandospirone, a serotonin-1A receptor partial agonist, on information processing and locomotion in dizocilpine-treated rats

    Czech Academy of Sciences Publication Activity Database

    Bubeníková-Valešová, V.; Svoboda, Jan; Horáček, J.; Sumiyoshi, T.

    2010-01-01

    Roč. 212, č. 2 (2010), s. 267-276 ISSN 0033-3158 R&D Projects: GA MŠk(CZ) 1M0517 Institutional research plan: CEZ:AV0Z50110509 Keywords : Tandospirone * Schizophrenia * NMDA receptor Subject RIV: FH - Neurology Impact factor: 3.817, year: 2010

  15. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists

    NARCIS (Netherlands)

    Liberato, Marcelo Vizoná; Nascimento, Alessandro S; Ayers, Steven D; Lin, Jean Z; Cvoro, Aleksandra; Silveira, Rodrigo L; Martínez, Leandro; Souza, Paulo C T; Saidemberg, Daniel; Deng, Tuo; Amato, Angela Angelica; Togashi, Marie; Hsueh, Willa A; Phillips, Kevin; Palma, Mário Sérgio; Neves, Francisco A R; Skaf, Munir S; Webb, Paul; Polikarpov, Igor

    2012-01-01

    Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of

  16. Overexpression of mineralocorticoid receptors partially prevents chronic stress-induced reductions in hippocampal memory and structural plasticity

    NARCIS (Netherlands)

    Kanatsou, Sofia; Fearey, Brenna C.; Kuil, Laura E.; Lucassen, Paul J.; Harris, Anjanette P.; Seckl, Jonathan R.; Krugers, Harm; Joels, Marian

    2015-01-01

    Exposure to chronic stress is a risk factor for cognitive decline and psychopathology in genetically predisposed individuals. Preliminary evidence in humans suggests that mineralocorticoid receptors (MRs) may confer resilience to these stress-related changes. We specifically tested this idea using a

  17. Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI-101 in awake rats

    DEFF Research Database (Denmark)

    Palner, Mikael; Underwood, Mark D; Kumar, Dileep J S

    2011-01-01

    [³H]CUMI-101 is a 5-HT(1A) partial agonist, which has been evaluated for use as a positron emission tracer in baboon and humans. We sought to evaluate the properties of [³H]CUMI-101 ex vivo in awake rats and determine if [³H]CUMI-101 can measure changes in synaptic levels of serotonin after diffe...

  18. Defining the minimal structural requirements for partial agonism at the type I myo-inositol 1,4,5-trisphosphate receptor.

    Science.gov (United States)

    Wilcox, R A; Fauq, A; Kozikowski, A P; Nahorski, S R

    1997-02-03

    The novel synthetic analogues D-3-fluoro-myo-inositol 1,5-bisphosphate-4-phosphorothioate, [3F-Ins(1,5)P2-4PS], D-3-fluoro-myo-inositol 1,4-bisphosphate-5-phosphorothioate [3F-Ins(1,4)P2-5PS], and D-3-fluoro-myo-inositol 1-phosphate-4,5-bisphosphorothioate [3F-Ins(1)P-(4,5)PS2] were utilised to define the structure-activity relationships which could produce partial agonism at the Ca2+ mobilising myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor. Based on prior structure-activity data we hypothesised that the minimal structural requirements for lns(1,4,5)P3 receptor partial agonism, were phosphorothioate substitution of the crucial vicinal 4,5-bisphosphate pair accompanied by another structural perturbation, such fluorination of 3-position of the myo-inositol ring. All the analogues fully displaced [3H]Ins(1,4,5)P3 from a single Ins(1,4,5)P3 binding site in pig cerebellar membranes [3F-Ins(1,5)P2-4PS (1C50 = 26 nM), 3F-Ins(1,4)P2-5PS (IC50 = 80 nM) and 3F-Ins(1)P-(4,5)PS2 (IC50 = 109 nM) cf. Ins(1,4,5)P3 (IC50 = 11 nM)]. In contrast, 3F-Ins(1,5)P2-4PS (IC50 = 424 nM) and 3F-Ins(1,4)P2-5PS (IC50 = 3579 nM) were weak full agonists at the Ca2+ mobilising Ins(1,4,5)P3 receptor of permeabilised SH-SY5Y neuroblastoma cells, being respectively 4- and 36-fold less potent than Ins(1,4,5)P3 (EC50 = 99 nM). While 3F-Ins(1)P-(4,5)PS2 (EC50 = 11345 nM) was a partial agonist releasing only 64.3 +/- 1.9% of the Ins(1,4,5)P3-sensitive intracellular Ca2+ pools. 3F-Ins(1)P-(4,5)PS2 was unique among the Ins(1,4,5)P3 receptor partial agonists so far identified in having a relatively high affinity for the Ins(1,4,5)P3 binding site, accompanied by a significant loss of intrinsic activity for Ca2+ mobilisation. This improved affinity was probably due to the retention of the 1-position phosphate, which enhances interaction with the Ins-(1,4,5)P3 receptor. 3F-Ins(1)P-(4,5)PS2 may be an important lead compound for the development of efficient Ins(1,4,5)P3 receptor antagonists.

  19. Species-specific action of (Pro3)GIP - an efficacious agonist on human GIP receptor, but partial agonist and competitive antagonist on rat and mouse GIP receptors

    DEFF Research Database (Denmark)

    Sparre-Ulrich, A H; Hansen, Lærke Smidt; Svendsen, B

    2016-01-01

    effect in murine studies. We conducted a pharmacological analysis of this ligand including interspecies differences between the rodent and human GIP system. EXPERIMENTAL APPROACH: Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation and assayed in competition...... level. Thus, in rodent models human GIP is a comparatively weak partial agonist. Human (Pro3)GIP is not an effective antagonist, so there is still a need for an effective antagonist for the elucidation of GIP's physiology....

  20. Functional characteristics of the naked mole rat μ-opioid receptor.

    Directory of Open Access Journals (Sweden)

    Melanie Busch-Dienstfertig

    Full Text Available While humans and most animals respond to µ-opioid receptor (MOR agonists with analgesia and decreased aggression, in the naked mole rat (NMR opioids induce hyperalgesia and severe aggression. Single nucleotide polymorphisms in the human mu-opioid receptor gene (OPRM1 can underlie altered behavioral responses to opioids. Therefore, we hypothesized that the primary structure of the NMR MOR may differ from other species. Sequencing of the NMR oprm1 revealed strong homology to other mammals, but exposed three unique amino acids that might affect receptor-ligand interactions. The NMR and rat oprm1 sequences were cloned into mammalian expression vectors and transfected into HEK293 cells. Radioligand binding and 3'-5'-cyclic adenosine monophosphate (cAMP enzyme immunoassays were used to compare opioid binding and opioid-mediated cAMP inhibition. At normalized opioid receptor protein levels we detected significantly lower [3H]DAMGO binding to NMR compared to rat MOR, but no significant difference in DAMGO-induced cAMP inhibition. Strong DAMGO-induced MOR internalization was detectable using radioligand binding and confocal imaging in HEK293 cells expressing rat or NMR receptor, while morphine showed weak or no effects. In summary, we found minor functional differences between rat and NMR MOR suggesting that other differences e.g. in anatomical distribution of MOR underlie the NMR's extreme reaction to opioids.

  1. Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior.

    Science.gov (United States)

    Thompson, Barbara L; Levitt, Pat

    2015-01-01

    Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity.

  2. Down-regulation of NR2B receptors partially contributes to analgesic effects of Gentiopicroside in persistent inflammatory pain.

    Science.gov (United States)

    Chen, Lei; Liu, Jin-cheng; Zhang, Xiao-nan; Guo, Yan-yan; Xu, Zhao-hui; Cao, Wei; Sun, Xiao-li; Sun, Wen-ji; Zhao, Ming-Gao

    2008-06-01

    Gentiopicroside is one of the secoiridoid compound isolated from Gentiana lutea. It exhibits analgesic activities in the mice. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission and induce glutamate NMDA NR2B receptor expression in the ACC. But little is known about Gentiopicroside on the persistent inflammatory pain and chronic pain-induced synaptic transmission changes in the ACC. The present study was undertaken to investigate its analgesic activities and central synaptic modulation to the peripheral painful inflammation. Gentiopicroside produced significant analgesic effects against persistent inflammatory pain stimuli in mice. Systemic administration of Gentiopicroside significantly reversed NR2B over-expression during the chronic phases of persistent inflammation caused by hind-paw administration of complete Freunds adjuvant (CFA) in mice. Whole-cell patch clamp recordings revealed that Gentiopicroside significantly reduced NR2B receptors mediated postsynaptic currents in the ACC. Our findings provide strong evidence that analgesic effects of Gentiopicroside involve down-regulation of NR2B receptors in the ACC to persistent inflammatory pain.

  3. Partial purification and identification of the thrombozane A2/prostaglandin H2 receptor protein in human platelets

    International Nuclear Information System (INIS)

    Lim, C.T.; Kattelman, E.J.; Arora, S.K.; Venton, D.L.; Le Breton, G.C.

    1986-01-01

    The thromboxane A 2 /prostaglandin H 2 (TXA 2 /PGH 2 ) receptor antagonist [ 3 H]-13-azaprostanoic acid (13-APA) was used to identify and purify the platelet TXA 2 /PGH 2 receptor protein. Optimal solubilization of the 13-APA binding protein was achieved by extraction with 3-[(3-cholamidopropyl)dimethyl-ammonio]-1-propanesulfonate (CHAPS) detergent. Preliminary purification of the crude solubilized membrane fraction was performed by gel filtration chromatography using a Sepharose 4B column. Further purification was accomplished by high performance liquid chromatography (HPLC) using a Synchropak GPC-500 column. The HPLC protein profile revealed two protein peaks, only one of which was enriched in [ 3 H]-13-APA. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of this peak revealed two bands with molecular weights of 65,000 and 60,000 daltons. In binding studies using the 60,000 dalton-enriched subfraction, unlabelled 13-APA, the TXA 2 /PGH 2 mimetic U46619 and the TXA 2 /PGH 2 antagonist SQ 29,548 all competed for [ 3 H]-13-APA binding whereas TXB 2 did not compete for binding. Heat denaturation of this subfraction resulted in a complete loss of binding activity. These findings indicate that a protein of approximately 60,000 daltons represents the human platelet TXA 2 /PGH 2 receptor

  4. Anti-Muellerian hormone, inhibin A, gonadotropins, and gonadotropin receptors in bull calves after partial scrotal resection, orchidectomy, and Burdizzo castration.

    Science.gov (United States)

    Scarlet, Dragos; Aurich, Christine; Ille, Natascha; Walter, Ingrid; Weber, Corinna; Pieler, Dagmar; Peinhopf, Walter; Wohlsein, Peter; Aurich, Jörg

    2017-01-01

    Eight-week-old calves were either castrated by partial scrotal resection (SR) without removing the testes (n = 10), Burdizzo (BZ) clamp (n = 10), orchidectomy (OR; n = 10), or were left gonad intact as controls (CO; n = 10). Concentrations of anti-Muellerian hormone (AMH), inhibin A, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in plasma were determined from 16 to 48 weeks of age. At 18 months, testes of SR, BZ, and CO bulls were obtained and the immunolocalization of LH and FSH receptors and AMH analyzed. Concentration of AMH in plasma of CO and SR bulls decreased with increasing age (P < 0.001). A similar AMH profile in CO and SR indicates that SR did not induce a true cryptorchid state. In groups OR and BZ, AMH was undetectable. Plasma inhibin concentration was higher in groups CO and SR than BZ and OR (P < 0.001). Plasma LH and FSH concentrations decreased over time (P < 0.001) and were higher in groups BZ and OR than SR and CO (P < 0.001). In the testes, immunolabeling for AMH existed in Sertoli cells of CO and SR but not BZ bulls. FSH receptors were localized in Sertoli cells, Leydig cells, spermatocytes, and the epididymis of CO and SR animals, whereas LH receptors were restricted to Leydig cells. In BZ animals, FSH and LH receptors and AMH were absent, indicating complete testicular degeneration. In conclusion, AMH is a more reliable marker for the presence of testicular tissue in bulls than inhibin. Scrotal resection did not induce a true inguinal cryptorchid state but affected testicular responsiveness to gonadotropic stimulation. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Endosulfine, endogenous ligand for the sulphonylurea receptor: isolation from porcine brain and partial structural determination of the alpha form.

    Science.gov (United States)

    Virsolvy-Vergine, A; Salazar, G; Sillard, R; Denoroy, L; Mutt, V; Bataille, D

    1996-02-01

    Anti-diabetic sulphonylureas act via high affinity binding sites coupled to K-ATP channels. Endosulfine, an endogenous ligand for these binding sites, was shown to exist in two molecular forms, alpha and beta, in both the pancreas and the central nervous system. We describe here the isolation, and partial structural characterization of alpha endosulfine derived from porcine brains by means of a series of chromatography runs and gel electrophoresis. Porcine alpha endosulfine is a protein with a molecular mass of 13,196 daltons as determined by mass spectrometry and which is N-terminally blocked. Tryptic digestion followed by separation of the fragments by HPLC and automated Edman degradation yielded a total of 72 amino acids in four partial sequences. Comparison of these sequences with that present in the National Biomedical Research Foundation protein data bank indicated a 82% identity with a 112-amino acid protein with a molecular mass of 12,353 daltons called "cyclic AMP-regulated phosphoprotein-19', isolated from the bovine brain as a substrate for protein kinase A.

  6. The truncated metabolite GLP-2 (3-33) interacts with the GLP-2 receptor as a partial agonist

    DEFF Research Database (Denmark)

    Thulesen, Jesper; Knudsen, Lotte Bjerre; Hartmann, Bolette

    2002-01-01

    . Functional (cAMP) and binding in vitro studies were carried out in cells expressing the transfected human GLP-2 receptor. Furthermore, a biologic response of GLP-2 (3-33) was tested in vivo. Mice were allocated to groups treated for 10 days (twice daily) with: (1) 5 microg GLP-2 (1-33), (2) 25 microg GLP-2...... with an efficacy of 15% and a potency more than two orders of magnitude lower than that of GLP-2 (1-33). Increasing doses of GLP-2 (3-33) (10(-7)-10(-5) M) caused a shift to the right in the dose-response curve of GLP-2 (1-33). Treatment of mice with either GLP-2 (1-33) or (3-33) induced significant growth...

  7. Isolation and partial characterization of peripheral blood CD4+ T cell clones expressing γδT cell receptors

    International Nuclear Information System (INIS)

    Kyoizumi, Seishi; Akiyama, Mitoshi; Hirai, Yuko; Kusunoki, Yoichiro.

    1990-06-01

    Rare T cell clones bearing both CD4 and T cell receptors (TCRγ and TCRδ) were obtained from human peripheral blood by cell sorting using anti-CD4 and anti-TCRδ1 antibodies. All the clones established were reactive with anti-TCRγδ1 antibody, whereas only about 20 % of the clones showed reactivity with anti-δTCS1 antibody. Unlike CD4 + T cells bearing TCRαβ, all the clones tested were lectin-dependent and showed CD3 antibody-redirected cytolytic activity. About 60 % exhibited natural killer cell-like activity. Immunoprecipitation analysis of TCRγδ showed that each clone expressed either a disulfide-linked or nondisulfide-linked heterodimer consisting of 37-44 kilodalton TCRγ and TCRδ chains. Southern blot analyses of TCRγ and TCRδ genes revealed some identical rearrangement patterns, suggesting the limited heterogeneity of CD4 + TCRγδ + T cells in peripheral blood. (author)

  8. Partial characterization of insulin-like growth factor I in primary human lung cancers using immunohistochemical and receptor autoradiographic techniques

    International Nuclear Information System (INIS)

    Shigematsu, K.; Kataoka, Y.; Kamio, T.; Kurihara, M.; Niwa, M.; Tsuchiyama, H.

    1990-01-01

    We investigated primary human lung cancers resected surgically or obtained at autopsy. Included were squamous cell carcinoma (SQC) (five cases), adenocarcinoma (ADC) (six cases), large cell carcinoma (LCC) (four cases), and small cell carcinoma (SCC) (two cases). The objective of the study was to search for the presence of insulin-like growth factor I (IGF-I)-like immunoreactivity using immunohistochemical staining and for the localization of IGF-I binding sites, using in vitro quantitative receptor autoradiographic techniques. IGF-I-like immunostaining was present in all cases of SQC, ADC, and LCC, but not in cases of SCC. Strong immunostaining was observed in cases of SQC. On the other hand, ADC and LCC tissues showed a moderate or weak staining. Specific binding sites for IGF-I were present in all cases of SQC, ADC, LCC, and SCC examined. High densities of 125I-IGF-I binding sites were localized in cases of SQC and SCC. Low to high densities of the binding sites were found in LCC. Cases of ADC showed low densities of 125I-IGF-I binding sites. Specific binding obtained at a concentration of 80 pM 125I-IGF-I was competitively displaced by unlabeled IGF-I, with a 50% inhibitory concentration value of 1.84 +/- 0.31 x 10(-10) mol, whereas human insulin was much less potent in displacing the binding. This specificity profile is consistent with characteristics of IGF-I receptors. Scatchard analysis showed the presence of a single class of high affinity binding sites for IGF-I, with a Kd of approximately 1 nmol. Thus, the possibility that IGF-I may play a role in the growth of human lung cancers would have to be considered

  9. Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression.

    Science.gov (United States)

    Liu, Jianhua; Yu, Li-Fang; Eaton, J Brek; Caldarone, Barbara; Cavino, Katie; Ruiz, Christina; Terry, Matthew; Fedolak, Allison; Wang, Daguang; Ghavami, Afshin; Lowe, David A; Brunner, Dani; Lukas, Ronald J; Kozikowski, Alan P

    2011-10-27

    Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment, targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenaline, is not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogues that interact with α4β2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450-related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.

  10. Two novel partial deletions of LDL-receptor gene in Italian patients with familial hypercholesterolemia (FH Siracusa and FH Reggio Emilia).

    Science.gov (United States)

    Garuti, R; Lelli, N; Barozzini, M; Tiozzo, R; Ghisellini, M; Simone, M L; Li Volti, S; Garozzo, R; Mollica, F; Vergoni, W; Bertolini, S; Calandra, S

    1996-03-01

    In the present study we report two novel partial deletions of the LDL-R gene. The first (FH Siracusa), found in an FH-heterozygote, consists of a 20 kb deletion spanning from the 5' flanking region to the intron 2 of the LDL-receptor gene. The elimination of the promoter and the first two exons prevents the transcription of the deleted allele, as shown by Northern blot analysis of LDL-R mRNA isolated from the proband's fibroblasts. The second deletion (FH Reggio Emilia), which eliminates 11 nucleotides of exon 10, was also found in an FH heterozygote. The characterization of this deletion was made possible by a combination of techniques such as single strand conformation polymorphism (SSCP) analysis, direct sequence of exon 10 and cloning of the normal and deleted exon 10 from the proband's DNA. The 11 nt deletion occurs in a region of exon 10 which contains three triplets (CTG) and two four-nucleotides (CTGG) direct repeats. This structural feature might render this region more susceptible to a slipped mispairing during DNA duplication. Since this deletion causes a shift of the BamHI site at the 5' end of exon 10, a method has been devised for its rapid screening which is based on the PCR amplification of exon 10 followed by BamHI digestion. FH Reggio Emilia deletion produces a shift in the reading frame downstream from Lys458, leading to a sequence of 51 novel amino acids before the occurrence of a premature stop codon (truncated receptor). However, since RT-PCR failed to demonstrate the presence of the mutant LDL-R mRNA in proband fibroblasts, it is likely that the amount of truncated receptor produced in these cells is negligible.

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

    International Nuclear Information System (INIS)

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

    2011-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Yasuda, Osamu [Department of Cardiovascular Clinical and Translational Research, Kumamoto University Hospital, Kumamoto (Japan); Fukuda, Masaya; Tokutomi, Yoshiko; Dong, Yi-Fei [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Ogawa, Hisao [Department of Cardiovascular Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Kim-Mitsuyama, Shokei, E-mail: kimmitsu@gpo.kumamoto-u.ac.jp [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan)

    2011-07-08

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

  13. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    Science.gov (United States)

    Young, R. B.; Bridge, K. Y.

    2003-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

  14. Characterization of the pharmacokinetics, brain distribution, and therapeutic efficacy of the adenosine A1 receptor partial agonist 2'-deoxy-N6-cyclopentyladenosine in sarin-poisoned rats

    International Nuclear Information System (INIS)

    Bueters, Tjerk J.H.; IJzerman, Ad P.; Helden, Herman P.M. van; Danhof, Meindert

    2003-01-01

    Characterization of the pharmacokinetics, brain distribution, and therapeutic efficacy of the adenosine A 1 receptor partial agonist 2'-deoxy-N 6 -cyclopentyladenosine in sarin-poisoned rats. Bueters, T.J.H., IJzerman, A.P., Van Helden, H.P.M., and Danhof, M. (2003). The objective of the present study was to determine (1) the influence of sarin poisoning (144 μg/kg sc) on the pharmacokinetics and brain distribution of the adenosine A 1 receptor partial agonist 2'-deoxy-N 6 -cyclopentyladenosine (2'dCPA), and (2) the effect of 2'dCPA (20 mg/kg iv) on the central acetylcholine (ACh) release and protection against sarin toxicity. A five-compartment model successfully described the pharmacokinetic profile of 2'dCPA in blood and brain microdialysate. A covariate analysis revealed that the volume of distribution of 2'dCPA in blood was different in sarin-poisoned rats, 177 ± 7 versus 148 ± 8 ml in control rats. However, the transport of 2'dCPA from blood to the brain was unaffected as reflected by the values of the intercompartmental transport clearances, 0.21 ± 0.02 and 0.21 ± 0.04 μl/min in control and sarin-poisoned rats, respectively. Also the area-under-curve (AUC) ratios of brain microdialysate and blood were identical with values of 0.02 ± 0.001 and 0.02 ± 0.002, respectively, demonstrating the restricted transport of 2'dCPA into the brain in both treatment groups. Treatment of sarin-poisoned rats by 2'dCPA did not adequately prevent the accumulation of ACh in the central nervous system. 2'dCPA delayed the emergence of concomitant symptoms compared to untreated rats, but eventually only 29% of the animals survived 24 h. In conclusion, the pharmacokinetic profile of 2'dCPA in blood was slightly changed by sarin, but not the distribution of 2'dCPA into the brain. The therapeutic efficacy of 2'dCPA against sarin was limited, presumably due to insufficient quantities of 2'dCPA reaching the brain

  15. GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects.

    Science.gov (United States)

    Burgdorf, Jeffrey; Zhang, Xiao-lei; Nicholson, Katherine L; Balster, Robert L; Leander, J David; Stanton, Patric K; Gross, Amanda L; Kroes, Roger A; Moskal, Joseph R

    2013-04-01

    Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.

  16. Partial direct contact transmission in ferrets of a mallard H7N3 influenza virus with typical avian-like receptor specificity

    Directory of Open Access Journals (Sweden)

    Araya Yonas

    2009-08-01

    Full Text Available Abstract Background Avian influenza viruses of the H7 subtype have caused multiple outbreaks in domestic poultry and represent a significant threat to public health due to their propensity to occasionally transmit directly from birds to humans. In order to better understand the cross species transmission potential of H7 viruses in nature, we performed biological and molecular characterizations of an H7N3 virus isolated from mallards in Canada in 2001. Results Sequence analysis that the HA gene of the mallard H7N3 virus shares 97% identity with the highly pathogenic avian influenza (HPAI H7N3 virus isolated from a human case in British Columbia, Canada in 2004. The mallard H7N3 virus was able to replicate in quail and chickens, and transmitted efficiently in quail but not in chickens. Interestingly, although this virus showed preferential binding to analogs of avian-like receptors with sialic acid (SA linked to galactose in an α2–3 linkage (SAα2–3Gal, it replicated to high titers in cultures of primary human airway epithelial (HAE cells, comparable to an avian H9N2 influenza virus with human-like α2–6 linkage receptors (SAα2–6Gal. In addition, the virus replicated in mice and ferrets without prior adaptation and was able to transmit partially among ferrets. Conclusion Our findings highlight the importance and need for systematic in vitro and in vivo analysis of avian influenza viruses isolated from the natural reservoir in order to define their zoonotic potential.

  17. Role of Nicotinic Acetylcholine Receptor α3 and α7 Subunits in Detrusor Overactivity Induced by Partial Bladder Outlet Obstruction in Rats

    Directory of Open Access Journals (Sweden)

    Hyo Sin Kim

    2015-03-01

    Full Text Available Purpose: To investigate the role of α3 and α7 nicotinic acetylcholine receptor subunits (nAChRs in the bladder, using a rat model with detrusor overactivity induced by partial bladder outlet obstruction (BOO. Methods: Forty Sprague-Dawley rats were used: 10 were sham-operated (control group and 30 were observed for 3 weeks after partial BOO. BOO-induced rats were further divided into 3 groups: Two groups of 10 rats each received intravesicular infusions with hexamethonium (HM group; n=10 or methyllycaconitine (MLC group; n=10, which are antagonists for α3 and α7 nAChRs, respectively. The remaining BOO-induced rats received only saline infusion (BOO group; n=10. Based on the contraction interval measurements using cystometrogram, the contraction pressure and nonvoiding bladder contractions were compared between the control and the three BOO-induced groups. Immunofluorescent staining and Western blotting were used to analyze α3 and α7 nAChRs levels. Results: The contraction interval of the MLC group was higher than that of the BOO group (P<0.05. Nonvoiding bladder contraction almost disappeared in the HM and MLC groups. Contraction pressure increased in the BOO group (P<0.05 compared with the control group and decreased in the HM and MLC groups compared with the BOO group (P<0.05. Immunofluorescence staining showed that the α3 nAChR signals increased in the urothelium, and the α7 nAChR signals increased in the urothelium and detrusor muscle of the BOO group compared with the control group. Western blot analysis showed that both α3 and α7 nAChR levels increased in the BOO group (P<0.05. Conclusions: Alpha3 and α7 nAChRs are associated with detrusor overactivity induced by BOO. Furthermore, nAChR antagonists could help in clinically improving detrusor overactivity.

  18. Analgesia produced by exposure to 2450-MHz radiofrequency radiation (RFR) is mediated by brain mu- and kappa-opioid receptors

    Energy Technology Data Exchange (ETDEWEB)

    Salomon, G.; Park, E.J.; Quock, R.M. (Univ. of Illinois, Rockford (United States))

    1992-02-26

    This study was conducted to identify the opioid receptor subtype(s) responsible for RFR-induced analgesia. Male Swiss Webster mice, 20-25 g, were exposed to 20 mW/cm{sup 2} RFR in a 2,450-MHz waveguide system for 10 min, then tested 15 min later in the abdominal constriction paradigm which detects {mu}- and {kappa}-opioid activity. Immediately following RFR exposure, different groups of mice were pretreated intracerebroventricularly with different opioid receptor blockers with selectivity for {mu}- or {kappa}-opioid receptors. Results show that RFR-induced analgesia was attenuated by higher but not lower doses of the non-selective antagonist naloxone, but the selective {mu}-opioid antagonist {beta}-funaltrexamine and by the selective {kappa}-opioid antagonist norbinaltorphimine. RFR-induced analgesia was also reduced by subcutaneous pretreatment with 5.0 mg/kg of the {mu}-/{kappa}-opioid antagonist({minus})-5,9-diethyl-{alpha}-5,9-dialkyl-2{prime}-hydroxy-6,7-benzomorphan(MR-2266). These findings suggest that RFR-induced analgesia may be mediated by both {mu}- and {kappa}-opioid mechanisms.

  19. Analysis of Drug Design for a Selection of G Protein-Coupled Neuro-Receptors Using Neural Network Techniques

    DEFF Research Database (Denmark)

    Agerskov, Claus; Mortensen, Rasmus M.; Bohr, Henrik G.

    2015-01-01

    A study is presented on how well possible drug-molecules can be predicted with respect to their function and binding to a selection of neuro-receptors by the use of artificial neural networks. The ligands investigated in this study are chosen to be corresponding to the G protein-coupled receptors...... computational tools, able to aid in drug-design in a fast and cheap fashion, compared to conventional pharmacological techniques....... mu-opioid, serotonin 2B (5-HT2B) and metabotropic glutamate D5. They are selected due to the availability of pharmacological drug-molecule binding data for these receptors. Feedback and deep belief artificial neural network architectures (NNs) were chosen to perform the task of aiding drug-design.......925. The performance of 8 category networks (8 output classes for binding strength) obtained a prediction accuracy of above 60 %. After training the networks, tests were done on how well the systems could be used as an aid in designing candidate drug molecules. Specifically, it was shown how a selection of chemical...

  20. Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

    Energy Technology Data Exchange (ETDEWEB)

    Camelo, J.S. Jr. [Departamento de Puericultura e Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Martins, A.R. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Instituto de Ciências Biológicas, Universidade Federal do Triângulo Mineiro, Uberaba, MG (Brazil); Rosa, E. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Ramos, S.G. [Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SPBrasil (Brazil); Hehre, D.; Bancalari, E.; Suguihara, C. [Department of Pediatrics, Division of Neonatology, Neonatal Developmental Biology Laboratory, University of Miami Miller School of Medicine, Miami, FL (United States)

    2012-02-10

    The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT{sub 1} receptor (AT{sub 1}-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO{sub 2} = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT{sub 1}-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT{sub 1}-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT{sub 1}-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT{sub 1}-R staining, but C animals showed weak iNOS and AT{sub 1}-R staining. Macrophages of L and P animals showed moderate and weak AT{sub 2}-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT{sub 1}-R blockade. We suggest that AT{sub 1}-R blockade might act through AT{sub 2}-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

  1. Hc-daf-2 encodes an insulin-like receptor kinase in the barber's pole worm, Haemonchus contortus, and restores partial dauer regulation.

    Science.gov (United States)

    Li, Facai; Lok, James B; Gasser, Robin B; Korhonen, Pasi K; Sandeman, Mark R; Shi, Deshi; Zhou, Rui; Li, Xiangrui; Zhou, Yanqin; Zhao, Junlong; Hu, Min

    2014-06-01

    Infective L3s (iL3s) of parasitic nematodes share common behavioural, morphological and developmental characteristics with the developmentally arrested (dauer) larvae of the free-living nematode Caenorhabditis elegans. It is proposed that similar molecular mechanisms regulate entry into or exit from the dauer stage in C. elegans, and the transition from free-living to parasitic forms of parasitic nematodes. In C. elegans, one of the key factors regulating the dauer transition is the insulin-like receptor (designated Ce-DAF-2) encoded by the gene Ce-daf-2. However, nothing is known about DAF-2 homologues in most parasitic nematodes. Here, using a PCR-based approach, we identified and characterised a gene (Hc-daf-2) and its inferred product (Hc-DAF-2) in Haemonchus contortus (a socioeconomically important parasitic nematode of ruminants). The sequence of Hc-DAF-2 displays significant sequence homology to insulin receptors (IR) in both vertebrates and invertebrates, and contains conserved structural domains. A sequence encoding an important proteolytic motif (RKRR) identified in the predicted peptide sequence of Hc-DAF-2 is consistent with that of the human IR, suggesting that it is involved in the formation of the IR complex. The Hc-daf-2 gene was transcribed in all life stages of H. contortus, with a significant up-regulation in the iL3 compared with other stages. To compare patterns of expression between Hc-daf-2 and Ce-daf-2, reporter constructs fusing the Ce-daf-2 or Hc-daf-2 promoter to sequence encoding GFP were microinjected into the N2 strain of C. elegans, and transgenic lines were established and examined. Both genes showed similar patterns of expression in amphidial (head) neurons, which relate to sensation and signal transduction. Further study by heterologous genetic complementation in a daf-2-deficient strain of C. elegans (CB1370) showed partial rescue of function by Hc-daf-2. Taken together, these findings provide a first insight into the roles of Hc

  2. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

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

  3. Towards a thermodynamic definition of efficacy in partial agonism: The thermodynamics of efficacy and ligand proton transfer in a G protein-coupled receptor of the rhodopsin class.

    Science.gov (United States)

    Broadley, Kenneth J; Sykes, Shane C; Davies, Robin H

    2010-11-15

    The thermodynamic binding profiles of agonist and antagonist complexes of the 4-hydroxypropanolamine partial agonist, prenalterol, on the chronotropic adrenergic response in guinea-pig right atria were determined over a 15 °C temperature range. The tissue response was compared with data on the ethanolamine agonist, isoprenaline, given by binding studies in a number of rat tissues. Utilising the residue conservatism surrounding the known active conformers bound to either of two aspartate residues (α-helices II, III) in both receptors (β(1), β(2)) and species (guinea-pig, rat and human), no significant deformation in the extended side chain could be found in prenalterol's agonist binding compared to isoprenaline. Antagonist binding gave a highly favourable entropy contribution at 30.0 °C of -4.7±1.2 kcal/mol. The enthalpy change between bound agonist and antagonist complexes, a function of the efficacy alone, was -6.4±1.1 kcal/mol, coincident with the calculated intrinsic preference of a primary/secondary amine-aspartate interaction for a neutral hydrogen-bonded form over its ion pair state, giving values of 6.3-6.6 kcal/mol with calculations of good quality, a figure expected to be close to that shown within a hydrophobic environment. Delivery of a proton to a conserved aspartate anion (α-helix II) becomes the critical determinant for agonist action with resultant proton transfer stabilisation dominating the enthalpy change. A proposed monocation-driven ligand proton pumping mechanism within the ternary complex is consistent with the data, delivery between two acid groups being created by the movement of the cation and the counter-movement of the ligand protonated amine moving from Asp 138 (α-helix III) to Asp 104 (α-helix II). Copyright © 2010 Elsevier Inc. All rights reserved.

  4. Species differences in the biotransformation of an alpha 4 beta 2 nicotinic acetylcholine receptor partial agonist: the effects of distinct glucuronide metabolites on overall compound disposition.

    Science.gov (United States)

    Shaffer, Christopher L; Gunduz, Mithat; Ryder, Tim F; O'Connell, Thomas N

    2010-02-01

    The metabolism and disposition of (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine (1), an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist, was investigated in Sprague-Dawley rats and cynomolgus monkeys receiving (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-4[(14)C]-3- benzazepine hydrochloride ([(14)C]1) orally. Although both species chiefly (>or=62%) cleared 1 metabolically, species-specific dispositional profiles were observed for both 1 and total radioactivity. Radioactivity was excreted equally in the urine and feces of intact rats but largely (72%) in bile in bile duct-cannulated animals. In monkeys, radioactivity recoveries were 50-fold greater in urine than feces and minimal (<5%) in bile. Both species metabolized 1 similarly: four-electron oxidation to one of four amino acids or two lactams (minor) and glucuronide formation (major). In rats, the latter pathway predominantly formed an N-carbamoyl glucuronide (M6), exclusively present in bile (69% of dose), whereas in monkeys it afforded an N-O-glucuronide (M5), a minor biliary component (4%) but the major plasma (62%) and urinary (42%) entity. In rats, first-pass hepatic conversion of 1 to M6, which was confirmed in rat hepatocytes, and its biliary secretion resulted in the indirect enterohepatic cycling of 1 via M6 and manifested in double-humped plasma concentration-time curves and long t(1/2) for both 1 and total radioactivity. In monkeys, in which only M5 was formed, double-humped plasma concentration-time curves were absent, and moderate t(1/2) for both 1 and total radioactivity were observed. A seemingly subtle, yet critical, difference in the chemical structures of these two glucuronide metabolites considerably affected the overall disposition of 1 in rats versus monkeys.

  5. Anhedonia to music and mu-opioids: Evidence from the administration of naltrexone

    Science.gov (United States)

    Mallik, Adiel; Chanda, Mona Lisa; Levitin, Daniel J.

    2017-01-01

    Music’s universality and its ability to deeply affect emotions suggest an evolutionary origin. Previous investigators have found that naltrexone (NTX), a μ-opioid antagonist, may induce reversible anhedonia, attenuating both positive and negative emotions. The neurochemical basis of musical experience is not well-understood, and the NTX-induced anhedonia hypothesis has not been tested with music. Accordingly, we administered NTX or placebo on two different days in a double-blind crossover study, and assessed participants’ responses to music using both psychophysiological (objective) and behavioral (subjective) measures. We found that both positive and negative emotions were attenuated. We conclude that endogenous opioids are critical to experiencing both positive and negative emotions in music, and that music uses the same reward pathways as food, drug and sexual pleasure. Our findings add to the growing body of evidence for the evolutionary biological substrates of music. PMID:28176798

  6. Differential effects of α4β2 nicotinic receptor antagonists and partial-agonists on contextual fear extinction in male C57BL/6 mice.

    Science.gov (United States)

    Kutlu, Munir Gunes; Tumolo, Jessica M; Cann, Courtney; Gould, Thomas J

    2018-04-01

    Numerous studies have attributed the psychopathology of post-traumatic stress disorder (PTSD) to maladaptive behavioral responses such as an inability to extinguish fear. While exposure therapies are mostly effective in treating these disorders by enhancing extinction learning, relapse of PTSD symptoms is common. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs to fear extinction OBJECTIVES: In the present study, we examined the effects of inhibition and desensitization of α4β2 nAChRs via a full antagonist (Dihydro-beta-erythroidine (DhβE)) and two α4β2 nAChR partial-agonists (varenicline and sazetidine-A) on contextual fear extinction, locomotor activity, and spontaneous recovery of contextual fear in mice. We trained and tested the subjects in a contextual fear extinction as well as an open field paradigm and spontaneous recovery following injections of DhβE, varenicline, and sazetidine-A. Our results demonstrated that lower doses of DhβE (1 mg/kg) and sazetidine-A (0.01 mg/kg) enhanced contextual fear extinction whereas higher doses of varenicline (0.1 mg/kg) and sazetidine-A (0.1 mg/kg) resulted in impaired contextual fear extinction. However, the higher dose of sazetidine-A (0.1 mg/kg) decreased locomotor activity, which may contribute to increased freezing response observed during fear extinction. Finally, we found that the low dose of DhβE, but not sazetidine-A, also decreased spontaneous recovery of contextual fear following fear extinction. Overall, these results suggest that inhibition and desensitization of α4β2 nAChRs enhance extinction of contextual fear memories. This suggests that modulation of α4β2 nAChRs may be employed as an alternative pharmacological strategy to aid exposure therapies associated with PTSD by augmenting contextual fear extinction

  7. A pepducin derived from the third intracellular loop of FPR2 is a partial agonist for direct activation of this receptor in neutrophils but a full agonist for cross-talk triggered reactivation of FPR2.

    Directory of Open Access Journals (Sweden)

    Michael Gabl

    Full Text Available We recently described a novel receptor cross-talk mechanism in neutrophils, unique in that the signals generated by the PAF receptor (PAFR and the ATP receptor (P2Y2R transfer formyl peptide receptor 1 (FPR1 from a desensitized (non-signaling state back to an actively signaling state (Forsman H et al., PLoS One, 8:e60169, 2013; Önnheim K, et al., Exp Cell Res, 323∶209, 2014. In addition to the G-protein coupled FPR1, neutrophils also express the closely related receptor FPR2. In this study we used an FPR2 specific pepducin, proposed to work as an allosteric modulator at the cytosolic signaling interface, to determine whether the cross-talk pathway is utilized also by FPR2. The pepducin used contains a fatty acid linked to a peptide sequence derived from the third intracellular loop of FPR2, and it activates as well as desensensitizes this receptor. We now show that neutrophils desensitized with the FPR2-specific pepducin display increased cellular responses to stimulation with PAF or ATP. The secondary PAF/ATP induced response was sensitive to FPR2-specific inhibitors, disclosing a receptor cross-talk mechanism underlying FPR2 reactivation. The pepducin induced an activity in naïve cells similar to that of a conventional FPR2 agonist, but with lower potency (partial efficacy, meaning that the pepducin is a partial agonist. The PAF- or ATP-induced reactivation was, however, much more pronounced when neutrophils had been desensitized to the pepducin as compared to cells desensitized to conventional agonists. The pepducin should thus in this respect be classified as a full agonist. In summary, we demonstrate that desensitized FPR2 can be transferred back to an actively signaling state by receptor cross-talk signals generated through PAFR and P2Y2R, and the difference in agonist potency with respect to pepducin-induced direct receptor activation and cross-talk reactivation of FPR2 puts the concept of functional selectivity in focus.

  8. Mu and delta opioid receptors oppositely regulate motor impulsivity in the signaled nose poke task.

    Directory of Open Access Journals (Sweden)

    Mary C Olmstead

    Full Text Available Impulsivity is a primary feature of many psychiatric disorders, most notably attention deficit hyperactivity disorder and drug addiction. Impulsivity includes a number of processes such as the inability to delay gratification, the inability to withhold a motor response, or acting before all of the relevant information is available. These processes are mediated by neural systems that include dopamine, serotonin, norepinephrine, glutamate and cannabinoids. We examine, for the first time, the role of opioid systems in impulsivity by testing whether inactivation of the mu- (Oprm1 or delta- (Oprd1 opioid receptor gene alters motor impulsivity in mice. Wild-type and knockout mice were examined on either a pure C57BL6/J (BL6 or a hybrid 50% C57Bl/6J-50% 129Sv/pas (HYB background. Mice were trained to respond for sucrose in a signaled nose poke task that provides independent measures of associative learning (responses to the reward-paired cue and motor impulsivity (premature responses. Oprm1 knockout mice displayed a remarkable decrease in motor impulsivity. This was observed on the two genetic backgrounds and did not result from impaired associative learning, as responses to the cue signaling reward did not differ across genotypes. Furthermore, mutant mice were insensitive to the effects of ethanol, which increased disinhibition and decreased conditioned responding in wild-type mice. In sharp contrast, mice lacking the Oprd1 gene were more impulsive than controls. Again, mutant animals showed no deficit in associative learning. Ethanol completely disrupted performance in these animals. Together, our results suggest that mu-opioid receptors enhance, whereas delta-opioid receptors inhibit, motor impulsivity. This reveals an unanticipated contribution of endogenous opioid receptor activity to disinhibition. In a broader context, these data suggest that alterations in mu- or delta-opioid receptor function may contribute to impulse control disorders.

  9. Impaired peroxisome proliferator-activated receptor γ function through mutation of a conserved salt bridge (R425C) in familial partial lipodystrophy

    NARCIS (Netherlands)

    Jeninga, E.H.; van Beekum, P.O; van Dijk, A.D.J.; Hamers, N.; Bonvin, A.M.J.J.; Berger, R.; Kalkhoven, E.

    2007-01-01

    The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ plays a key role in the regulation of glucose and lipid metabolism in adipocytes by regulating their differentiation, maintenance, and function. A heterozygous mutation in the PPARG gene, which changes an arginine residue at

  10. Delta-opioid receptor analgesia is independent of microglial activation in a rat model of neuropathic pain.

    Directory of Open Access Journals (Sweden)

    Joanna Mika

    Full Text Available The analgesic effect of delta-opioid receptor (DOR ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p. over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t. administered morphine (10-20 µg, DAMGO (1-2 µg and U50,488H (25-50 µg were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10-20 µg, deltorphin II (1.5-15 µg and SNC80 (10-20 µg administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR and kappa-opioid receptors (KOR, further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain.

  11. ( sup 3 H)(D-PEN sup 2 , D-PEN sup 5 ) enkephalin binding to delta opioid receptors on intact neuroblastoma-glioma (NG 108-15) hybrid cells

    Energy Technology Data Exchange (ETDEWEB)

    Knapp, R.J.; Yamamura, H.I. (Univ. of Arizona College of Medicine, Tucson (USA))

    1990-01-01

    ({sup 3}H)(D-Pen{sup 2}, D-Pen{sup 5})enkephalin binding to intact NG 108-15 cells has been measured under physiological conditions of temperature and medium. The dissociation constant, receptor density, and Hill slope values measured under these conditions are consistent with values obtained by others using membranes prepared from these cells. Kinetic analysis of the radioligand binding to these cells show biphasic association and monophasic dissociation processes suggesting the presence of different receptor affinity states for the agonist. The data show that the binding affinity of ({sup 3}H)(D-Pen{sup 2}, D-Pen{sup 5})enkephalin under physiological conditions is not substantially different to that measured in 50 mM Tris buffer using cell membrane fractions. Unlike DPDPE, the {mu} opioid agonists morphine, normorphine, PL-17, and DAMGO, have much lower affinity for the {delta} receptor measured under these conditions than is observed by studies using 50 mM Tris buffer. The results described here suggest that this assay may serve as a useful model of {delta} opioid receptor binding in vivo.

  12. Dgroup: DG01000 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available pioid receptor agonist ... DG01563 ... mu-Opioid receptor agonist Analgesic ... DG01984 ... Opioid analgesics Other ... DG01718 ... Drugs... for addictive disorder ... DG01717 ... Drugs for opioid dependence Cyp su

  13. Dgroup: DG01339 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available il citrate (USAN) Neuropsychiatric agent ... DG01564 ... Opioid receptor agonist ... DG01563 ... mu-Opioid receptor ago... DG01339 Chemical ... DGroup Carfentanil ... D07620 ... Carfentanil (INN) D03405 ... Carfentan

  14. Dgroup: DG00823 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00823 Chemical ... DGroup Tilidine ... D08597 ... Tilidine (INN) D06147 ... Tilidine hydrochloride (USAN) Neuropsych...iatric agent ... DG01564 ... Opioid receptor agonist ... DG01563 ... mu-Opioid receptor agonis

  15. alpha-Adrenoceptor and opioid receptor modulation of clonidine-induced antinociception.

    Science.gov (United States)

    Sierralta, F; Naquira, D; Pinardi, G; Miranda, H F

    1996-10-01

    1. The antinociceptive action of clonidine (Clon) and the interactions with alpha 1, alpha 2 adrenoceptor and opioid receptor antagonists was evaluated in mice by use of chemical algesiometric test (acetic acid writhing test). 2. Clon produced a dose-dependent antinociceptive action and the ED50 for intracerebroventricular (i.c.v.) was lower than for intraperitoneal (i.p.) administration (1 ng kg-1 vs 300 ng kg-1). The parallelism of the dose-response curves indicates activation of a common receptor subtype. 3. Systemic administration of prazosin and terazosin displayed antinociceptive activity. Pretreatment with prazosin produced a dual action: i.c.v. Clon effect did not change, and i.p. Clon effect was enhanced. Yohimbine i.c.v. or i.p. did not induce antinonciception, but antagonized Clon-induced activity. These results suggest that alpha 1- and alpha 2-adrenoceptors, either located at the pre- and/or post-synaptic level, are involved in the control of spinal antinociception. 4. Naloxone (NX) and naltrexone (NTX) induced antinociceptive effects at low doses (microgram kg-1 range) and a lower antinociceptive effect at higher doses (mg kg-1 range). Low doses of NX or NTX antagonized Clon antinociception, possibly in relation to a preferential mu opioid receptor antagonism. In contrast, high doses of NX or NTX increased the antinociceptive activity of Clon, which could be due to an enhanced inhibition of the release of substance P. 5. The results obtained in the present work suggest the involvement of alpha 1-, alpha 2-adrenoceptor and opioid receptors in the modulation of the antinociceptive activity of clonidine, which seems to be exerted either at spinal and/or supraspinal level.

  16. Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats.

    Science.gov (United States)

    Rojas, Jennifer M; Stafford, John M; Saadat, Sanaz; Printz, Richard L; Beck-Sickinger, Annette G; Niswender, Kevin D

    2012-12-15

    Elevated plasma triglyceride (TG) levels contribute to an atherogenic dyslipidemia that is associated with obesity, diabetes, and metabolic syndrome. Numerous models of obesity are characterized by increased central nervous system (CNS) neuropeptide Y (NPY) tone that contributes to excess food intake and obesity. Previously, we demonstrated that intracerebroventricular (icv) administration of NPY in lean fasted rats also elevates hepatic production of very low-density lipoprotein (VLDL)-TG. Thus, we hypothesize that elevated CNS NPY action contributes to not only the pathogenesis of obesity but also dyslipidemia. Here, we sought to determine whether the effects of NPY on feeding and/or obesity are dissociable from effects on hepatic VLDL-TG secretion. Pair-fed, icv NPY-treated, chow-fed Long-Evans rats develop hypertriglyceridemia in the absence of increased food intake and body fat accumulation compared with vehicle-treated controls. We then modulated CNS NPY signaling by icv injection of selective NPY receptor agonists and found that Y1, Y2, Y4, and Y5 receptor agonists all induced hyperphagia in lean, ad libitum chow-fed Long-Evans rats, with the Y2 receptor agonist having the most pronounced effect. Next, we found that at equipotent doses for food intake NPY Y1 receptor agonist had the most robust effect on VLDL-TG secretion, a Y2 receptor agonist had a modest effect, and no effect was observed for Y4 and Y5 receptor agonists. These findings, using selective agonists, suggest the possibility that the effect of CNS NPY signaling on hepatic VLDL-TG secretion may be relatively dissociable from effects on feeding behavior via the Y1 receptor.

  17. Anti-analgesic effect of the mu/delta opioid receptor heteromer revealed by ligand-biased antagonism.

    Directory of Open Access Journals (Sweden)

    Laura Milan-Lobo

    Full Text Available Delta (DOR and mu opioid receptors (MOR can complex as heteromers, conferring functional properties in agonist binding, signaling and trafficking that can differ markedly from their homomeric counterparts. Because of these differences, DOR/MOR heteromers may be a novel therapeutic target in the treatment of pain. However, there are currently no ligands selective for DOR/MOR heteromers, and, consequently, their role in nociception remains unknown. In this study, we used a pharmacological opioid cocktail that selectively activates and stabilizes the DOR/MOR heteromer at the cell surface by blocking its endocytosis to assess its role in antinociception. We found that mice treated chronically with this drug cocktail showed a significant right shift in the ED50 for opioid-mediated analgesia, while mice treated with a drug that promotes degradation of the heteromer did not. Furthermore, promoting degradation of the DOR/MOR heteromer after the right shift in the ED50 had occurred, or blocking signal transduction from the stabilized DOR/MOR heteromer, shifted the ED50 for analgesia back to the left. Taken together, these data suggest an anti-analgesic role for the DOR/MOR heteromer in pain. In conclusion, antagonists selective for DOR/MOR heteromer could provide an avenue for alleviating reduced analgesic response during chronic pain treatment.

  18. The alpha7 nicotinic acetylcholine receptor-selective antagonist, methyllycaconitine, partially protects against beta-amyloid1-42 toxicity in primary neuron-enriched cultures.

    Science.gov (United States)

    Martin, Shelley E; de Fiebre, Nancy Ellen C; de Fiebre, Christopher M

    2004-10-01

    Studies have suggested that the neuroprotective actions of alpha7 nicotinic agonists arise from activation of receptors and not from the extensive desensitization which rapidly follows activation. Here, we report that the alpha7-selective nicotinic antagonist, methyllycaconitine (MLA), protects against beta-amyloid-induced neurotoxicity; whereas the alpha4beta2-selective antagonist, dihydro-beta-erythroidine, does not. These findings suggest that neuroprotective actions of alpha7-acting agents arise from receptor inhibition/desensitization and that alpha7 antagonists may be useful neuroprotective agents.

  19. Modulation of voltage-gated Ca2+ channels by G protein-coupled receptors in celiac-mesenteric ganglion neurons of septic rats.

    Directory of Open Access Journals (Sweden)

    Mohamed Farrag

    Full Text Available Septic shock, the most severe complication associated with sepsis, is manifested by tissue hypoperfusion due, in part, to cardiovascular and autonomic dysfunction. In many cases, the splanchnic circulation becomes vasoplegic. The celiac-superior mesenteric ganglion (CSMG sympathetic neurons provide the main autonomic input to these vessels. We used the cecal ligation puncture (CLP model, which closely mimics the hemodynamic and metabolic disturbances observed in septic patients, to examine the properties and modulation of Ca2+ channels by G protein-coupled receptors in acutely dissociated rat CSMG neurons. Voltage-clamp studies 48 hr post-sepsis revealed that the Ca2+ current density in CMSG neurons from septic rats was significantly lower than those isolated from sham control rats. This reduction coincided with a significant increase in membrane surface area and a negligible increase in Ca2+ current amplitude. Possible explanations for these findings include either cell swelling or neurite outgrowth enhancement of CSMG neurons from septic rats. Additionally, a significant rightward shift of the concentration-response relationship for the norepinephrine (NE-mediated Ca2+ current inhibition was observed in CSMG neurons from septic rats. Testing for the presence of opioid receptor subtypes in CSMG neurons, showed that mu opioid receptors were present in ~70% of CSMG, while NOP opioid receptors were found in all CSMG neurons tested. The pharmacological profile for both opioid receptor subtypes was not significantly affected by sepsis. Further, the Ca2+ current modulation by propionate, an agonist for the free fatty acid receptors GPR41 and GPR43, was not altered by sepsis. Overall, our findings suggest that CSMG function is affected by sepsis via changes in cell size and α2-adrenergic receptor-mediated Ca2+ channel modulation.

  20. Combined α7 nicotinic acetylcholine receptor agonism and partial serotonin transporter inhibition produce antidepressant-like effects in the mouse forced swim and tail suspension tests

    DEFF Research Database (Denmark)

    Andreasen, Jesper T; Redrobe, John P; Nielsen, Elsebet Ø

    2012-01-01

    Emerging evidence points to an involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. Nicotine improves symptoms of depression in humans and shows antidepressant-like effects in rodents. Monoamine release is facilitated by nAChR stimulation, and nicotine-evoked serotonin (5...

  1. Synthesis, molecular modeling, and opioid receptor affinity of 9, 10-diazatricyclo[4.2.1.1(2,5)]decanes and 2,7-diazatricyclo[4.4.0. 0(3,8)]decanes structurally related to 3,8-diazabicyclo[3.2. 1]octanes.

    Science.gov (United States)

    Vianello, P; Albinati, A; Pinna, G A; Lavecchia, A; Marinelli, L; Borea, P A; Gessi, S; Fadda, P; Tronci, S; Cignarella, G

    2000-06-01

    Various lines of evidence, including molecular modeling studies, imply that the endoethylenic bridge of 3,8-diazabicyclo[3.2. 1]octanes (DBO, 1) plays an essential role in modulating affinity toward mu opioid receptors. This hypothesis, together with the remarkable analgesic properties observed for N(3) propionyl, N(8) arylpropenyl derivatives (2) and of the reverted isomers (3), has prompted us to insert an additional endoethylenic bridge on the piperazine moiety in order to identify derivatives with increased potency toward this receptor class. In the present report, we describe the synthesis of the novel compounds 9,10-diazatricyclo[4.2. 1.1(2,5)]decane (4) and 2,7-diazatricyclo[4.4.0.0(3,8)]decane (5), as well as the representative derivatives functionalized at the two nitrogen atoms by propionyl and arylpropenyl groups (6a-e, 7a-d). Opioid receptor binding assays revealed that, among the compounds tested, the N-propionyl-N-cinnamyl derivatives 6a and 7a exhibited the highest mu-receptor affinity, and remarkably, compound 7a displayed in vivo (mice) an analgesic potency 6-fold that of morphine.

  2. Interacting cannabinoid and opioid receptors in the nucleus accumbens core control adolescent social play

    Directory of Open Access Journals (Sweden)

    Antonia Manduca

    2016-11-01

    Full Text Available Social play behavior is a highly rewarding, developmentally important form of social interaction in young mammals. However, its neurobiological underpinnings remain incompletely understood. Previous work has suggested that opioid and endocannabinoid neurotransmission interact in the modulation of social play. Therefore, we combined behavioral, pharmacological, electrophysiological and genetic approaches to elucidate the role of the endocannabinoid 2-arachidonoylglycerol (2-AG in social play, and how cannabinoid and opioid neurotransmission interact to control social behavior in adolescent rodents. Systemic administration of the 2-AG hydrolysis inhibitor JZL184 or the opioid receptor agonist morphine increased social play behavior in adolescent rats. These effects were blocked by systemic pretreatment with either CB1 cannabinoid receptor (CB1R or mu-opioid receptor (MOR antagonists. The social play-enhancing effects of systemic morphine or JZL184 treatment were also prevented by direct infusion of the CB1R antagonist SR141716 and the MOR antagonist naloxone into the nucleus accumbens core (NAcC. Searching for synaptic correlates of these effects in adolescent NAcC excitatory synapses, we observed that CB1R antagonism blocked the effect of the MOR agonist DAMGO and, conversely, that naloxone reduced the effect of a cannabinoid agonist. These results were recapitulated in mice, and completely abolished in CB1R and MOR knockout mice, suggesting that the functional interaction between CB1R and MOR in the NAcC in the modulation of mediates social behavior is widespread in rodents. The data shed new light on the mechanism by which endocannabinoid lipids and opioid peptides interact to orchestrate rodent socioemotional behaviors.

  3. Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Towards the therapeutics of cognitive impairment of schizophrenia

    Directory of Open Access Journals (Sweden)

    Takashi eUehara

    2014-09-01

    Full Text Available Rationale Augmentation therapy with serotonin-1A (5-HT1A receptor partial agonists has been suggested to improve cognitive deficits in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production.Objectives and methods The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days of tandospirone (0.05 and 5 mg/kg on brain energy metabolism, as represented by extracellular lactate concentration (eLAC in the medial prefrontal cortex (mPFC of young adult rats..Results Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot shock stress (FS. Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment.Conclusions These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism based on brain energy metabolism by which 5-HT1A agonism improve cognitive impairment in schizophrenia and related disorders.

  4. Intrauterine growth restriction modifies the hedonic response to sweet taste in newborn pups - Role of the accumbal μ-opioid receptors.

    Science.gov (United States)

    Laureano, D P; Dalle Molle, R; Alves, M B; Luft, C; Desai, M; Ross, M G; Silveira, P P

    2016-05-13

    Intrauterine growth restriction (IUGR) is associated with increased preference for palatable foods. The hedonic response to sweet taste, modulated by the nucleus accumbens μ-opioid-receptors, may be involved. We investigated hedonic responses and receptor levels in IUGR and Control animals. From pregnancy day 10, Sprague-Dawley dams received either an ad libitum (Control), or a 50% food restricted (FR) diet. At birth, pups were cross-fostered, and nursed by Adlib fed dams. The hedonic response was evaluated at 1 day after birth and at 90 days of life, by giving sucrose solution or water and analyzing the hedonic facial responses (within 60s). Control pups exposed either to water or sucrose resolved their hedonic responses after 16 and 18s, respectively, while FR hedonic responses to sucrose persisted over 20s. FR pups had deceased phospho-μ-opioid-receptor (p=0.009) and reduced phosphor:total mu opioid receptor ratio compared to controls pups (p=0.003). In adults, there was an interaction between group and solution at the end of the evaluation (p=0.044): Control decreased the response after sucrose solution, FR did not change over time. There were no differences in phosphorylation of μ-opioid-receptor in adults. These results demonstrate IUGR newborn rats exhibit alterations in hedonic response accompanied by a decrease in μ-opioid-receptor phosphorylation, though these alterations do not persist at 3 months of age. Opioid system alterations in early life may contribute to the development of preference for highly palatable foods and contribute to rapid weight gain and obesity in IUGR offspring. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Naloxegol

    Science.gov (United States)

    ... acting mu-opioid receptor antagonists. It works by protecting the bowel from the effects of opiate (narcotic) ... such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child- ...

  6. Methylnaltrexone Injection

    Science.gov (United States)

    ... acting mu-opioid receptor antagonists. It works by protecting the bowel from the effects of opioid (narcotic) ... such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child- ...

  7. Methylnaltrexone

    Science.gov (United States)

    ... acting mu-opioid receptor antagonists. It works by protecting the bowel from the effects of opioid (narcotic) ... such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child- ...

  8. Drug: D02102 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available gonist ... DG01563 ... mu-Opioid receptor agonist Analgesic ... DG01984 ... Opioid analgesics Other ... DG01718 ... Drugs for... addictive disorder ... DG01717 ... Drugs for opioid dependence Cyp substrate ... DG01633

  9. Drug: D07810 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available gonist ... DG01563 ... mu-Opioid receptor agonist Analgesic ... DG01984 ... Opioid analgesics Other ... DG01718 ... Drugs for... addictive disorder ... DG01717 ... Drugs for opioid dependence ATC code: N07BC06 Chem

  10. Dgroup: DG00999 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available agonist ... DG01563 ... mu-Opioid receptor agonist Analgesic ... DG01984 ... Opioid analgesics Other ... DG01718 ... Drugs fo...r addictive disorder ... DG01717 ... Drugs for opioid dependence Cyp substrate ... DG0163

  11. Dgroup: DG01002 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available gonist ... DG01563 ... mu-Opioid receptor agonist Analgesic ... DG01984 ... Opioid analgesics Other ... DG01718 ... Drugs for... addictive disorder ... DG01717 ... Drugs for opioid dependence Cyp substrate ... DG01633

  12. Acute detoxification of opioid-addicted patients with naloxone during propofol or methohexital anesthesia: a comparison of withdrawal symptoms, neuroendocrine, metabolic, and cardiovascular patterns

    NARCIS (Netherlands)

    Kienbaum, P.; Scherbaum, N.; Thürauf, N.; Michel, M. C.; Gastpar, M.; Peters, J.

    2000-01-01

    OBJECTIVE: Mu-Opioid receptor blockade during general anesthesia is a new treatment for detoxification of opioid addicted patients. We assessed catecholamine plasma concentrations, oxygen consumption, cardiovascular variables, and withdrawal symptoms after naloxone and tested the hypothesis that

  13. Antagonist-agonist combinations as therapies for heroin addiction: back to the future?

    Science.gov (United States)

    Nutt, David J

    2010-02-01

    Psychopharmacology is a powerful approach to the treatment of many psychiatric disorders. In this article I discuss the conceptual and practical issues in relation to the use of mu opioid receptor agonist, antagonist and partial agonist drugs in the treatment of opioid addiction, as this is one therapeutic area where all three types of agents are currently available. The choice of pharmacological agent is largely determined by patient profile, existence of ongoing drug misuse, and the kinetics of the drugs available. These principles, however, can be applied to other disorders as and when other pharmacological approaches become refined in these areas.

  14. Evidence for a partial deficiency of the LDL (apo B,E) receptor within a family of rhesus monkeys with a spontaneous hypercholesterolemia

    International Nuclear Information System (INIS)

    Scanu, A.M.; Khalil, A.; Tidore, M.; Kaiser, M.; Pfaffinger, D.; Carey, D.; Dawson, G.

    1987-01-01

    Spontaneous hypercholesterolemia is rare among non-human primates. Through screening of a rhesus monkey colony they have identified a family in which 3 out of its 6 members have a persistent hypercholesterolemia on a cholesterol-free Purina Chow diet and are high responders to a dietary fat challenge. On a basal diet the 3 affected animals also exhibited high plasma levels of LDL and apoB. To shed light on the mechanism of the hypercholesterolemia they have grown in culture fibroblasts from skin biopsies obtained from all members of the rhesus monkey family and 12 control. Binding studies at 4 0 C and ligand blotting experiments using 125 I-LDL of either normolipidemic rhesus monkeys or human subjects have shown that the fibroblasts from the 3 monkeys with a spontaneous hypercholesterolemia have a significant reduction of the number of LDL receptor and to the same extent as fibroblasts derived from subjects with heterozygous FH studied at the same time. The data suggest that the spontaneous elevation of plasma cholesterol observed in the 3 family members is related, at least in part, to a defective uptake of LDL by the LDL receptor pathway

  15. Partial rescue of postnatal growth plate abnormalities in Ihh mutants by expression of a constitutively active PTH/PTHrP receptor.

    Science.gov (United States)

    Maeda, Yukiko; Schipani, Ernestina; Densmore, Michael J; Lanske, Beate

    2010-02-01

    Indian hedgehog (Ihh) is essential for chondrocyte proliferation/differentiation and osteoblast differentiation during prenatal endochondral bone formation. Ihh expression in postnatal chondrocytes has a non-redundant role in maintaining a growth plate and sustaining trabecular bone after birth. Loss of Ihh in postnatal chondrocytes results in fusion of the growth plate and a decrease in trabecular bone. In order to normalize this abnormal chondrocyte phenotype and to investigate whether a putative rescue of the growth plate anomalies is sufficient to correct the severe alterations in the bone, we expressed a constitutively active PTH/PTHrP receptor (an Ihh downstream target) in the chondrocytes of Col2 alpha 1-Cre ER; Ihh(dld) mice by mating Col2 alpha 1-Cre ER; Ihh(fl/fl) mice with Col2 alpha 1-constitutively active PTH/PTHrP receptor transgenic mice (Jansen, J). Col2 alpha 1-Cre ER; Ihh(f/f); J mice were then injected with tamoxifen at P0 to generate Col2 alpha 1-Cre ER; Ihh(d/d); J mice. In contrast with the previously reported growth plate phenotype of Col2 alpha 1-Cre ER; Ihh(d/d) mice that displayed ectopic chondrocyte hypertrophy at P7, growth plates of Col2 alpha 1-Cre ER; Ihh(d/d); J double mutants were well organized, and exhibited a gene expression pattern similar to the one of control mice. However, expression of osteoblast markers and Dkk1, a Wnt signaling target, remains decreased in the bone collar of Col2 alpha 1-Cre ER; Ihh(d/d); J mice when compared to control mice despite the rescue of abnormal chondrocyte differentiation. Moreover, proliferation of chondrocytes was still significantly impaired in Col2 alpha 1-Cre ER; Ihh(d/d); J mice, and this eventually led to the fusion of the growth plate at P14. In summary, we have demonstrated that expression of a Jansen receptor in chondrocytes was able to rescue abnormal chondrocyte differentiation but not impaired chondrocyte proliferation and the bone anomalies in mice lacking the Ihh gene in

  16. Partial Cancellation

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Partial Cancellation. Full Cancellation is desirable. But complexity requirements are enormous. 4000 tones, 100 Users billions of flops !!! Main Idea: Challenge: To determine which cross-talker to cancel on what “tone” for a given victim. Constraint: Total complexity is ...

  17. Specificity of DNA-binding by the FAX-1 and NHR-67 nuclear receptors of Caenorhabditis elegans is partially mediated via a subclass-specific P-box residue

    Directory of Open Access Journals (Sweden)

    Smith Eric L

    2008-01-01

    Full Text Available Abstract Background The nuclear receptors of the NR2E class play important roles in pattern formation and nervous system development. Based on a phylogenetic analysis of DNA-binding domains, we define two conserved groups of orthologous NR2E genes: the NR2E1 subclass, which includes C. elegans nhr-67, Drosophila tailless and dissatisfaction, and vertebrate Tlx (NR2E2, NR2E4, NR2E1, and the NR2E3 subclass, which includes C. elegans fax-1 and vertebrate PNR (NR2E5, NR2E3. PNR and Tll nuclear receptors have been shown to bind the hexamer half-site AAGTCA, instead of the hexamer AGGTCA recognized by most other nuclear receptors, suggesting unique DNA-binding properties for NR2E class members. Results We show that NR2E3 subclass member FAX-1, unlike NHR-67 and other NR2E1 subclass members, binds to hexamer half-sites with relaxed specificity: it will bind hexamers with the sequence ANGTCA, although it prefers a purine to a pyrimidine at the second position. We use site-directed mutagenesis to demonstrate that the difference between FAX-1 and NHR-67 binding preference is partially mediated by a conserved subclass-specific asparagine or aspartate residue at position 19 of the DNA-binding domain. This amino acid position is part of the "P box" that plays a critical role in defining binding site specificity and has been shown to make hydrogen-bond contacts to the second position of the hexamer in co-crystal structures for other nuclear receptors. The relaxed specificity allows FAX-1 to bind a much larger repertoire of half-sites than NHR-67. While NR2E1 class proteins bind both monomeric and dimeric sites, the NR2E3 class proteins bind only dimeric sites. The presence of a single strong site adjacent to a very weak site allows dimeric FAX-1 binding, further increasing the number of dimeric binding sites to which FAX-1 may bind in vivo. Conclusion These findings identify subclass-specific DNA-binding specificities and dimerization properties for the NR2E1

  18. The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse.

    Science.gov (United States)

    Kruegel, Andrew C; Grundmann, Oliver

    2017-08-19

    The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu-opioid receptors and competitive antagonists at kappa- and delta-opioid receptors. Furthermore, both alkaloids are G protein-biased agonists of the mu-opioid receptor and therefore, may induce less respiratory depression than classical opioid agonists. The Mitragyna alkaloids also appear to exert diverse activities at other brain receptors (including adrenergic, serotonergic, and dopaminergic receptors), which may explain the complex pharmacological profile of raw kratom extracts, although characterization of effects at these other targets remains extremely limited. Through allometric scaling, doses of pure mitragynine and 7-hydroxymitragynine used in animal studies can be related to single doses of raw kratom plant commonly consumed by humans, permitting preliminary interpretation of expected behavioral and physiological effects in man based on this preclinical data and comparison to both anecdotal human experience and multiple epidemiological surveys. Kratom exposure alone has not been causally associated with human fatalities to date. However, further research is needed to clarify the complex mechanism of action of the Mitragyna alkaloids and unlock their full therapeutic potential. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Partial processing

    International Nuclear Information System (INIS)

    1978-11-01

    This discussion paper considers the possibility of applying to the recycle of plutonium in thermal reactors a particular method of partial processing based on the PUREX process but named CIVEX to emphasise the differences. The CIVEX process is based primarily on the retention of short-lived fission products. The paper suggests: (1) the recycle of fission products with uranium and plutonium in thermal reactor fuel would be technically feasible; (2) it would, however, take ten years or more to develop the CIVEX process to the point where it could be launched on a commercial scale; (3) since the majority of spent fuel to be reprocessed this century will have been in storage for ten years or more, the recycling of short-lived fission products with the U-Pu would not provide an effective means of making refabrication fuel ''inaccessible'' because the radioactivity associated with the fission products would have decayed. There would therefore be no advantage in partial processing

  20. Partial gigantism

    Directory of Open Access Journals (Sweden)

    М.М. Karimova

    2017-05-01

    Full Text Available A girl with partial gigantism (the increased I and II fingers of the left foot is being examined. This condition is a rare and unresolved problem, as the definite reason of its development is not determined. Wait-and-see strategy is recommended, as well as correcting operations after closing of growth zones, and forming of data pool for generalization and development of schemes of drug and radial therapeutic methods.

  1. Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189.

    Science.gov (United States)

    Liu, Yu; McAfee, Samuel S; Guley, Natalie M; Del Mar, Nobel; Bu, Wei; Heldt, Scott A; Honig, Marcia G; Moore, Bob M; Reiner, Anton; Heck, Detlef H

    2017-01-01

    Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression, and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1). Although mTBI did not alter the power of oscillations, it did cause increased coherence of θ (4-10 Hz) and β (10-30 Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple (SWR)-evoked LFP activity in mPFC, downshifted SWR frequencies in CA1, and enhanced θ-γ phase-amplitude coupling (PAC) within mPFC. These abnormalities might be linked to the impaired memory, depression, and persevering fear seen after mTBI. Treatment with the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189 has been shown to mitigate functional deficits and neuronal injury after mTBI in mice. We found that SMM-189 also reversed most of the observed neurophysiological abnormalities. This neurophysiological rescue is likely to stem from the previously reported reduction in neuron loss and/or the preservation of neuronal function and connectivity resulting from SMM-189 treatment, which appears to stem from the biasing of microglia from the proinflammatory M1 state to the prohealing M2 state by SMM-189.

  2. Down, But Not Out: Partial Elimination of Androgen Receptors in the Male Mouse Brain Does Not Affect Androgenic Regulation of Anxiety or HPA Activity.

    Science.gov (United States)

    Chen, Chieh V; Brummet, Jennifer L; Jordan, Cynthia L; Breedlove, S Marc

    2016-02-01

    We previously found that androgen receptor (AR) activity mediates two effects of T in adult male mice: reduction of anxiety-like behaviors and dampening of the hypothalamic-pituitary-adrenal response to stress. To determine whether brain ARs mediate these effects, we used the Cre/loxP technology seeking to disable AR throughout the central nervous system (CNS). Female mice carrying the floxed AR allele (ARlox) were crossed with males carrying cre recombinase transgene controlled by the nestin promoter (NesCre), producing cre in developing neurons and glia. Among male offspring, four genotypes resulted: males carrying ARlox and NesCre (NesARko), and three control groups (wild types, NesCre, and ARlox). Reporter mice indicated ubiquitous Cre expression throughout the CNS. Nevertheless, AR immunocytochemistry in NesARko mice revealed efficient knockout (KO) of AR in some brain regions (hippocampus and medial prefrontal cortex [mPFC]), but not others. Substantial AR protein was seen in the amygdala and hypothalamus among other regions, whereas negligible AR remained in others like the bed nucleus of the stria terminalis and dorsal periaqueductal gray. This selective KO allowed for testing the role of AR in hippocampus and mPFC. Males were castrated and implanted with T at postnatal day 60 before testing on postnatal day 90-100. In contrast with males with global KO of AR, T still modulated anxiety-related behavior and hypothalamic-pituitary-adrenal activity in NesARko males. These results leave open the possibility that AR acting in the CNS mediates these effects of T, but demonstrate that AR is not required in the hippocampus or mPFC for T's anxiolytic effects.

  3. Toll-like receptor 3 stimulation promotes Ro52/TRIM21 synthesis and nuclear redistribution in salivary gland epithelial cells, partially via type I interferon pathway

    Science.gov (United States)

    Kyriakidis, N C; Kapsogeorgou, E K; Gourzi, V C; Konsta, O D; Baltatzis, G E; Tzioufas, A G

    2014-01-01

    Up-regulated expression of Ro52/tripartite motif-containing protein 21 (TRIM21), Ro60/TROVE domain family, member 2 (TROVE2) and lupus LA protein/Sjögren's syndrome antigen B (La/SSB) autoantigens has been described in the salivary gland epithelial cells (SGEC) of patients with Sjögren's syndrome (SS). SGECs, the key regulators of autoimmune SS responses, express high levels of surface functional Toll-like receptor (TLR)-3, whereas Ro52/TRIM21 negatively regulates TLR-3-mediated inflammation. Herein, we investigated the effect of TLR-3-signalling on the expression of Ro52/TRIM21, as well as Ro60/TROVE2 and La/SSB autoantigens, by SGECs. The effect of TLR-3 or TLR-4 stimulation on autoantigen expression was evaluated by polyI:C or lipopolysaccharide (LPS) treatment, respectively, of SGEC lines (10 from SS patients, 12 from non-SS controls) or HeLa cells, followed by analysis of mRNA and protein expression. PolyI:C, but not LPS, resulted in a two-step induction of Ro52/TRIM21 mRNA expression by SGECs, a 12-fold increment at 6 h followed by a 2·5-fold increment at 24–48 h, whereas it induced a late two-fold up-regulation of Ro60/TROVE2 and La/SSB mRNAs at 48 h. Although protein expression levels were not affected significantly, the late up-regulation of Ro52/TRIM21 mRNA was accompanied by protein redistribution, from nucleolar-like pattern to multiple coarse dots spanning throughout the nucleus. These late phenomena were mediated significantly by interferon (IFN)-β production, as attested by cognate secretion and specific inhibition experiments and associated with IFN regulatory factor (IRF)3 degradation. TLR-3-signalling had similar effects on SGECs obtained from SS patients and controls, whereas it did not affect the expression of these autoantigens in HeLa cells. TLR-3 signalling regulates the expression of autoantigens by SGECs, implicating innate immunity pathways in their over-expression in inflamed tissues and possibly in their exposure to the immune

  4. Ivy and neurogliaform interneurons are a major target of μ opioid receptor modulation

    Science.gov (United States)

    Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

    2011-01-01

    Mu opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform cells are not only numerous, but also have unique properties, including promiscuous gap junctions formed with various interneuronal subtypes, volume transmission, and the ability to produce a postsynaptic GABAB response after a single presynaptic spike. Using a mouse line expressing green fluorescent protein under the neuropeptide Y promoter, we find that across all layers of CA1, activation of μORs hyperpolarizes Ivy and neurogliaform cells. Further, paired recordings between synaptically coupled Ivy and pyramidal cells show that Ivy cell terminals are dramatically inhibited by μOR-activation. Effects in Ivy and neurogliaform cells are seen at similar concentrations of agonist as those producing inhibition in fast-spiking PV basket cells. We also report that Ivy cells display the recently described phenomenon of persistent firing, a state of continued firing in the absence of continued input, and that induction of persistent firing is inhibited by μOR-activation. Together these findings identify a major, previously unrecognized, target of μOR-modulation. Given the prominence of this cell type in and beyond CA1, as well as its unique role in microcircuitry, opioid modulation of neurogliaform cells has wide implications. PMID:22016519

  5. Total and partial sleep deprivation: Effects on plasma TNF-αRI, TNF-αRII, and IL-6, and reversal by caffeine operating through adenosine A2 receptor

    Science.gov (United States)

    Shearer, William T.; Reuben, James M.; Lee, Bang-Ning; Mullington, Janet; Price, Nicholas; Dinges, David F.

    2000-01-01

    Plasma levels of IL-6 and TNF-α are elevated in individuals who are deprived of sleep. TNF-α regulates expression of its soluble receptors, sTNF-αRI and sTNF-αRII. Sleep deprivation (SD) also increases extracellular adenosine that induces sedation and sleep. An antagonist of adenosine, caffeine, raises exogenous adenosine levels, stimulates the expression of IL-6 and inhibits the release of TNF-α. Our objective was to determine the effect of total SD (TSD) or partial SD (PSD) on the levels of these sleep regulatory molecules in volunteers who experienced SD with or without the consumption of caffeine. Plasma levels of IL-6, sTNF-αRI and sTNF-αRII were assayed by ELISA in samples collected at 90-min intervals from each subject over an 88-hour period. The results were analyzed by the repeated measures ANOVA. Whereas only TSD significantly increased sTNF-αRI over time, caffeine suppressed both sTNF-α receptors in TSD and PSD subjects. The selective increase in the expression of sTNF-αRI and not sTNF-αRII in subjects experiencing TSD with caffeine compared with others experiencing PSD with caffeine has not been previously reported. Moreover, caffeine significantly increased IL-6 in TSD subjects compared with those who did not receive caffeine. However, subjects who were permitted intermittent naps (PSD) ablated the effects of caffeine and reduced their level of IL-6 to that of the TSD group. These data further lend support to the hypothesis that the sTNF-αRI and not the sTNF-αRII plays a significant role in sleep regulation by TNF-α. .

  6. Misexpression of AtTX12 encoding a Toll/interleukin-1 receptor domain induces growth defects and expression of defense-related genes partially independently of EDS1 in Arabidopsis.

    Science.gov (United States)

    Song, Sang-Kee

    2016-12-01

    In this study, a tissue-specific GAL4/UAS activation tagging system was used for the characterization of genes which could induce lethality when ubiquitously expressed. A dominant mutant exhibiting stunted growth was isolated and named defective root development 1-D (drd1-D). The T-DNA tag was located within the promoter region of AtTX12, which is predicted to encode a truncated nucleotide-binding leucinerich repeat (NLR) protein, containing a Toll/interleukin-1 receptor (TIR) domain. The transcript levels of AtTX12 and defense-related genes were elevated in drd1-D, and the misexpression of AtTX12 recapitulated the drd1-D phenotypes. In the presence of ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1), a key transducer of signals triggered by TIR-type NLRs, a low-level of AtTX12 misexpression induced strong defective phenotypes including seedling lethality whereas, in the absence of EDS1, a high-level of AtTX12 misexpression induced weak growth defects like dwarfism, suggesting that AtTX12 might function mainly in an EDS1-dependent and partially in an EDS1-independent manner. [BMB Reports 2016; 49(12): 693-698].

  7. Cloning of partial putative gonadotropin hormone receptor ...

    Indian Academy of Sciences (India)

    Department of Genetics, School of Biological Sciences, Madurai Kamaraj University, Madurai 625 021, India. *Corresponding author ... and LH, is of a single type or two types is still controversial .... Since sex regulation is an important aspect.

  8. Opioid receptor mediated anticonvulsant effect of pentazocine.

    Science.gov (United States)

    Khanna, N; Khosla, R; Kohli, J

    1998-01-01

    Intraperitoneal (i.p.) administration of (+/-) pentazocine (10, 30 & 50 mg/kg), a Sigma opioid agonist, resulted in a dose dependent anticonvulsant action against maximal electroshock seizures in mice. This anticonvulsant effect of pentazocine was not antagonized by both the doses of naloxone (1 and 10 mg/kg) suggesting thereby that its anticonvulsant action is probably mediated by Sigma opiate binding sites. Its anticonvulsant effect was potentiated by both the anticonvulsant drugs viz. diazepam and diphenylhydantoin. Morphine, mu opioid agonist, on the other hand, failed to protect the animals against maximal electroshock seizures when it was given in doses of 10-40 mg/kg body wt.

  9. Interaction between Mu and Delta Opioid Receptor Agonists in an Assay of Capsaicin-Induced Thermal Allodynia in Rhesus Monkeys

    Directory of Open Access Journals (Sweden)

    S. Stevens Negus

    2012-01-01

    Full Text Available Delta opioid agonists enhance antinociceptive effects of mu-opioid agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+-4-[(αR-α-((2S,5R-4-allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine. Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg. SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception.

  10. Unilateral Partial Nephrectomy with Warm Ischemia Results in Acute Hypoxia Inducible Factor 1-Alpha (HIF-1α and Toll-Like Receptor 4 (TLR4 Overexpression in a Porcine Model.

    Directory of Open Access Journals (Sweden)

    Zhiyong Zhang

    Full Text Available Ischemia/reperfusion (I/R during partial nephrectomy (PN contributes to acute kidney injury (AKI, which is inaccurately assessed using existent clinical markers of renal function. We evaluated I/R-related changes in expression in hypoxia inducible factor 1α (HIF-1α and toll-like receptor 4 (TLR4, within kidney tissue and peripheral blood leukocytes (PBL in a porcine model of PN.Three adult pigs each underwent unilateral renal hilar cross clamping for 180 min followed by a 15 min reperfusion. The contralateral kidney served as control. Biopsies of clamped kidneys were obtained at baseline (time 0, every 60 min during the hypoxic phase, and post-reperfusion. Control kidneys were biopsied once at 180 min. Peripheral blood was sampled at time 0, every 30 min during the hypoxic phase, and post-reperfusion. HIF-1α and TLR4 expression in kidney tissue and PBL were analyzed by Western blotting. I/R-related histological changes were assessed.Expression of HIF-1α in clamped kidneys and PBL was below detection level at baseline, rising to detectable levels after 60 min of hypoxia, and continuing to rise throughout the hypoxic and reperfusion phases. Expression of TLR-4 in clamped kidneys followed a similar trend with initial detection after 30-60 min of hypoxia. Control kidneys exhibited no change in HIF-1α or TLR-4 expression. I/R-related histologic changes were minimal, primarily mild tubular dilatation.In a porcine model of PN, HIF-1α and TLR4 exhibited robust, I/R-related increases in expression in kidney tissue and PBL. Further studies investigating these molecules as potential markers of AKI are warranted.

  11. Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species.

    Science.gov (United States)

    Varty, G B; Hyde, L A; Hodgson, R A; Lu, S X; McCool, M F; Kazdoba, T M; Del Vecchio, R A; Guthrie, D H; Pond, A J; Grzelak, M E; Xu, X; Korfmacher, W A; Tulshian, D; Parker, E M; Higgins, G A

    2005-10-01

    Previous studies have demonstrated behaviors indicative of anxiolysis in rats pretreated with the nociceptin receptor (opioid receptor like-1, ORL-1) agonist, Ro64-6198. The aim of this study was to examine the effects of Ro64-6198 in anxiety models across three species: rat, guinea pig, and mouse. In addition, the receptor specificity of Ro64-6198 was studied, using the ORL-1 receptor antagonist, J-113397, and ORL-1 receptor knockout (KO) mice. Finally, neurological studies examined potential side effects of Ro64-6198 in the rat and mouse. Ro64-6198 (3-10 mg/kg) increased punished responding in a rat conditioned lick suppression test similarly to chlordiazepoxide (6 mg/kg). This effect of Ro64-6198 was attenuated by J-113397 (10 mg/kg), but not the mu opioid antagonist, naltrexone (3 mg/kg). In addition, Ro64-6198 (1-3 mg/kg) reduced isolation-induced vocalizations in rat and guinea pig pups. Ro64-6198 (3 mg/kg) increased the proportion of punished responding in a mouse Geller-Seifter test in wild-type (WT) but not ORL-1 KO mice, whereas diazepam (1-5.6 mg/kg) was effective in both genotypes. In rats, Ro64-6198 reduced locomotor activity (LMA) and body temperature and impaired rotarod, beam walking, and fixed-ratio (FR) performance at doses of 10-30 mg/kg, i.e., three to ten times higher than an anxiolytic dose. In WT mice, Ro64-6198 (3-10 mg/kg) reduced LMA and rotarod performance, body temperature, and FR responding, but these same measures were unaffected in ORL-1 KO mice. Haloperidol (0.3-3 mg/kg) reduced these measures to a similar extent in both genotypes. These studies confirm the potent, ORL-1 receptor-mediated, anxiolytic-like effects of Ro64-6198, extending the findings across three species. Ro64-6198 has target-based side effects, although the magnitude of these effects varies across species.

  12. Sex Differences in Kappa Opioid Receptor Function and Their Potential Impact on Addiction

    Science.gov (United States)

    Chartoff, Elena H.; Mavrikaki, Maria

    2015-01-01

    Behavioral, biological, and social sequelae that lead to drug addiction differ between men and women. Our efforts to understand addiction on a mechanistic level must include studies in both males and females. Stress, anxiety, and depression are tightly linked to addiction, and whether they precede or result from compulsive drug use depends on many factors, including biological sex. The neuropeptide dynorphin (DYN), an endogenous ligand at kappa opioid receptors (KORs), is necessary for stress-induced aversive states and is upregulated in the brain after chronic exposure to drugs of abuse. KOR agonists produce signs of anxiety, fear, and depression in laboratory animals and humans, findings that have led to the hypothesis that drug withdrawal-induced DYN release is instrumental in negative reinforcement processes that drive addiction. However, these studies were almost exclusively conducted in males. Only recently is evidence available that there are sex differences in the effects of KOR activation on affective state. This review focuses on sex differences in DYN and KOR systems and how these might contribute to sex differences in addictive behavior. Much of what is known about how biological sex influences KOR systems is from research on pain systems. The basic molecular and genetic mechanisms that have been discovered to underlie sex differences in KOR function in pain systems may apply to sex differences in KOR function in reward systems. Our goals are to discuss the current state of knowledge on how biological sex contributes to KOR function in the context of pain, mood, and addiction and to explore potential mechanisms for sex differences in KOR function. We will highlight evidence that the function of DYN-KOR systems is influenced in a sex-dependent manner by: polymorphisms in the prodynorphin (pDYN) gene, genetic linkage with the melanocortin-1 receptor (MC1R), heterodimerization of KORs and mu opioid receptors (MORs), and gonadal hormones. Finally, we

  13. Sex differences in kappa opioid receptor function and their potential impact on addiction

    Directory of Open Access Journals (Sweden)

    Elena eChartoff

    2015-12-01

    Full Text Available Behavioral, biological and social sequelae that lead to drug addiction differ between men and women. Our efforts to understand addiction on a mechanistic level must include studies in both males and females. Stress, anxiety, and depression are tightly linked to addiction, and whether they precede or result from compulsive drug use depends on many factors, including biological sex. The neuropeptide dynorphin (DYN, an endogenous ligand at kappa opioid receptors (KORs, is necessary for stress-induced aversive states and is upregulated in the brain after chronic exposure to drugs of abuse. KOR agonists produce signs of anxiety, fear, and depression in laboratory animals and humans, findings that have led to the hypothesis that drug withdrawal-induced DYN release is instrumental in negative reinforcement processes that drive addiction. However, these studies were almost exclusively conducted in males. Only recently is evidence available that there are sex differences in the effects of KOR activation on affective state. This review focuses on sex differences in DYN and KOR systems and how these might contribute to sex differences in addictive behavior. Much of what is known about how biological sex influences KOR systems is from research on pain systems. The basic molecular and genetic mechanisms that have been discovered to underlie sex differences in KOR function in pain systems may apply to sex differences in KOR function in reward systems. Our goals are to discuss the current state of knowledge on how biological sex contributes to KOR function in the context of pain,mood and addiction and to explore potential mechanisms for sex differences in KOR function. We will highlight evidence that the function of DYN-KOR systems is influenced in a sex-dependent manner by: polymorphisms in the prodynorphin (pDYN gene, genetic linkage with the melanocortin-1 receptor (MC1R, heterodimerization of KORs and mu opioid receptors (MORs, and gonadal hormones

  14. Sex Differences in Kappa Opioid Receptor Function and Their Potential Impact on Addiction.

    Science.gov (United States)

    Chartoff, Elena H; Mavrikaki, Maria

    2015-01-01

    Behavioral, biological, and social sequelae that lead to drug addiction differ between men and women. Our efforts to understand addiction on a mechanistic level must include studies in both males and females. Stress, anxiety, and depression are tightly linked to addiction, and whether they precede or result from compulsive drug use depends on many factors, including biological sex. The neuropeptide dynorphin (DYN), an endogenous ligand at kappa opioid receptors (KORs), is necessary for stress-induced aversive states and is upregulated in the brain after chronic exposure to drugs of abuse. KOR agonists produce signs of anxiety, fear, and depression in laboratory animals and humans, findings that have led to the hypothesis that drug withdrawal-induced DYN release is instrumental in negative reinforcement processes that drive addiction. However, these studies were almost exclusively conducted in males. Only recently is evidence available that there are sex differences in the effects of KOR activation on affective state. This review focuses on sex differences in DYN and KOR systems and how these might contribute to sex differences in addictive behavior. Much of what is known about how biological sex influences KOR systems is from research on pain systems. The basic molecular and genetic mechanisms that have been discovered to underlie sex differences in KOR function in pain systems may apply to sex differences in KOR function in reward systems. Our goals are to discuss the current state of knowledge on how biological sex contributes to KOR function in the context of pain, mood, and addiction and to explore potential mechanisms for sex differences in KOR function. We will highlight evidence that the function of DYN-KOR systems is influenced in a sex-dependent manner by: polymorphisms in the prodynorphin (pDYN) gene, genetic linkage with the melanocortin-1 receptor (MC1R), heterodimerization of KORs and mu opioid receptors (MORs), and gonadal hormones. Finally, we

  15. Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine

    Directory of Open Access Journals (Sweden)

    Rodríguez-Muñoz María

    2009-03-01

    Full Text Available Abstract Background Although the systemic administration of cannabinoids produces antinociception, their chronic use leads to analgesic tolerance as well as cross-tolerance to morphine. These effects are mediated by cannabinoids binding to peripheral, spinal and supraspinal CB1 and CB2 receptors, making it difficult to determine the relevance of each receptor type to these phenomena. However, in the brain, the CB1 receptors (CB1Rs are expressed at high levels in neurons, whereas the expression of CB2Rs is marginal. Thus, CB1Rs mediate the effects of smoked cannabis and are also implicated in emotional behaviors. We have analyzed the production of supraspinal analgesia and the development of tolerance at CB1Rs by the direct injection of a series of cannabinoids into the brain. The influence of the activation of CB1Rs on supraspinal analgesia evoked by morphine was also evaluated. Results Intracerebroventricular (icv administration of cannabinoid receptor agonists, WIN55,212-2, ACEA or methanandamide, generated a dose-dependent analgesia. Notably, a single administration of these compounds brought about profound analgesic tolerance that lasted for more than 14 days. This decrease in the effect of cannabinoid receptor agonists was not mediated by depletion of CB1Rs or the loss of regulated G proteins, but, nevertheless, it was accompanied by reduced morphine analgesia. On the other hand, acute morphine administration produced tolerance that lasted only 3 days and did not affect the CB1R. We found that both neural mu-opioid receptors (MORs and CB1Rs interact with the HINT1-RGSZ module, thereby regulating pertussis toxin-insensitive Gz proteins. In mice with reduced levels of these Gz proteins, the CB1R agonists produced no such desensitization or morphine cross-tolerance. On the other hand, experimental enhancement of Gz signaling enabled an acute icv administration of morphine to produce a long-lasting tolerance at MORs that persisted for more than

  16. Characterization of the 1H-cyclopentapyrimidine-2,4(1H,3H)-dione derivative (S)-CPW399 as a novel, potent, and subtype-selective AMPA receptor full agonist with partial desensitization properties

    DEFF Research Database (Denmark)

    Campiani, G; Morelli, E; Nacci, V

    2001-01-01

    (S)-CPW399 (2b) is a novel, potent, and subtype-selective AMPA receptor full agonist that, unlike (S)-willardiine and related compounds, in mouse cerebellar granule cells, stimulated an increase in [Ca(2+)](i), and induced neuronal cell death in a time- and concentration-dependent manner. Compound...... 2b appears to be a weakly desensitizing, full agonist at AMPA receptors and therefore represents a new pharmacological tool to investigate the role of AMPA receptors in excitotoxicity and their molecular mechanisms of desensitization....

  17. A Pepducin Derived from the Third Intracellular Loop of FPR2 Is a Partial Agonist for Direct Activation of This Receptor in Neutrophils But a Full Agonist for Cross-Talk Triggered Reactivation of FPR2

    DEFF Research Database (Denmark)

    Gabl, Michael; Winther, Malene; Skovbakke, Sarah Line

    2014-01-01

    We recently described a novel receptor cross-talk mechanism in neutrophils, unique in that the signals generated by the PAF receptor (PAFR) and the ATP receptor (P2Y2R) transfer formyl peptide receptor 1 (FPR1) from a desensitized (non-signaling) state back to an actively signaling state (Forsman H...... et al., PLoS One, 8:e60169, 2013; Önnheim K, et al., Exp Cell Res, 323:209, 2014). In addition to the G-protein coupled FPR1, neutrophils also express the closely related receptor FPR2. In this study we used an FPR2 specific pepducin, proposed to work as an allosteric modulator at the cytosolic...... signaling interface, to determine whether the cross-talk pathway is utilized also by FPR2. The pepducin used contains a fatty acid linked to a peptide sequence derived from the third intracellular loop of FPR2, and it activates as well as desensensitizes this receptor. We now show that neutrophils...

  18. The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra.

    Directory of Open Access Journals (Sweden)

    Margaret I Davis

    Full Text Available Presynaptic cannabinoid-1 receptors (CB1-R bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB1-Rs are expressed throughout the basal ganglia, including striatum and substantia nigra, where they play a role in learning and control of motivated actions. However, the pattern of CB1-R expression across different striatal compartments, microcircuits and efferent targets, and the contribution of different CB1-R-expressing neurons to this pattern, are unclear. We use a combination of conventional techniques and novel genetic models to evaluate CB1-R expression in striosome (patch and matrix compartments of the striatum, and in nigral targets of striatal medium spiny projection neurons (MSNs. CB1-R protein and mRNA follow a descending dorsolateral-to-ventromedial intensity gradient in the caudal striatum, with elevated expression in striosomes relative to the surrounding matrix. The lateral predominance of striosome CB1-Rs contrasts with that of the classical striosomal marker, the mu opioid receptor (MOR, which is expressed most prominently in rostromedial striosomes. The dorsolateral-to-ventromedial CB1-R gradient is similar to Drd2 dopamine receptor immunoreactivity and opposite to Substance P. This topology of CB1-R expression is maintained downstream in the globus pallidus and substantia nigra. Dense CB1-R-expressing striatonigral fibers extend dorsally within the substantia nigra pars reticulata, and colocalize with bundles of ventrally extending, striosome-targeted, dendrites of dopamine-containing neurons in the substantia nigra pars compacta (striosome-dendron bouquets. Within striatum, CB1-Rs colocalize with fluorescently labeled MSN collaterals within the striosomes. Cre recombinase-mediated deletion of CB1-Rs from cortical projection neurons or MSNs, and MSN-selective reintroduction of CB1-Rs in knockout mice, demonstrate that the principal source of CB1-Rs in dorsolateral striosomes is local MSN collaterals

  19. Partial tooth gear bearings

    Science.gov (United States)

    Vranish, John M. (Inventor)

    2010-01-01

    A partial gear bearing including an upper half, comprising peak partial teeth, and a lower, or bottom, half, comprising valley partial teeth. The upper half also has an integrated roller section between each of the peak partial teeth with a radius equal to the gear pitch radius of the radially outwardly extending peak partial teeth. Conversely, the lower half has an integrated roller section between each of the valley half teeth with a radius also equal to the gear pitch radius of the peak partial teeth. The valley partial teeth extend radially inwardly from its roller section. The peak and valley partial teeth are exactly out of phase with each other, as are the roller sections of the upper and lower halves. Essentially, the end roller bearing of the typical gear bearing has been integrated into the normal gear tooth pattern.

  20. Essays on partial retirement

    NARCIS (Netherlands)

    Kantarci, T.

    2012-01-01

    The five essays in this dissertation address a range of topics in the micro-economic literature on partial retirement. The focus is on the labor market behavior of older age groups. The essays examine the economic and non-economic determinants of partial retirement behavior, the effect of partial

  1. Insulin receptors

    International Nuclear Information System (INIS)

    Kahn, C.R.; Harrison, L.C.

    1988-01-01

    This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

  2. Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

    DEFF Research Database (Denmark)

    Højlund, K.; Wojtaszewski, Jørgen; Birk, Jesper Bratz

    2006-01-01

    AIMS/HYPOTHESIS: Recently we reported the coexistence of postprandial hypoglycaemia and moderate insulin resistance in heterozygous carriers of the Arg1174Gln mutation in the insulin receptor gene (INSR). Controlled studies of in vivo insulin signalling in humans with mutant INSR are unavailable,...

  3. PARTIAL AGONISTS, FULL AGONISTS, ANTAGONISTS - DILEMMAS OF DEFINITION

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

    The absence of selective antagonists makes receptor characterization difficult, and largely dependent on the use of agonists. However, there has been considerable debate as to whether certain drugs acting at G protein-coupled receptors are better described as agonists, partial agonists or

  4. Recurrent Partial Words

    Directory of Open Access Journals (Sweden)

    Francine Blanchet-Sadri

    2011-08-01

    Full Text Available Partial words are sequences over a finite alphabet that may contain wildcard symbols, called holes, which match or are compatible with all letters; partial words without holes are said to be full words (or simply words. Given an infinite partial word w, the number of distinct full words over the alphabet that are compatible with factors of w of length n, called subwords of w, refers to a measure of complexity of infinite partial words so-called subword complexity. This measure is of particular interest because we can construct partial words with subword complexities not achievable by full words. In this paper, we consider the notion of recurrence over infinite partial words, that is, we study whether all of the finite subwords of a given infinite partial word appear infinitely often, and we establish connections between subword complexity and recurrence in this more general framework.

  5. Sex differences in subcellular distribution of delta opioid receptors in the rat hippocampus in response to acute and chronic stress

    Directory of Open Access Journals (Sweden)

    Sanoara Mazid

    2016-12-01

    Full Text Available Drug addiction requires associative learning processes that critically involve hippocampal circuits, including the opioid system. We recently found that acute and chronic stress, important regulators of addictive processes, affect hippocampal opioid levels and mu opioid receptor trafficking in a sexually dimorphic manner. Here, we examined whether acute and chronic stress similarly alters the levels and trafficking of hippocampal delta opioid receptors (DORs. Immediately after acute immobilization stress (AIS or one-day after chronic immobilization stress (CIS, the brains of adult female and male rats were perfusion-fixed with aldehydes. The CA3b region and the dentate hilus of the dorsal hippocampus were quantitatively analyzed by light microscopy using DOR immunoperoxidase or dual label electron microscopy for DOR using silver intensified immunogold particles (SIG and GABA using immunoperoxidase. At baseline, females compared to males had more DORs near the plasmalemma of pyramidal cell dendrites and about 3 times more DOR-labeled CA3 dendritic spines contacted by mossy fibers. In AIS females, near-plasmalemmal DOR-SIGs decreased in GABAergic hilar dendrites. However, in AIS males, near-plasmalemmal DOR-SIGs increased in CA3 pyramidal cell and hilar GABAergic dendrites and the percentage of CA3 dendritic spines contacted by mossy fibers increased to about half that seen in unstressed females. Conversely, after CIS, near-plasmalemmal DOR-SIGs increased in hilar GABA-labeled dendrites of females whereas in males plasmalemmal DOR-SIGs decreased in CA3 pyramidal cell dendrites and near-plasmalemmal DOR-SIGs decreased hilar GABA-labeled dendrites. As CIS in females, but not males, redistributed DOR-SIGs near the plasmalemmal of hilar GABAergic dendrites, a subsequent experiment examined the acute affect of oxycodone on the redistribution of DOR-SIGs in a separate cohort of CIS females. Plasmalemmal DOR-SIGs were significantly elevated on hilar

  6. Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia

    Directory of Open Access Journals (Sweden)

    Sung Won Lee

    2015-06-01

    Full Text Available Gynecomastia is a benign enlargement of the male breast caused by the proliferation of glandular breast tissue. Determining the various causes of gynecomastia such as physiological causes, drugs, systemic diseases, and endocrine disorders is important. Androgen insensitivity syndrome (AIS is a rare endocrine disorder presenting with gynecomastia and is a disorder of male sexual differentiation caused by mutations within the androgen receptor gene. All individuals with AIS have the 46 XY karyotype, although AIS phenotypes can be classified as mild, partial or complete and can differ among both males and females including ambiguous genitalia or infertility in males. We experienced a case of partial AIS presenting with gynecomastia and identified the androgen receptor gene mutation.

  7. Drug: D05938 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05938 Drug Sufentanil (USAN/INN) ... C22H30N2O2S D05938.gif ... Neuropsychiatric agent ... DG02030 ... Anesthetic...s ... DG02027 ... General anesthetics ... DG02026 ... Opioid anesthetics ... DG02027 ... General anesthetic...s ... DG02026 ... Opioid anesthetics ... DG01564 ... Opioid receptor agonist ... DG01563 ... mu-Opioid receptor agonis

  8. Dgroup: DG00792 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available hydrochloride (USP) ... Neuropsychiatric agent ... DG02030 ... Anesthetics ... DG02027 ... General anesthetics ... DG02026 ... Opioid anesthetics... ... DG02027 ... General anesthetics ... DG02026 ... Opioid anesthetics ... DG01564 ... Opioid receptor ...agonist ... DG01563 ... mu-Opioid receptor agonist ATC code: N01AH02 General anesthetics OPRM1 [HSA:4988] [KO:K04215] Enzyme: CYP3A [HSA:1576 1577 1551] ...

  9. Dgroup: DG00793 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available anil citrate (USP) ... Neuropsychiatric agent ... DG02030 ... Anesthetics ... DG02027 ... General anesthetics ... DG02026 ... Opioid anesthetics... ... DG02027 ... General anesthetics ... DG02026 ... Opioid anesthetics ... DG01564 ... Opioid receptor a...gonist ... DG01563 ... mu-Opioid receptor agonist Analgesic ... DG01984 ... Opioid analgesics ATC code: N01AH03 General anesthetics OPRM1 [HSA:4988] [KO:K04215] ...

  10. Hyperbolic partial differential equations

    CERN Document Server

    Witten, Matthew

    1986-01-01

    Hyperbolic Partial Differential Equations III is a refereed journal issue that explores the applications, theory, and/or applied methods related to hyperbolic partial differential equations, or problems arising out of hyperbolic partial differential equations, in any area of research. This journal issue is interested in all types of articles in terms of review, mini-monograph, standard study, or short communication. Some studies presented in this journal include discretization of ideal fluid dynamics in the Eulerian representation; a Riemann problem in gas dynamics with bifurcation; periodic M

  11. Successful removable partial dentures.

    Science.gov (United States)

    Lynch, Christopher D

    2012-03-01

    Removable partial dentures (RPDs) remain a mainstay of prosthodontic care for partially dentate patients. Appropriately designed, they can restore masticatory efficiency, improve aesthetics and speech, and help secure overall oral health. However, challenges remain in providing such treatments, including maintaining adequate plaque control, achieving adequate retention, and facilitating patient tolerance. The aim of this paper is to review the successful provision of RPDs. Removable partial dentures are a successful form of treatment for replacing missing teeth, and can be successfully provided with appropriate design and fabrication concepts in mind.

  12. Beginning partial differential equations

    CERN Document Server

    O'Neil, Peter V

    2011-01-01

    A rigorous, yet accessible, introduction to partial differential equations-updated in a valuable new edition Beginning Partial Differential Equations, Second Edition provides a comprehensive introduction to partial differential equations (PDEs) with a special focus on the significance of characteristics, solutions by Fourier series, integrals and transforms, properties and physical interpretations of solutions, and a transition to the modern function space approach to PDEs. With its breadth of coverage, this new edition continues to present a broad introduction to the field, while also addres

  13. Partial knee replacement - slideshow

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/presentations/100225.htm Partial knee replacement - series—Normal anatomy To use the sharing ... A.M. Editorial team. Related MedlinePlus Health Topics Knee Replacement A.D.A.M., Inc. is accredited ...

  14. Beginning partial differential equations

    CERN Document Server

    O'Neil, Peter V

    2014-01-01

    A broad introduction to PDEs with an emphasis on specialized topics and applications occurring in a variety of fields Featuring a thoroughly revised presentation of topics, Beginning Partial Differential Equations, Third Edition provides a challenging, yet accessible,combination of techniques, applications, and introductory theory on the subjectof partial differential equations. The new edition offers nonstandard coverageon material including Burger's equation, the telegraph equation, damped wavemotion, and the use of characteristics to solve nonhomogeneous problems. The Third Edition is or

  15. Somatostatin receptors

    DEFF Research Database (Denmark)

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

    2003-01-01

    functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual......-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype...

  16. Ecdysteroid receptors in Drosophila melanogaster adult females

    Science.gov (United States)

    Ecdysteroid receptors were identified and partially characterized from total cell extracts of whole animals and dissected tissues from Drosophila melanogaster adult females. Binding studies indicated the presence of two ecdysteroid binding components having high affinity and specificity consistent w...

  17. Partial differential equations

    CERN Document Server

    Evans, Lawrence C

    2010-01-01

    This text gives a comprehensive survey of modern techniques in the theoretical study of partial differential equations (PDEs) with particular emphasis on nonlinear equations. The exposition is divided into three parts: representation formulas for solutions; theory for linear partial differential equations; and theory for nonlinear partial differential equations. Included are complete treatments of the method of characteristics; energy methods within Sobolev spaces; regularity for second-order elliptic, parabolic, and hyperbolic equations; maximum principles; the multidimensional calculus of variations; viscosity solutions of Hamilton-Jacobi equations; shock waves and entropy criteria for conservation laws; and, much more.The author summarizes the relevant mathematics required to understand current research in PDEs, especially nonlinear PDEs. While he has reworked and simplified much of the classical theory (particularly the method of characteristics), he primarily emphasizes the modern interplay between funct...

  18. Optimization of partial search

    International Nuclear Information System (INIS)

    Korepin, Vladimir E

    2005-01-01

    A quantum Grover search algorithm can find a target item in a database faster than any classical algorithm. One can trade accuracy for speed and find a part of the database (a block) containing the target item even faster; this is partial search. A partial search algorithm was recently suggested by Grover and Radhakrishnan. Here we optimize it. Efficiency of the search algorithm is measured by the number of queries to the oracle. The author suggests a new version of the Grover-Radhakrishnan algorithm which uses a minimal number of such queries. The algorithm can run on the same hardware that is used for the usual Grover algorithm. (letter to the editor)

  19. Auxiliary partial liver transplantation

    NARCIS (Netherlands)

    C.B. Reuvers (Cornelis Bastiaan)

    1986-01-01

    textabstractIn this thesis studies on auxiliary partial liver transplantation in the dog and the pig are reported. The motive to perform this study was the fact that patients with acute hepatic failure or end-stage chronic liver disease are often considered to form too great a risk for successful

  20. Partial Remission Definition

    DEFF Research Database (Denmark)

    Andersen, Marie Louise Max; Hougaard, Philip; Pörksen, Sven

    2014-01-01

    OBJECTIVE: To validate the partial remission (PR) definition based on insulin dose-adjusted HbA1c (IDAA1c). SUBJECTS AND METHODS: The IDAA1c was developed using data in 251 children from the European Hvidoere cohort. For validation, 129 children from a Danish cohort were followed from the onset...

  1. Fundamental partial compositeness

    DEFF Research Database (Denmark)

    Sannino, Francesco; Strumia, Alessandro; Tesi, Andrea

    2016-01-01

    We construct renormalizable Standard Model extensions, valid up to the Planck scale, that give a composite Higgs from a new fundamental strong force acting on fermions and scalars. Yukawa interactions of these particles with Standard Model fermions realize the partial compositeness scenario. Unde...

  2. Partially ordered models

    NARCIS (Netherlands)

    Fernandez, R.; Deveaux, V.

    2010-01-01

    We provide a formal definition and study the basic properties of partially ordered chains (POC). These systems were proposed to model textures in image processing and to represent independence relations between random variables in statistics (in the later case they are known as Bayesian networks).

  3. Partially Hidden Markov Models

    DEFF Research Database (Denmark)

    Forchhammer, Søren Otto; Rissanen, Jorma

    1996-01-01

    Partially Hidden Markov Models (PHMM) are introduced. They differ from the ordinary HMM's in that both the transition probabilities of the hidden states and the output probabilities are conditioned on past observations. As an illustration they are applied to black and white image compression where...

  4. Honesty in partial logic

    NARCIS (Netherlands)

    W. van der Hoek (Wiebe); J.O.M. Jaspars; E. Thijsse

    1995-01-01

    textabstractWe propose an epistemic logic in which knowledge is fully introspective and implies truth, although truth need not imply epistemic possibility. The logic is presented in sequential format and is interpreted in a natural class of partial models, called balloon models. We examine the

  5. Algebraic partial Boolean algebras

    International Nuclear Information System (INIS)

    Smith, Derek

    2003-01-01

    Partial Boolean algebras, first studied by Kochen and Specker in the 1960s, provide the structure for Bell-Kochen-Specker theorems which deny the existence of non-contextual hidden variable theories. In this paper, we study partial Boolean algebras which are 'algebraic' in the sense that their elements have coordinates in an algebraic number field. Several of these algebras have been discussed recently in a debate on the validity of Bell-Kochen-Specker theorems in the context of finite precision measurements. The main result of this paper is that every algebraic finitely-generated partial Boolean algebra B(T) is finite when the underlying space H is three-dimensional, answering a question of Kochen and showing that Conway and Kochen's infinite algebraic partial Boolean algebra has minimum dimension. This result contrasts the existence of an infinite (non-algebraic) B(T) generated by eight elements in an abstract orthomodular lattice of height 3. We then initiate a study of higher-dimensional algebraic partial Boolean algebras. First, we describe a restriction on the determinants of the elements of B(T) that are generated by a given set T. We then show that when the generating set T consists of the rays spanning the minimal vectors in a real irreducible root lattice, B(T) is infinite just if that root lattice has an A 5 sublattice. Finally, we characterize the rays of B(T) when T consists of the rays spanning the minimal vectors of the root lattice E 8

  6. Drug: D07122 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available hetics ... DG02027 ... General anesthetics ... DG02026 ... Opioid anesthetics ... DG02027 ... General anesthetic...s ... DG02026 ... Opioid anesthetics ... DG01564 ... Opioid receptor agonist ... DG01563 ... mu-Opioid recepto... D07122 Drug Alfentanil (INN); Rapifen (TN) ... C21H32N6O3 D07122.gif ... Neuropsychiatric agent ... DG02030 ... Anest

  7. Drug: D08473 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available tric agent ... DG02030 ... Anesthetics ... DG02027 ... General anesthetics ... DG02026 ... Opioid anesthetics ... DG02027 ... General anesthetic...s ... DG02026 ... Opioid anesthetics ... DG01564 ... Opioid receptor agonist ... DG01563 ... mu-Opioid recept... D08473 Drug Remifentanil (INN); Ultiva (TN) ... C20H28N2O5 D08473.gif ... Neuropsychia

  8. Analysis of Remifentanil with Liquid Chromatography-Tandem Mass Spectrometry and an Extensive Stability Investigation in EDTA Whole Blood and Acidified EDTA Plasma

    NARCIS (Netherlands)

    Koster, Remco A.; Vereecke, Hugo E. M.; Greijdanus, Ben; Touw, Daan J.; Struys, Michel M. R. F.; Alffenaar, Jan Willem C.

    BACKGROUND: Remifentanil is a mu-opioid receptor agonist that was developed as a synthetic opioid for use in anesthesia and intensive care medicine. Remifentanil is rapidly metabolized in both blood and tissues, which results in a very short duration of action. Even after blood sampling,

  9. Endogenous Opioid-Masked Latent Pain Sensitization

    DEFF Research Database (Denmark)

    Pereira, Manuel P; Donahue, Renee R; Dahl, Jørgen B

    2015-01-01

    UNLABELLED: Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chr...

  10. Neural response to alcohol taste cues in youth : Effects of the OPRM1 gene

    NARCIS (Netherlands)

    Korucuoglu, Ozlem; Gladwin, Thomas E.; Baas, Frank; Mocking, Roel J. T.; Ruhé, Henricus G.; Groot, Paul F. C.; Wiers, Reinout W.

    2017-01-01

    Genetic variations in the mu-opioid receptor (OPRM1) gene have been related to high sensitivity to rewarding effects of alcohol. The current study focuses on the neural circuitry underlying this phenomenon using an alcohol versus water taste-cue reactivity paradigm in a young sample at relatively

  11. Neural response to alcohol taste cues in youth : effects of the OPRM1 gene

    NARCIS (Netherlands)

    Korucuoglu, O.; Gladwin, T.E.; Baas, F.; Mocking, R.J.T.; Ruhé, H.G.; Groot, P.F.C.; Wiers, R.W.

    2017-01-01

    Genetic variations in the mu-opioid receptor (OPRM1) gene have been related to high sensitivity to rewarding effects of alcohol. The current study focuses on the neural circuitry underlying this phenomenon using an alcohol versus water taste-cue reactivity paradigm in a young sample at relatively

  12. Partially composite Higgs models

    DEFF Research Database (Denmark)

    Alanne, Tommi; Buarque Franzosi, Diogo; Frandsen, Mads T.

    2018-01-01

    We study the phenomenology of partially composite-Higgs models where electroweak symmetry breaking is dynamically induced, and the Higgs is a mixture of a composite and an elementary state. The models considered have explicit realizations in terms of gauge-Yukawa theories with new strongly...... interacting fermions coupled to elementary scalars and allow for a very SM-like Higgs state. We study constraints on their parameter spaces from vacuum stability and perturbativity as well as from LHC results and find that requiring vacuum stability up to the compositeness scale already imposes relevant...... constraints. A small part of parameter space around the classically conformal limit is stable up to the Planck scale. This is however already strongly disfavored by LHC results. in different limits, the models realize both (partially) composite-Higgs and (bosonic) technicolor models and a dynamical extension...

  13. Photogenic partial seizures.

    Science.gov (United States)

    Hennessy, M J; Binnie, C D

    2000-01-01

    To establish the incidence and symptoms of partial seizures in a cohort of patients investigated on account of known sensitivity to intermittent photic stimulation and/or precipitation of seizures by environmental visual stimuli such as television (TV) screens or computer monitors. We report 43 consecutive patients with epilepsy, who had exhibited a significant EEG photoparoxysmal response or who had seizures precipitated by environmental visual stimuli and underwent detailed assessment of their photosensitivity in the EEG laboratory, during which all were questioned concerning their ictal symptoms. All patients were considered on clinical grounds to have an idiopathic epilepsy syndrome. Twenty-eight (65%) patients reported visually precipitated attacks occurring initially with maintained consciousness, in some instances evolving to a period of confusion or to a secondarily generalized seizure. Visual symptoms were most commonly reported and included positive symptoms such as coloured circles or spots, but also blindness and subjective symptoms such as "eyes going funny." Other symptoms described included nonspecific cephalic sensations, deja-vu, auditory hallucinations, nausea, and vomiting. No patient reported any clear spontaneous partial seizures, and there were no grounds for supposing that any had partial epilepsy excepting the ictal phenomenology of some or all of the visually induced attacks. These findings provide clinical support for the physiological studies that indicate that the trigger mechanism for human photosensitivity involves binocularly innervated cells located in the visual cortex. Thus the visual cortex is the seat of the primary epileptogenic process, and the photically triggered discharges and seizures may be regarded as partial with secondary generalization.

  14. Arthroscopic partial medial meniscectomy

    Directory of Open Access Journals (Sweden)

    Dašić Žarko

    2011-01-01

    Full Text Available Background/Aim. Meniscal injuries are common in professional or recreational sports as well as in daily activities. If meniscal lesions lead to physical impairment they usually require surgical treatment. Arthroscopic treatment of meniscal injuries is one of the most often performed orthopedic operative procedures. Methods. The study analyzed the results of arthroscopic partial medial meniscectomy in 213 patients in a 24-month period, from 2006, to 2008. Results. In our series of arthroscopically treated medial meniscus tears we noted 78 (36.62% vertical complete bucket handle lesions, 19 (8.92% vertical incomplete lesions, 18 (8.45% longitudinal tears, 35 (16.43% oblique tears, 18 (8.45% complex degenerative lesions, 17 (7.98% radial lesions and 28 (13.14% horisontal lesions. Mean preoperative International Knee Documentation Committee (IKDC score was 49.81%, 1 month after the arthroscopic partial medial meniscectomy the mean IKDC score was 84.08%, and 6 months after mean IKDC score was 90.36%. Six months after the procedure 197 (92.49% of patients had good or excellent subjective postoperative clinical outcomes, while 14 (6.57% patients subjectively did not notice a significant improvement after the intervention, and 2 (0.93% patients had no subjective improvement after the partial medial meniscectomy at all. Conclusion. Arthroscopic partial medial meniscetomy is minimally invasive diagnostic and therapeutic procedure and in well selected cases is a method of choice for treatment of medial meniscus injuries when repair techniques are not a viable option. It has small rate of complications, low morbidity and fast rehabilitation.

  15. Hierarchical partial order ranking

    International Nuclear Information System (INIS)

    Carlsen, Lars

    2008-01-01

    Assessing the potential impact on environmental and human health from the production and use of chemicals or from polluted sites involves a multi-criteria evaluation scheme. A priori several parameters are to address, e.g., production tonnage, specific release scenarios, geographical and site-specific factors in addition to various substance dependent parameters. Further socio-economic factors may be taken into consideration. The number of parameters to be included may well appear to be prohibitive for developing a sensible model. The study introduces hierarchical partial order ranking (HPOR) that remedies this problem. By HPOR the original parameters are initially grouped based on their mutual connection and a set of meta-descriptors is derived representing the ranking corresponding to the single groups of descriptors, respectively. A second partial order ranking is carried out based on the meta-descriptors, the final ranking being disclosed though average ranks. An illustrative example on the prioritisation of polluted sites is given. - Hierarchical partial order ranking of polluted sites has been developed for prioritization based on a large number of parameters

  16. Partially ordered algebraic systems

    CERN Document Server

    Fuchs, Laszlo

    2011-01-01

    Originally published in an important series of books on pure and applied mathematics, this monograph by a distinguished mathematician explores a high-level area in algebra. It constitutes the first systematic summary of research concerning partially ordered groups, semigroups, rings, and fields. The self-contained treatment features numerous problems, complete proofs, a detailed bibliography, and indexes. It presumes some knowledge of abstract algebra, providing necessary background and references where appropriate. This inexpensive edition of a hard-to-find systematic survey will fill a gap i

  17. Infinite partial summations

    International Nuclear Information System (INIS)

    Sprung, D.W.L.

    1975-01-01

    This paper is a brief review of those aspects of the effective interaction problem that can be grouped under the heading of infinite partial summations of the perturbation series. After a brief mention of the classic examples of infinite summations, the author turns to the effective interaction problem for two extra core particles. Their direct interaction is summed to produce the G matrix, while their indirect interaction through the core is summed in a variety of ways under the heading of core polarization. (orig./WL) [de

  18. On universal partial words

    OpenAIRE

    Chen, Herman Z. Q.; Kitaev, Sergey; Mütze, Torsten; Sun, Brian Y.

    2016-01-01

    A universal word for a finite alphabet $A$ and some integer $n\\geq 1$ is a word over $A$ such that every word in $A^n$ appears exactly once as a subword (cyclically or linearly). It is well-known and easy to prove that universal words exist for any $A$ and $n$. In this work we initiate the systematic study of universal partial words. These are words that in addition to the letters from $A$ may contain an arbitrary number of occurrences of a special `joker' symbol $\\Diamond\

  19. Partial differential equations

    CERN Document Server

    Agranovich, M S

    2002-01-01

    Mark Vishik's Partial Differential Equations seminar held at Moscow State University was one of the world's leading seminars in PDEs for over 40 years. This book celebrates Vishik's eightieth birthday. It comprises new results and survey papers written by many renowned specialists who actively participated over the years in Vishik's seminars. Contributions include original developments and methods in PDEs and related fields, such as mathematical physics, tomography, and symplectic geometry. Papers discuss linear and nonlinear equations, particularly linear elliptic problems in angles and gener

  20. Partial differential equations

    CERN Document Server

    Levine, Harold

    1997-01-01

    The subject matter, partial differential equations (PDEs), has a long history (dating from the 18th century) and an active contemporary phase. An early phase (with a separate focus on taut string vibrations and heat flow through solid bodies) stimulated developments of great importance for mathematical analysis, such as a wider concept of functions and integration and the existence of trigonometric or Fourier series representations. The direct relevance of PDEs to all manner of mathematical, physical and technical problems continues. This book presents a reasonably broad introductory account of the subject, with due regard for analytical detail, applications and historical matters.

  1. Partial differential equations

    CERN Document Server

    Sloan, D; Süli, E

    2001-01-01

    /homepage/sac/cam/na2000/index.html7-Volume Set now available at special set price ! Over the second half of the 20th century the subject area loosely referred to as numerical analysis of partial differential equations (PDEs) has undergone unprecedented development. At its practical end, the vigorous growth and steady diversification of the field were stimulated by the demand for accurate and reliable tools for computational modelling in physical sciences and engineering, and by the rapid development of computer hardware and architecture. At the more theoretical end, the analytical insight in

  2. Elliptic partial differential equations

    CERN Document Server

    Han, Qing

    2011-01-01

    Elliptic Partial Differential Equations by Qing Han and FangHua Lin is one of the best textbooks I know. It is the perfect introduction to PDE. In 150 pages or so it covers an amazing amount of wonderful and extraordinary useful material. I have used it as a textbook at both graduate and undergraduate levels which is possible since it only requires very little background material yet it covers an enormous amount of material. In my opinion it is a must read for all interested in analysis and geometry, and for all of my own PhD students it is indeed just that. I cannot say enough good things abo

  3. Generalized Partial Volume

    DEFF Research Database (Denmark)

    Darkner, Sune; Sporring, Jon

    2011-01-01

    Mutual Information (MI) and normalized mutual information (NMI) are popular choices as similarity measure for multimodal image registration. Presently, one of two approaches is often used for estimating these measures: The Parzen Window (PW) and the Generalized Partial Volume (GPV). Their theoret...... of view as well as w.r.t. computational complexity. Finally, we present algorithms for both approaches for NMI which is comparable in speed to Sum of Squared Differences (SSD), and we illustrate the differences between PW and GPV on a number of registration examples....

  4. Receptor assay

    Energy Technology Data Exchange (ETDEWEB)

    Kato, K; Ibayashi, H [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

    1975-05-01

    This paper summarized present status and problems of analysis of hormone receptor and a few considerations on clinical significance of receptor abnormalities. It was pointed that in future clinical field quantitative and qualitative analysis of receptor did not remain only in the etiological discussion, but that it was an epoch-making field of investigation which contained the possiblity of artificial change of sensitivity of living body on drugs and the development connected directly with treatment of various diseases.

  5. Unilateral removable partial dentures.

    Science.gov (United States)

    Goodall, W A; Greer, A C; Martin, N

    2017-01-27

    Removable partial dentures (RPDs) are widely used to replace missing teeth in order to restore both function and aesthetics for the partially dentate patient. Conventional RPD design is frequently bilateral and consists of a major connector that bridges both sides of the arch. Some patients cannot and will not tolerate such an extensive appliance. For these patients, bridgework may not be a predictable option and it is not always possible to provide implant-retained restorations. This article presents unilateral RPDs as a potential treatment modality for such patients and explores indications and contraindications for their use, including factors relating to patient history, clinical presentation and patient wishes. Through case examples, design, material and fabrication considerations will be discussed. While their use is not widespread, there are a number of patients who benefit from the provision of unilateral RPDs. They are a useful treatment to have in the clinician's armamentarium, but a highly-skilled dental team and a specific patient presentation is required in order for them to be a reasonable and predictable prosthetic option.

  6. Tutorial on Online Partial Evaluation

    Directory of Open Access Journals (Sweden)

    William R. Cook

    2011-09-01

    Full Text Available This paper is a short tutorial introduction to online partial evaluation. We show how to write a simple online partial evaluator for a simple, pure, first-order, functional programming language. In particular, we show that the partial evaluator can be derived as a variation on a compositionally defined interpreter. We demonstrate the use of the resulting partial evaluator for program optimization in the context of model-driven development.

  7. Type-Directed Partial Evaluation

    DEFF Research Database (Denmark)

    Danvy, Olivier

    1998-01-01

    Type-directed partial evaluation uses a normalization function to achieve partial evaluation. These lecture notes review its background, foundations, practice, and applications. Of specific interest is the modular technique of offline and online type-directed partial evaluation in Standard ML...

  8. Type-Directed Partial Evaluation

    DEFF Research Database (Denmark)

    Danvy, Olivier

    1998-01-01

    Type-directed partial evaluation uses a normalization function to achieve partial evaluation. These lecture notes review its background, foundations, practice, and applications. Of specific interest is the modular technique of offline and online type-directed partial evaluation in Standard ML of ...

  9. Applied partial differential equations

    CERN Document Server

    Logan, J David

    2004-01-01

    This primer on elementary partial differential equations presents the standard material usually covered in a one-semester, undergraduate course on boundary value problems and PDEs. What makes this book unique is that it is a brief treatment, yet it covers all the major ideas: the wave equation, the diffusion equation, the Laplace equation, and the advection equation on bounded and unbounded domains. Methods include eigenfunction expansions, integral transforms, and characteristics. Mathematical ideas are motivated from physical problems, and the exposition is presented in a concise style accessible to science and engineering students; emphasis is on motivation, concepts, methods, and interpretation, rather than formal theory. This second edition contains new and additional exercises, and it includes a new chapter on the applications of PDEs to biology: age structured models, pattern formation; epidemic wave fronts, and advection-diffusion processes. The student who reads through this book and solves many of t...

  10. Inductance loop and partial

    CERN Document Server

    Paul, Clayton R

    2010-01-01

    "Inductance is an unprecedented text, thoroughly discussing "loop" inductance as well as the increasingly important "partial" inductance. These concepts and their proper calculation are crucial in designing modern high-speed digital systems. World-renowned leader in electromagnetics Clayton Paul provides the knowledge and tools necessary to understand and calculate inductance." "With the present and increasing emphasis on high-speed digital systems and high-frequency analog systems, it is imperative that system designers develop an intimate understanding of the concepts and methods in this book. Inductance is a much-needed textbook designed for senior and graduate-level engineering students, as well as a hands-on guide for working engineers and professionals engaged in the design of high-speed digital and high-frequency analog systems."--Jacket.

  11. Fundamental partial compositeness

    CERN Document Server

    Sannino, Francesco

    2016-11-07

    We construct renormalizable Standard Model extensions, valid up to the Planck scale, that give a composite Higgs from a new fundamental strong force acting on fermions and scalars. Yukawa interactions of these particles with Standard Model fermions realize the partial compositeness scenario. Successful models exist because gauge quantum numbers of Standard Model fermions admit a minimal enough 'square root'. Furthermore, right-handed SM fermions have an SU(2)$_R$-like structure, yielding a custodially-protected composite Higgs. Baryon and lepton numbers arise accidentally. Standard Model fermions acquire mass at tree level, while the Higgs potential and flavor violations are generated by quantum corrections. We further discuss accidental symmetries and other dynamical features stemming from the new strongly interacting scalars. If the same phenomenology can be obtained from models without our elementary scalars, they would reappear as composite states.

  12. Fundamental partial compositeness

    International Nuclear Information System (INIS)

    Sannino, Francesco; Strumia, Alessandro; Tesi, Andrea; Vigiani, Elena

    2016-01-01

    We construct renormalizable Standard Model extensions, valid up to the Planck scale, that give a composite Higgs from a new fundamental strong force acting on fermions and scalars. Yukawa interactions of these particles with Standard Model fermions realize the partial compositeness scenario. Under certain assumptions on the dynamics of the scalars, successful models exist because gauge quantum numbers of Standard Model fermions admit a minimal enough ‘square root’. Furthermore, right-handed SM fermions have an SU(2)_R-like structure, yielding a custodially-protected composite Higgs. Baryon and lepton numbers arise accidentally. Standard Model fermions acquire mass at tree level, while the Higgs potential and flavor violations are generated by quantum corrections. We further discuss accidental symmetries and other dynamical features stemming from the new strongly interacting scalars. If the same phenomenology can be obtained from models without our elementary scalars, they would reappear as composite states.

  13. Partial oxidation process

    International Nuclear Information System (INIS)

    Najjar, M.S.

    1987-01-01

    A process is described for the production of gaseous mixtures comprising H/sub 2/+CO by the partial oxidation of a fuel feedstock comprising a heavy liquid hydrocarbonaceous fuel having a nickel, iron, and vanadium-containing ash or petroleum coke having a nickel, iron, and vanadium-containing ash, or mixtures thereof. The feedstock includes a minimum of 0.5 wt. % of sulfur and the ash includes a minimum of 5.0 wt. % vanadium, a minimum of 0.5 ppm nickel, and a minimum of 0.5 ppm iron. The process comprises: (1) mixing together a copper-containing additive with the fuel feedstock; wherein the weight ratio of copper-containing additive to ash in the fuel feedstock is in the range of about 1.0-10.0, and there is at least 10 parts by weight of copper for each part by weight of vanadium; (2) reacting the mixture from (1) at a temperature in the range of 2200 0 F to 2900 0 F and a pressure in the range of about 5 to 250 atmospheres in a free-flow refactory lined partial oxidation reaction zone with a free-oxygen containing gas in the presence of a temperature moderator and in a reducing atmosphere to produce a hot raw effluent gas stream comprising H/sub 2/+CO and entrained molten slag; and where in the reaction zone and the copper-containing additive combines with at least a portion of the nickel and iron constituents and sulfur found in the feedstock to produce a liquid phase washing agent that collects and transports at least a portion of the vanadium-containing oxide laths and spinels and other ash components and refractory out of the reaction zone; and (3) separating nongaseous materials from the hot raw effluent gas stream

  14. Experts' understanding of partial derivatives using the Partial Derivative Machine

    OpenAIRE

    Roundy, David; Dorko, Allison; Dray, Tevian; Manogue, Corinne A.; Weber, Eric

    2014-01-01

    Partial derivatives are used in a variety of different ways within physics. Most notably, thermodynamics uses partial derivatives in ways that students often find confusing. As part of a collaboration with mathematics faculty, we are at the beginning of a study of the teaching of partial derivatives, a goal of better aligning the teaching of multivariable calculus with the needs of students in STEM disciplines. As a part of this project, we have performed a pilot study of expert understanding...

  15. Partial Actions and Power Sets

    Directory of Open Access Journals (Sweden)

    Jesús Ávila

    2013-01-01

    Full Text Available We consider a partial action (X,α with enveloping action (T,β. In this work we extend α to a partial action on the ring (P(X,Δ,∩ and find its enveloping action (E,β. Finally, we introduce the concept of partial action of finite type to investigate the relationship between (E,β and (P(T,β.

  16. Algorithms over partially ordered sets

    DEFF Research Database (Denmark)

    Baer, Robert M.; Østerby, Ole

    1969-01-01

    in partially ordered sets, answer the combinatorial question of how many maximal chains might exist in a partially ordered set withn elements, and we give an algorithm for enumerating all maximal chains. We give (in § 3) algorithms which decide whether a partially ordered set is a (lower or upper) semi......-lattice, and whether a lattice has distributive, modular, and Boolean properties. Finally (in § 4) we give Algol realizations of the various algorithms....

  17. Anatomic partial nephrectomy: technique evolution.

    Science.gov (United States)

    Azhar, Raed A; Metcalfe, Charles; Gill, Inderbir S

    2015-03-01

    Partial nephrectomy provides equivalent long-term oncologic and superior functional outcomes as radical nephrectomy for T1a renal masses. Herein, we review the various vascular clamping techniques employed during minimally invasive partial nephrectomy, describe the evolution of our partial nephrectomy technique and provide an update on contemporary thinking about the impact of ischemia on renal function. Recently, partial nephrectomy surgical technique has shifted away from main artery clamping and towards minimizing/eliminating global renal ischemia during partial nephrectomy. Supported by high-fidelity three-dimensional imaging, novel anatomic-based partial nephrectomy techniques have recently been developed, wherein partial nephrectomy can now be performed with segmental, minimal or zero global ischemia to the renal remnant. Sequential innovations have included early unclamping, segmental clamping, super-selective clamping and now culminating in anatomic zero-ischemia surgery. By eliminating 'under-the-gun' time pressure of ischemia for the surgeon, these techniques allow an unhurried, tightly contoured tumour excision with point-specific sutured haemostasis. Recent data indicate that zero-ischemia partial nephrectomy may provide better functional outcomes by minimizing/eliminating global ischemia and preserving greater vascularized kidney volume. Contemporary partial nephrectomy includes a spectrum of surgical techniques ranging from conventional-clamped to novel zero-ischemia approaches. Technique selection should be tailored to each individual case on the basis of tumour characteristics, surgical feasibility, surgeon experience, patient demographics and baseline renal function.

  18. Partial order infinitary term rewriting

    DEFF Research Database (Denmark)

    Bahr, Patrick

    2014-01-01

    We study an alternative model of infinitary term rewriting. Instead of a metric on terms, a partial order on partial terms is employed to formalise convergence of reductions. We consider both a weak and a strong notion of convergence and show that the metric model of convergence coincides with th...... to the metric setting -- orthogonal systems are both infinitarily confluent and infinitarily normalising in the partial order setting. The unique infinitary normal forms that the partial order model admits are Böhm trees....

  19. Blockade of Nociceptin Signaling Reduces Biochemical, Structural and Cognitive Deficits after Traumatic Brain Injury

    Science.gov (United States)

    2010-07-01

    also will determine if ORL1 antagonists block downstream gene transcription subsequent to enzyme activation. BODY: Task 1a was to optimize blast...value between 60 and 80 psi at which defects in vestibulomotor function can be detected. These findings could potentially become a clinical...nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: a molecular mechanism for

  20. Molecular analysis of the nerve growth factor receptor

    International Nuclear Information System (INIS)

    Hempstead, B.; Patil, N.; Olson, K.; Chao, M.

    1988-01-01

    An essential molecule in the translocation of information by nerve growth factor (NGF) to responsive cells is the cell-surface receptor for NGF. This paper presents information on the genomic structure of the NGF receptor gene, NGF receptor models, and transfection of NGF receptors. Equilibrium binding of [ 125 I]NGF to cells reveals two distinct affinity states for the NGF receptor. The human NGF receptor gene is a single-copy gene, consisting of six exons that span 23 kb. The receptor gene is capable of being transferred to fibroblast cells from human genomic DNA and expressed at high levels. The constitutive nature of the receptor promoter sequence is a partial explanation of why this tissue-specific gene is expressed efficiently in a variety of nonneuronal cells after genomic gene transfer. The two kinetic forms of the NGF receptor appear to be encoded by the same protein, which is the product of a single gene

  1. On Degenerate Partial Differential Equations

    OpenAIRE

    Chen, Gui-Qiang G.

    2010-01-01

    Some of recent developments, including recent results, ideas, techniques, and approaches, in the study of degenerate partial differential equations are surveyed and analyzed. Several examples of nonlinear degenerate, even mixed, partial differential equations, are presented, which arise naturally in some longstanding, fundamental problems in fluid mechanics and differential geometry. The solution to these fundamental problems greatly requires a deep understanding of nonlinear degenerate parti...

  2. [Acrylic resin removable partial dentures

    NARCIS (Netherlands)

    Baat, C. de; Witter, D.J.; Creugers, N.H.J.

    2011-01-01

    An acrylic resin removable partial denture is distinguished from other types of removable partial dentures by an all-acrylic resin base which is, in principle, solely supported by the edentulous regions of the tooth arch and in the maxilla also by the hard palate. When compared to the other types of

  3. Partial Epilepsy with Auditory Features

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2004-07-01

    Full Text Available The clinical characteristics of 53 sporadic (S cases of idiopathic partial epilepsy with auditory features (IPEAF were analyzed and compared to previously reported familial (F cases of autosomal dominant partial epilepsy with auditory features (ADPEAF in a study at the University of Bologna, Italy.

  4. Partial twisting for scalar mesons

    International Nuclear Information System (INIS)

    Agadjanov, Dimitri; Meißner, Ulf-G.; Rusetsky, Akaki

    2014-01-01

    The possibility of imposing partially twisted boundary conditions is investigated for the scalar sector of lattice QCD. According to the commonly shared belief, the presence of quark-antiquark annihilation diagrams in the intermediate state generally hinders the use of the partial twisting. Using effective field theory techniques in a finite volume, and studying the scalar sector of QCD with total isospin I=1, we however demonstrate that partial twisting can still be performed, despite the fact that annihilation diagrams are present. The reason for this are delicate cancellations, which emerge due to the graded symmetry in partially quenched QCD with valence, sea and ghost quarks. The modified Lüscher equation in case of partial twisting is given

  5. Cast Partial Denture versus Acrylic Partial Denture for Replacement of Missing Teeth in Partially Edentulous Patients

    Directory of Open Access Journals (Sweden)

    Pramita Suwal

    2017-03-01

    Full Text Available Aim: To compare the effects of cast partial denture with conventional all acrylic denture in respect to retention, stability, masticatory efficiency, comfort and periodontal health of abutments. Methods: 50 adult partially edentulous patient seeking for replacement of missing teeth having Kennedy class I and II arches with or without modification areas were selected for the study. Group-A was treated with cast partial denture and Group-B with acrylic partial denture. Data collected during follow-up visit of 3 months, 6 months, and 1 year by evaluating retention, stability, masticatory efficiency, comfort, periodontal health of abutment. Results: Chi-square test was applied to find out differences between the groups at 95% confidence interval where p = 0.05. One year comparison shows that cast partial denture maintained retention and stability better than acrylic partial denture (p< 0.05. The masticatory efficiency was significantly compromising from 3rd month to 1 year in all acrylic partial denture groups (p< 0.05. The comfort of patient with cast partial denture was maintained better during the observation period (p< 0.05. Periodontal health of abutment was gradually deteriorated in all acrylic denture group (p

  6. Tweaking agonist efficacy at N-methyl-D-aspartate receptors by site-directed mutagenesis

    DEFF Research Database (Denmark)

    Hansen, Kasper B; Clausen, Rasmus P; Bjerrum, Esben J

    2005-01-01

    The structural basis for partial agonism at N-methyl-D-aspartate (NMDA) receptors is currently unresolved. We have characterized several partial agonists at the NR1/NR2B receptor and investigated the mechanisms underlying their reduced efficacy by introducing mutations in the glutamate binding site...

  7. Physics of partially ionized plasmas

    CERN Document Server

    Krishan, Vinod

    2016-01-01

    Plasma is one of the four fundamental states of matter; the other three being solid, liquid and gas. Several components, such as molecular clouds, diffuse interstellar gas, the solar atmosphere, the Earth's ionosphere and laboratory plasmas, including fusion plasmas, constitute the partially ionized plasmas. This book discusses different aspects of partially ionized plasmas including multi-fluid description, equilibrium and types of waves. The discussion goes on to cover the reionization phase of the universe, along with a brief description of high discharge plasmas, tokomak plasmas and laser plasmas. Various elastic and inelastic collisions amongst the three particle species are also presented. In addition, the author demonstrates the novelty of partially ionized plasmas using many examples; for instance, in partially ionized plasma the magnetic induction is subjected to the ambipolar diffusion and the Hall effect, as well as the usual resistive dissipation. Also included is an observation of kinematic dynam...

  8. Partially massless fields during inflation

    Science.gov (United States)

    Baumann, Daniel; Goon, Garrett; Lee, Hayden; Pimentel, Guilherme L.

    2018-04-01

    The representation theory of de Sitter space allows for a category of partially massless particles which have no flat space analog, but could have existed during inflation. We study the couplings of these exotic particles to inflationary perturbations and determine the resulting signatures in cosmological correlators. When inflationary perturbations interact through the exchange of these fields, their correlation functions inherit scalings that cannot be mimicked by extra massive fields. We discuss in detail the squeezed limit of the tensor-scalar-scalar bispectrum, and show that certain partially massless fields can violate the tensor consistency relation of single-field inflation. We also consider the collapsed limit of the scalar trispectrum, and find that the exchange of partially massless fields enhances its magnitude, while giving no contribution to the scalar bispectrum. These characteristic signatures provide clean detection channels for partially massless fields during inflation.

  9. Introduction to partial differential equations

    CERN Document Server

    Greenspan, Donald

    2000-01-01

    Designed for use in a one-semester course by seniors and beginning graduate students, this rigorous presentation explores practical methods of solving differential equations, plus the unifying theory underlying the mathematical superstructure. Topics include basic concepts, Fourier series, second-order partial differential equations, wave equation, potential equation, heat equation, approximate solution of partial differential equations, and more. Exercises appear at the ends of most chapters. 1961 edition.

  10. [Acrylic resin removable partial dentures].

    Science.gov (United States)

    de Baat, C; Witter, D J; Creugers, N H J

    2011-01-01

    An acrylic resin removable partial denture is distinguished from other types of removable partial dentures by an all-acrylic resin base which is, in principle, solely supported by the edentulous regions of the tooth arch and in the maxilla also by the hard palate. When compared to the other types of removable partial dentures, the acrylic resin removable partial denture has 3 favourable aspects: the economic aspect, its aesthetic quality and the ease with which it can be extended and adjusted. Disadvantages are an increased risk of caries developing, gingivitis, periodontal disease, denture stomatitis, alveolar bone reduction, tooth migration, triggering of the gag reflex and damage to the acrylic resin base. Present-day indications are ofa temporary or palliative nature or are motivated by economic factors. Special varieties of the acrylic resin removable partial denture are the spoon denture, the flexible denture fabricated of non-rigid acrylic resin, and the two-piece sectional denture. Furthermore, acrylic resin removable partial dentures can be supplied with clasps or reinforced by fibers or metal wires.

  11. Characterization of the chicken muscle insulin receptor

    International Nuclear Information System (INIS)

    Adamo, M.; Simon, J.; Rosebrough, R.W.; McMurtry, J.P.; Steele, N.C.; LeRoith, D.

    1987-01-01

    Insulin receptors are present in chicken skeletal muscle. Crude membrane preparations demonstrated specific 125 I-insulin binding. The nonspecific binding was high (36-55% of total binding) and slightly lower affinity receptors were found than are typically observed for crude membrane insulin binding in other chicken tissues. Affinity crosslinking of 125 I-insulin to crude membranes revealed insulin receptor alpha-subunits of Mr 128K, intermediate between those of liver (134K) and brain (124K). When solubilized and partially purified on wheat germ agglutinin (WGA) affinity columns, chicken muscle insulin receptors exhibited typical high affinity binding, with approximately 10(-10) M unlabeled insulin producing 50% inhibition of the specific 125 I-insulin binding. WGA purified chicken muscle insulin receptors also exhibited insulin-stimulated autophosphorylation of the beta-subunit, which appeared as phosphorylated bands of 92- and 81K. Both bands were immunoprecipitated by anti-receptor antiserum (B10). WGA purified membranes also demonstrated dose-dependent insulin-stimulated phosphorylation of the exogenous substrate poly(Glu,Tyr)4:1. However, unlike chicken liver, chicken muscle insulin receptor number and tyrosine kinase activity were unaltered by 48 hr of fasting or 48 hr of fasting and 24 hr of refeeding. Thus, despite the presence of insulin receptors in chicken muscle showing normal coupling to receptor tyrosine kinase activity, nutritional alterations modulate these parameters in a tissue-specific manner in chickens

  12. Parachute technique for partial penectomy

    Directory of Open Access Journals (Sweden)

    Fernando Korkes

    2010-04-01

    Full Text Available PURPOSE: Penile carcinoma is a rare but mutilating malignancy. In this context, partial penectomy is the most commonly applied approach for best oncological results. We herein propose a simple modification of the classic technique of partial penectomy, for better cosmetic and functional results. TECHNIQUE: If partial penectomy is indicated, the present technique can bring additional benefits. Different from classical technique, the urethra is spatulated only ventrally. An inverted "V" skin flap with 0.5 cm of extension is sectioned ventrally. The suture is performed with vicryl 4-0 in a "parachute" fashion, beginning from the ventral portion of the urethra and the "V" flap, followed by the "V" flap angles and than by the dorsal portion of the penis. After completion of the suture, a Foley catheter and light dressing are placed for 24 hours. CONCLUSIONS: Several complex reconstructive techniques have been previously proposed, but normally require specific surgical abilities, adequate patient selection and staged procedures. We believe that these reconstructive techniques are very useful in some specific subsets of patients. However, the technique herein proposed is a simple alternative that can be applied to all men after a partial penectomy, and takes the same amount of time as that in the classic technique. In conclusion, the "parachute" technique for penile reconstruction after partial amputation not only improves the appearance of the penis, but also maintains an adequate function.

  13. Partial Transposition on Bipartite System

    International Nuclear Information System (INIS)

    Xi-Jun, Ren; Yong-Jian, Han; Yu-Chun, Wu; Guang-Can, Guo

    2008-01-01

    Many properties of partial transposition are unclear as yet. Here we carefully consider the number of the negative eigenvalues of ρ T (ρ's partial transposition) when ρ is a two-partite state. There is strong evidence to show that the number of negative eigenvalues of ρ T is N(N − 1)/2 at most when ρ is a state in Hilbert space C N C N . For the special case, the 2 × 2 system, we use this result to give a partial proof of the conjecture |ρ T | T ≥ 0. We find that this conjecture is strongly connected with the entanglement of the state corresponding to the negative eigenvalue of ρ T or the negative entropy of ρ

  14. Partial volume effect in MRI

    International Nuclear Information System (INIS)

    Maeda, Munehiro; Yoshiya, Kazuhiko; Suzuki, Eiji

    1989-01-01

    According to the direction and the thickness of the imaging slice in tomography, the border between the tissues becomes unclear (partial volume effect). In the present MRI experiment, we examined border area between fat and water components using phantom in order to investigate the partial volume effect in MRI. In spin echo sequences, the intensity of the border area showed a linear relationship with composition of fat and water. Whereas, in inversion recovery and field echo sequences, we found the parameters to produce an extremely low intensity area at the border region between fat and water. This low intensity area was explained by cancellation of NMR signals from fat and water due to the difference in the direction of magnetic vectors. Clinically, partial volume effect can cause of mis-evaluation of walls, small nodules, tumor capsules and the tumor invasion in the use of inversion recovery and field echo sequences. (author)

  15. Partially composite Goldstone Higgs boson

    DEFF Research Database (Denmark)

    Alanne, Tommi; Franzosi, Diogo Buarque; Frandsen, Mads T.

    2017-01-01

    We consider a model of dynamical electroweak symmetry breaking with a partially composite Goldstone Higgs boson. The model is based on a strongly interacting fermionic sector coupled to a fundamental scalar sector via Yukawa interactions. The SU(4)×SU(4) global symmetry of these two sectors...... is broken to a single SU(4) via Yukawa interactions. Electroweak symmetry breaking is dynamically induced by condensation due to the strong interactions in the new fermionic sector which further breaks the global symmetry SU(4)→Sp(4). The Higgs boson arises as a partially composite state which is an exact...... Goldstone boson in the limit where SM interactions are turned off. Terms breaking the SU(4) global symmetry explicitly generate a mass for the Goldstone Higgs boson. The model realizes in different limits both (partially) composite Higgs and (bosonic) technicolor models, thereby providing a convenient...

  16. Landsliding in partially saturated materials

    Science.gov (United States)

    Godt, J.W.; Baum, R.L.; Lu, N.

    2009-01-01

    [1] Rainfall-induced landslides are pervasive in hillslope environments around the world and among the most costly and deadly natural hazards. However, capturing their occurrence with scientific instrumentation in a natural setting is extremely rare. The prevailing thinking on landslide initiation, particularly for those landslides that occur under intense precipitation, is that the failure surface is saturated and has positive pore-water pressures acting on it. Most analytic methods used for landslide hazard assessment are based on the above perception and assume that the failure surface is located beneath a water table. By monitoring the pore water and soil suction response to rainfall, we observed shallow landslide occurrence under partially saturated conditions for the first time in a natural setting. We show that the partially saturated shallow landslide at this site is predictable using measured soil suction and water content and a novel unified effective stress concept for partially saturated earth materials. Copyright 2009 by the American Geophysical Union.

  17. Basic linear partial differential equations

    CERN Document Server

    Treves, Francois

    1975-01-01

    Focusing on the archetypes of linear partial differential equations, this text for upper-level undergraduates and graduate students features most of the basic classical results. The methods, however, are decidedly nontraditional: in practically every instance, they tend toward a high level of abstraction. This approach recalls classical material to contemporary analysts in a language they can understand, as well as exploiting the field's wealth of examples as an introduction to modern theories.The four-part treatment covers the basic examples of linear partial differential equations and their

  18. Elements of partial differential equations

    CERN Document Server

    Sneddon, Ian Naismith

    1957-01-01

    Geared toward students of applied rather than pure mathematics, this volume introduces elements of partial differential equations. Its focus is primarily upon finding solutions to particular equations rather than general theory.Topics include ordinary differential equations in more than two variables, partial differential equations of the first and second orders, Laplace's equation, the wave equation, and the diffusion equation. A helpful Appendix offers information on systems of surfaces, and solutions to the odd-numbered problems appear at the end of the book. Readers pursuing independent st

  19. Timed Testing under Partial Observability

    DEFF Research Database (Denmark)

    David, Alexandre; Larsen, Kim Guldstrand; Li, Shuhao

    2009-01-01

    observability of SUT using a set of predicates over the TGA state space, and specify the test purposes in Computation Tree Logic (CTL) formulas. A recently developed partially observable timed game solver is used to generate winning strategies, which are used as test cases. We propose a conformance testing...

  20. Variable Selection via Partial Correlation.

    Science.gov (United States)

    Li, Runze; Liu, Jingyuan; Lou, Lejia

    2017-07-01

    Partial correlation based variable selection method was proposed for normal linear regression models by Bühlmann, Kalisch and Maathuis (2010) as a comparable alternative method to regularization methods for variable selection. This paper addresses two important issues related to partial correlation based variable selection method: (a) whether this method is sensitive to normality assumption, and (b) whether this method is valid when the dimension of predictor increases in an exponential rate of the sample size. To address issue (a), we systematically study this method for elliptical linear regression models. Our finding indicates that the original proposal may lead to inferior performance when the marginal kurtosis of predictor is not close to that of normal distribution. Our simulation results further confirm this finding. To ensure the superior performance of partial correlation based variable selection procedure, we propose a thresholded partial correlation (TPC) approach to select significant variables in linear regression models. We establish the selection consistency of the TPC in the presence of ultrahigh dimensional predictors. Since the TPC procedure includes the original proposal as a special case, our theoretical results address the issue (b) directly. As a by-product, the sure screening property of the first step of TPC was obtained. The numerical examples also illustrate that the TPC is competitively comparable to the commonly-used regularization methods for variable selection.

  1. Adaptive Partially Hidden Markov Models

    DEFF Research Database (Denmark)

    Forchhammer, Søren Otto; Rasmussen, Tage

    1996-01-01

    Partially Hidden Markov Models (PHMM) have recently been introduced. The transition and emission probabilities are conditioned on the past. In this report, the PHMM is extended with a multiple token version. The different versions of the PHMM are applied to bi-level image coding....

  2. Partially molten magma ocean model

    International Nuclear Information System (INIS)

    Shirley, D.N.

    1983-01-01

    The properties of the lunar crust and upper mantle can be explained if the outer 300-400 km of the moon was initially only partially molten rather than fully molten. The top of the partially molten region contained about 20% melt and decreased to 0% at 300-400 km depth. Nuclei of anorthositic crust formed over localized bodies of magma segregated from the partial melt, then grew peripherally until they coverd the moon. Throughout most of its growth period the anorthosite crust floated on a layer of magma a few km thick. The thickness of this layer is regulated by the opposing forces of loss of material by fractional crystallization and addition of magma from the partial melt below. Concentrations of Sr, Eu, and Sm in pristine ferroan anorthosites are found to be consistent with this model, as are trends for the ferroan anorthosites and Mg-rich suites on a diagram of An in plagioclase vs. mg in mafics. Clustering of Eu, Sr, and mg values found among pristine ferroan anorthosites are predicted by this model

  3. [Posterior ceramic bonded partial restorations].

    Science.gov (United States)

    Mainjot, Amélie; Vanheusden, Alain

    2006-01-01

    Posterior ceramic bonded partial restorations are conservative and esthetic approaches for compromised teeth. Overlays constitute a less invasive alternative for tooth tissues than crown preparations. With inlays and onlays they are also indicated in case of full arch or quadrant rehabilitations including several teeth. This article screens indications and realization of this type of restorations.

  4. Implementing circularity using partial evaluation

    DEFF Research Database (Denmark)

    Lawall, Julia Laetitia

    2001-01-01

    of an imperative C-like language, by extending the language with a new construct, persistent variables. We show that an extension of partial evaluation can eliminate persistent variables, producing a staged C program. This approach has been implemented in the Tempo specializer for C programs, and has proven useful...

  5. Neurobiological mechanisms involved in nicotine dependence and reward: participation of the endogenous opioid system

    Science.gov (United States)

    Berrendero, Fernando; Robledo, Patricia; Trigo, José Manuel; Martín-García, Elena; Maldonado, Rafael

    2010-01-01

    Nicotine is the primary component of tobacco that maintains the smoking habit and develops addiction. The adaptive changes of nicotinic acetylcholine receptors produced by repeated exposure to nicotine play a crucial role in the establishment of dependence. However, other neurochemical systems also participate in the addictive effects of nicotine including glutamate, cannabinoids, GABA and opioids. This review will cover the involvement of these neurotransmitters in nicotine addictive properties, with a special emphasis on the endogenous opioid system. Thus, endogenous enkephalins and beta-endorphins acting on mu-opioid receptors are involved in nicotine rewarding effects, whereas opioid peptides derived from prodynorphin participate in nicotine aversive responses. An upregulation of mu-opioid receptors has been reported after chronic nicotine treatment that could counteract the development of nicotine tolerance, whereas the downregulation induced on kappa-opioid receptors seems to facilitate nicotine tolerance. Endogenous enkephalins acting on mu-opioid receptors also play a role in the development of physical dependence to nicotine. In agreement with these actions of the endogenous opioid system, the opioid antagonist naltrexone has shown to be effective for smoking cessation in certain subpopulations of smokers. PMID:20170672

  6. The partial-birth stratagem.

    Science.gov (United States)

    1998-06-01

    In Wisconsin, physicians stopped performing abortions when a Federal District Court Judge refused to issue a temporary restraining order against the state's newly enacted "partial birth" abortion ban that was couched in such vague language it actually covered all abortions. While ostensibly attempting to ban late-term "intact dilation and extraction," the language of the law did not refer to that procedure or to late terms. Instead, it prohibited all abortions in which a physician "partially vaginally delivers a living child, causes the death of the partially delivered child with the intent to kill the child and then completes the delivery of the child." The law also defined "child" as "a human being from the time of fertilization" until birth. It is clear that this abortion ban is unconstitutional under Row v. Wade, and this unconstitutionality is compounded by the fact that the law allowed no exception to protect a woman's health, which is required by Roe for abortion bans after fetal viability. Wisconsin is only one of about 28 states that have enacted similar laws, and only two have restricted the ban to postviability abortions. Many of these laws have been struck down in court, and President Clinton has continued to veto the Federal partial-birth bill. The Wisconsin Judge acknowledged that opponents of the ban will likely prevail when the case is heard, but his action in denying the temporary injunction means that many women in Wisconsin will not receive timely medical care. The partial birth strategy is really only another anti-abortion strategy.

  7. The strategic value of partial vertical integration

    OpenAIRE

    Fiocco, Raffaele

    2014-01-01

    We investigate the strategic incentives for partial vertical integration, namely, partial ownership agreements between manufacturers and retailers, when retailers privately know their costs and engage in differentiated good price competition. The partial misalignment between the profit objectives within a partially integrated manufacturer-retailer hierarchy entails a higher retail price than under full integration. This `information vertical effect' translates into an opposite ...

  8. 32 CFR 751.13 - Partial payments.

    Science.gov (United States)

    2010-07-01

    ... voucher and all other information related to the partial payment shall be placed in the claim file. Action... 32 National Defense 5 2010-07-01 2010-07-01 false Partial payments. 751.13 Section 751.13 National... Claims Against the United States § 751.13 Partial payments. (a) Partial payments when hardship exists...

  9. Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model

    DEFF Research Database (Denmark)

    Springborg, Anders D; Jensen, Elisabeth K; Taylor, Bradley K

    2016-01-01

    /kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2, and 165 to 169 hours after the thermal injury (day 1-4). The secondary outcomes were pin-prick pain thresholds assessed by weighted-pin instrument (8-512 mN) at primary......Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory...... injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone...

  10. Removable partial dentures: clinical concepts.

    Science.gov (United States)

    Bohnenkamp, David M

    2014-01-01

    This article provides a review of the traditional clinical concepts for the design and fabrication of removable partial dentures (RPDs). Although classic theories and rules for RPD designs have been presented and should be followed, excellent clinical care for partially edentulous patients may also be achieved with computer-aided design/computer-aided manufacturing technology and unique blended designs. These nontraditional RPD designs and fabrication methods provide for improved fit, function, and esthetics by using computer-aided design software, composite resin for contours and morphology of abutment teeth, metal support structures for long edentulous spans and collapsed occlusal vertical dimensions, and flexible, nylon thermoplastic material for metal-supported clasp assemblies. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Partial scram incident in FBTR

    International Nuclear Information System (INIS)

    Usha, S.; Pillai, C.P.; Muralikrishna, G.

    1989-01-01

    Evaluation of a partial scram incident occurred at the Fast Breeder Test Reactor at Kalpakkam was carried out. Based on the observations of the experiments it was ascertained that the nonpersistant order was due to superimposed noise component on the channel that was close to the threshold and had resulted in intermittent supply to electro-magnetic (EM) coils. Owing to a larger discharge time and a smaller charge time, the EM coils got progressively discharged. It was confirmed that during the incident, partial scram took place since the charging and discharging patterns of the EM coils are dissimilar and EM coils of rods A, E and F had discharged faster than others for noise component of a particular duty cycle. However, nonlatching of scram order was because of the fact that noise pulse duration was less than latching time. (author)

  12. The marketing of partial hospitalization.

    Science.gov (United States)

    Millsap, P; Brown, E; Kiser, L; Pruitt, D

    1987-09-01

    Health-care professionals are currently operating in the context of a rapidly changing health-care delivery system, including the move away from inpatient services to outpatient services in order to control costs. Those who practice in partial-hospital settings are in a position to offer effective, cost-efficient services; however, there continue to be obstacles which hinder appropriate utilization of the modality. The development and use of a well-designed marketing plan is one strategy for removing these obstacles. This paper presents a brief overview of the marketing process, ideas for developing a marketing plan, and several examples of specific marketing strategies as well as ways to monitor their effectiveness. Partial-hospital providers must take an active role in answering the calls for alternative sources of psychiatric care. A comprehensive, education-oriented marketing approach will increase the public's awareness of such alternatives and enable programs to survive in a competitive environment.

  13. Introduction to partial differential equations

    CERN Document Server

    Borthwick, David

    2016-01-01

    This modern take on partial differential equations does not require knowledge beyond vector calculus and linear algebra. The author focuses on the most important classical partial differential equations, including conservation equations and their characteristics, the wave equation, the heat equation, function spaces, and Fourier series, drawing on tools from analysis only as they arise.Within each section the author creates a narrative that answers the five questions: (1) What is the scientific problem we are trying to understand? (2) How do we model that with PDE? (3) What techniques can we use to analyze the PDE? (4) How do those techniques apply to this equation? (5) What information or insight did we obtain by developing and analyzing the PDE? The text stresses the interplay between modeling and mathematical analysis, providing a thorough source of problems and an inspiration for the development of methods.

  14. Dynamics of partial differential equations

    CERN Document Server

    Wayne, C Eugene

    2015-01-01

    This book contains two review articles on the dynamics of partial differential equations that deal with closely related topics but can be read independently. Wayne reviews recent results on the global dynamics of the two-dimensional Navier-Stokes equations. This system exhibits stable vortex solutions: the topic of Wayne's contribution is how solutions that start from arbitrary initial conditions evolve towards stable vortices. Weinstein considers the dynamics of localized states in nonlinear Schrodinger and Gross-Pitaevskii equations that describe many optical and quantum systems. In this contribution, Weinstein reviews recent bifurcations results of solitary waves, their linear and nonlinear stability properties, and results about radiation damping where waves lose energy through radiation.   The articles, written independently, are combined into one volume to showcase the tools of dynamical systems theory at work in explaining qualitative phenomena associated with two classes of partial differential equ...

  15. Partial Cooperative Equilibria: Existence and Characterization

    Directory of Open Access Journals (Sweden)

    Amandine Ghintran

    2010-09-01

    Full Text Available We study the solution concepts of partial cooperative Cournot-Nash equilibria and partial cooperative Stackelberg equilibria. The partial cooperative Cournot-Nash equilibrium is axiomatically characterized by using notions of rationality, consistency and converse consistency with regard to reduced games. We also establish sufficient conditions for which partial cooperative Cournot-Nash equilibria and partial cooperative Stackelberg equilibria exist in supermodular games. Finally, we provide an application to strategic network formation where such solution concepts may be useful.

  16. Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity.

    Science.gov (United States)

    Tuplin, Erin W; Holahan, Matthew R

    2017-11-14

    The treatment of schizophrenia is challenging due to the wide range of symptoms (positive, negative, cognitive) associated with the disease. Typical antipsychotics that antagonize D2 receptors are effective in treating positive symptoms, but extrapyramidal side-effects (EPS) are a common occurrence. Atypical antipsychotics targeting 5-HT2A and D2 receptors are more effective at treating cognitive and negative symptoms compared to typical antipsychotics, but these drugs also result in side-effects such as metabolic syndromes. To identify evidence in the literature that elucidates the pharmacological profile of aripiprazole.s. We searched PubMed for peer reviewed articles on aripiprazole and its clinical efficacy, side-effects, pharmacology, and effects in animal models of schizophrenia symptoms. Aripiprazole is a newer atypical antipsychotic that displays a unique pharmacological profile, including partial D2 agonism and functionally selective properties. Aripiprazole is effective at treating the positive symptoms of schizophrenia and has the potential to treat negative and cognitive symptoms at least as well as other atypical antipsychotics. The drug has a favorable side-effect profile and has a low propensity to result in EPS or metabolic syndromes. Animal models of schizophrenia have been used to determine the efficacy of aripiprazole in symptom management. In these instances, aripiprazole resulted in the reversal of deficits in extinction, pre-pulse inhibition, and social withdrawal. Because aripiprazole requires a greater than 90% occupancy rate at D2 receptors to be clinically active and does not produce EPS, this suggests a functionally selective effect on intracellular signaling pathways. A combination of factors such as dopamine system stabilization via partial agonism, functional selectivity at D2 receptors, and serotonin-dopamine system interaction may contribute to the ability of aripiprazole to successfully manage schizophrenia symptoms. This review

  17. Partial dependency parsing for Irish

    OpenAIRE

    Uí Dhonnchadha, Elaine; van Genabith, Josef

    2010-01-01

    In this paper we present a partial dependency parser for Irish, in which Constraint Grammar (CG) rules are used to annotate dependency relations and grammatical functions in unrestricted Irish text. Chunking is performed using a regular-expression grammar which operates on the dependency tagged sentences. As this is the first implementation of a parser for unrestricted Irish text (to our knowledge), there were no guidelines or precedents available. Therefore deciding what constitutes a syntac...

  18. Matching games with partial information

    Science.gov (United States)

    Laureti, Paolo; Zhang, Yi-Cheng

    2003-06-01

    We analyze different ways of pairing agents in a bipartite matching problem, with regard to its scaling properties and to the distribution of individual “satisfactions”. Then we explore the role of partial information and bounded rationality in a generalized Marriage Problem, comparing the benefits obtained by self-searching and by a matchmaker. Finally we propose a modified matching game intended to mimic the way consumers’ information makes firms to enhance the quality of their products in a competitive market.

  19. The LDL receptor.

    Science.gov (United States)

    Goldstein, Joseph L; Brown, Michael S

    2009-04-01

    In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

  20. Radiosequence analysis of the human progestin receptor charged with [3H]promegestone. A comparison with the glucocorticoid receptor

    International Nuclear Information System (INIS)

    Stroemstedt, P.E.B.; Berkenstam, A.; Joernvall, H.G.; Gustafsson, J.A.; Carlstedt-Duke, J.

    1990-01-01

    Partially purified preparations of the human progestin receptor and the human and rat glucocorticoid receptor proteins were covalently charged with the synthetic progestin, [ 3 H]promegestone, by photoaffinity labeling. After labeling, the denaturated protein was cleaved and the mixture of peptides subjected to radiosequence analysis as previously described for the rat glucocorticoid receptor protein. The radioactivity labels identified, corresponded to Met-759 and Met-909 after photoaffinity labeling of the human progestin receptor, and Met-622 and Cys-754 after labeling of the rat glucocorticoid receptor. The residues labeled in the glucocorticoid receptor are the same as those previously reported to bind triamcinolone actonide. The corresponding residues were also labeled in the human glucocorticoid receptor. Met-759 of the progestin receptor and Met-622 of the rat glucocorticoid receptor are positioned within a segment with an overall high degree of sequence similarity and are equivalent. However, Met-909 (progestin receptor) and Cys-754 (glucocorticoid receptor) do not occur within equivalent segments of the two proteins. Thus, although the two classes of steroid hormone share a common structure within the A-ring, there are subtle differences in their interaction with the two separate receptor proteins

  1. The Neuroanatomy of Sexual Dimorphism in Opioid Analgesia

    Science.gov (United States)

    2014-04-13

    2012 for review). Studies utilizing orofacial , somatosensory or visceral pain assays typically report that morphine produces a significantly greater...Review The neuroanatomy of sexual dimorphism in opioid analgesia Dayna R. Loyd a, Anne Z. Murphy b,⁎ a Pain Management Research Area, United States...online 13 April 2014 Keywords: Pain Periaqueductal gray Morphine Mu opioid receptor The influence of sex has been neglected in clinical studies on pain

  2. Regional brain [(11)C]carfentanil binding following tobacco smoking.

    Science.gov (United States)

    Domino, Edward F; Hirasawa-Fujita, Mika; Ni, Lisong; Guthrie, Sally K; Zubieta, Jon Kar

    2015-06-03

    To determine if overnight tobacco abstinent carriers of the AG or GG (*G) vs. the AA variant of the human mu opioid receptor (OPRM1) A118G polymorphism (rs1799971) differ in [(11)C]carfentanil binding after tobacco smoking. Twenty healthy American male smokers who abstained from tobacco overnight were genotyped and completed positron emission tomography (PET) scans with the mu opioid receptor agonist, [(11)C]carfentanil. They smoked deniconized (denic) and average nicotine (avnic) cigarettes during the PET scans. Smoking avnic cigarette decreased the binding potential (BPND) of [(11)C]carfentanil in the right medial prefrontal cortex (mPfc; 6, 56, 18), left anterior medial prefrontal cortex (amPfc; -2, 46, 44), right ventral striatum (vStr; 16, 3, -10), left insula (Ins; -42, 10, -12), right hippocampus (Hippo; 18, -6, -14) and left cerebellum (Cbl; -10, -88, -34), and increased the BPND in left amygdala (Amy; -20, 0, -22), left putamen (Put; -22, 10, -6) and left nucleus accumbens (NAcc; -10, 12, -8). In the AA allele carriers, avnic cigarette smoking significantly changed the BPND compared to after denic smoking in most brain areas listed above. However in the *G carriers the significant BPND changes were confirmed in only amPfc and vStr. Free mu opioid receptor availability was significantly less in the *G than the AA carriers in the Amy and NAcc. The present study demonstrates that BPND changes induced by avnic smoking in OPRM1 *G carriers were blunted compared to the AA carriers. Also *G smokers had less free mu opioid receptor availability in Amy and NAcc. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Changing the insulin receptor to possess insulin-like growth factor I ligand specificity

    International Nuclear Information System (INIS)

    Andersen, A.S.; Kjeldsen, T.; Wiberg, F.C.; Christensen, P.M.; Rasmussen, J.S.; Norris, K.; Moeller, K.B.; Moeller, N.P.H.

    1990-01-01

    To examine the role of the N-terminal part of the insulin-like growth factor I (IGF-I) receptor and insulin receptor in determining ligand specificity, the authors prepared an expression vector encoding a hybrid receptor where exon 1 (encoding the signal peptide and seven amino acids of the α-subunit), exon 2, and exon 3 of the insulin receptor were replaced with the corresponding IGF-I receptor cDNA (938 nucleotides). To allow direct quantitative comparison of the binding capabilities of this hybrid receptor with those of the human IGF-I receptor and the insulin receptor, all three receptors were expressed in baby hamster kidney (BHK) cells as soluble molecules and partially purified before characterization. The hybrid IGF-I/insulin receptor bound IGF-I with an affinity comparable to that of the wild-type IGF-I receptor. In contrast, the hybrid receptor no longer displayed high-affinity binding of insulin. These results directly demonstrate that it is possible to change the specificity of the insulin receptor to that of the IGF-I receptor and, furthermore, that the binding specificity for IGF-I is encoded within the nucleotide sequence from 135 to 938 of the IGF-I receptor cDNA. Since the hybrid receptor only bound insulin with low affinity, the insulin binding region is likely to be located within exons 2 and 3 of the insulin receptor

  4. Synchronizing Strategies under Partial Observability

    DEFF Research Database (Denmark)

    Larsen, Kim Guldstrand; Laursen, Simon; Srba, Jiri

    2014-01-01

    Embedded devices usually share only partial information about their current configurations as the communication bandwidth can be restricted. Despite this, we may wish to bring a failed device into a given predetermined configuration. This problem, also known as resetting or synchronizing words, has...... been intensively studied for systems that do not provide any information about their configurations. In order to capture more general scenarios, we extend the existing theory of synchronizing words to synchronizing strategies, and study the synchronization, short-synchronization and subset...

  5. Partial differential equations an introduction

    CERN Document Server

    Colton, David

    2004-01-01

    Intended for a college senior or first-year graduate-level course in partial differential equations, this text offers students in mathematics, engineering, and the applied sciences a solid foundation for advanced studies in mathematics. Classical topics presented in a modern context include coverage of integral equations and basic scattering theory. This complete and accessible treatment includes a variety of examples of inverse problems arising from improperly posed applications. Exercises at the ends of chapters, many with answers, offer a clear progression in developing an understanding of

  6. Laparoscopic Partial Hepatectomy: Animal Experiments

    Directory of Open Access Journals (Sweden)

    Haruhiro Inoue

    1995-01-01

    Full Text Available As a first step in firmly establishing laparoscopic hepatectomy, we introduce a porcine model of laparoscopic partial hepatectomy. This procedure has been successfully performed under the normal-pressure or low-pressure pneumoperitoneum condition supported by the full-thickness abdominal wall lifting technique. An ultrasonic dissector combined with electrocautery, newly developed by Olympus Optical Corporation (Japan was effectively utilized in facilitating safe and smooth incisions into the liver parenchyma. Although indications for this procedure seem to be limited only to peripheral lesions and not to central lesions, clinical application of this method may be useful for some patients in the near future.

  7. Complex partial seizures: cerebellar metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Theodore, W.H.; Fishbein, D.; Deitz, M.; Baldwin, P.

    1987-07-01

    We used positron emission tomography (PET) with (/sup 18/F)2-deoxyglucose to study cerebellar glucose metabolism (LCMRglu) and the effect of phenytoin (PHT) in 42 patients with complex partial seizures (CPS), and 12 normal controls. Mean +/- SD patient LCMRglu was 6.9 +/- 1.8 mg glucose/100 g/min (left = right), significantly lower than control values of 8.5 +/- 1.8 (left, p less than 0.006), and 8.3 +/- 1.6 (right, p less than 0.02). Only four patients had cerebellar atrophy on CT/MRI; cerebellar LCMRglu in these was 5.5 +/- 1.5 (p = 0.054 vs. total patient sample). Patients with unilateral temporal hypometabolism or EEG foci did not have lateralized cerebellar hypometabolism. Patients receiving phenytoin (PHT) at the time of scan and patients with less than 5 years total PHT exposure had lower LCMRglu, but the differences were not significant. There were weak inverse correlations between PHT level and cerebellar LCMRglu in patients receiving PHT (r = -0.36; 0.05 less than p less than 0.1), as well as between length of illness and LCMRglu (r = -0.22; 0.05 less than p less than 0.1). Patients with complex partial seizures have cerebellar hypometabolism that is bilateral and due only in part to the effect of PHT.

  8. [Removable partial dentures. Oral functions and types].

    Science.gov (United States)

    Creugers, N H J; de Baat, C

    2009-11-01

    A removable partial denture enables the restoration or improvement of 4 oral functions: aesthetics, mandibular stability, mastication, and speech. However, wearing a removable partial denture should not cause oral comfort to deteriorate. There are 3 types of removable partial dentures: acrylic tissue-supported dentures, dentures with cast metal frameworks en dentures with cast metal frameworks and (semi)precision attachments. Interrupted tooth arches,free-ending tooth arches, and a combination of interrupted as well as free-ending tooth arches can be restored using these dentures. Well-known disadvantages of removable partial dentures are problematic oral hygiene, negative influence on the remaining dentition and limited oral comfort. Due to the advanced possibilities of fixed tooth- or implant-supported partial dentures, whether or not free-ending, or tooth- as well as implant-supported partial dentures, the indication of removable partial dentures is restricted. Nevertheless, for the time being the demand for removable partial dentures is expected to continue.

  9. Abstract methods in partial differential equations

    CERN Document Server

    Carroll, Robert W

    2012-01-01

    Detailed, self-contained treatment examines modern abstract methods in partial differential equations, especially abstract evolution equations. Suitable for graduate students with some previous exposure to classical partial differential equations. 1969 edition.

  10. Male patients with partial androgen insensitivity syndrome

    DEFF Research Database (Denmark)

    Hellmann, Philip; Christiansen, Peter; Johannsen, Trine Holm

    2012-01-01

    To describe the natural history of phenotype, growth and gonadal function in patients with partial androgen insensitivity syndrome.......To describe the natural history of phenotype, growth and gonadal function in patients with partial androgen insensitivity syndrome....

  11. PARALLEL SOLUTION METHODS OF PARTIAL DIFFERENTIAL EQUATIONS

    Directory of Open Access Journals (Sweden)

    Korhan KARABULUT

    1998-03-01

    Full Text Available Partial differential equations arise in almost all fields of science and engineering. Computer time spent in solving partial differential equations is much more than that of in any other problem class. For this reason, partial differential equations are suitable to be solved on parallel computers that offer great computation power. In this study, parallel solution to partial differential equations with Jacobi, Gauss-Siedel, SOR (Succesive OverRelaxation and SSOR (Symmetric SOR algorithms is studied.

  12. [Removable partial dentures. Oral functions and types

    NARCIS (Netherlands)

    Creugers, N.H.J.; Baat, C. de

    2009-01-01

    A removable partial denture enables the restoration or improvement of 4 oral functions: aesthetics, mandibular stability, mastication, and speech. However, wearing a removable partial denture should not cause oral comfort to deteriorate. There are 3 types of removable partial dentures: acrylic

  13. [Conventional retaining of removable partial dentures

    NARCIS (Netherlands)

    Keltjens, H.M.A.M.; Witter, D.J.; Creugers, N.H.J.

    2009-01-01

    Mechanical and biological criteria have to be met in retaining the metal frame of a removable partial denture. Additionally, a removable partial denture is part of the occlusal interface by the clasps and the denture teeth. With respect to mechanical aspects, all rigid parts of the removable partial

  14. Deficiency of leptin receptor in myeloid cells disrupts hypothalamic metabolic circuits and causes body weight increase

    Directory of Open Access Journals (Sweden)

    Yuanqing Gao

    2018-01-01

    Conclusions: Myeloid cell leptin receptor deficient mice partially replicate the db/db phenotype. Leptin signaling in hypothalamic microglia is important for microglial function and a correct formation of the hypothalamic neuronal circuit regulating metabolism.

  15. Precipitation in partially stabilized zirconia

    International Nuclear Information System (INIS)

    Bansal, G.K.

    1975-01-01

    Transmission electron microscopy was used to study the substructure of partially stabilized ZrO 2 (PSZ) samples, i.e., 2-phase systems containing both cubic and monoclinic modifications of zirconia, after various heat treatments. Monoclinic ZrO 2 exists as (1) isolated grains within the polycrystalline aggregate (a grain- boundary phase) and (2) small plate-like particles within cubic grains. These intragranular precipitates are believed to contribute to the useful properties of PSZ via a form of precipitation hardening. These precipitates initially form as tetragonal ZrO 2 , with a habit plane parallel to the brace 100 brace matrix planes. The orientation relations between the tetragonal precipitates and the cubic matrix are brace 100 brace/sub matrix/ 2 parallel brace 100 brace /sub precipitate/ or (001)/sub precipitate/ and broken bracket 100 broken bracket/sub matrix/ 2 parallel broken bracket 100 broken bracket/sub precipitate/ or [001]/sub precipitate/. (U.S.)

  16. Partially coherent isodiffracting pulsed beams

    Science.gov (United States)

    Koivurova, Matias; Ding, Chaoliang; Turunen, Jari; Pan, Liuzhan

    2018-02-01

    We investigate a class of isodiffracting pulsed beams, which are superpositions of transverse modes supported by spherical-mirror laser resonators. By employing modal weights that, for stationary light, produce a Gaussian Schell-model beam, we extend this standard model to pulsed beams. We first construct the two-frequency cross-spectral density function that characterizes the spatial coherence in the space-frequency domain. By assuming a power-exponential spectral profile, we then employ the generalized Wiener-Khintchine theorem for nonstationary light to derive the two-time mutual coherence function that describes the space-time coherence of the ensuing beams. The isodiffracting nature of the laser resonator modes permits all (paraxial-domain) calculations at any propagation distance to be performed analytically. Significant spatiotemporal coupling is revealed in subcycle, single-cycle, and few-cycle domains, where the partial spatial coherence also leads to reduced temporal coherence even though full spectral coherence is assumed.

  17. Partial dynamical systems, fell bundles and applications

    CERN Document Server

    Exel, Ruy

    2017-01-01

    Partial dynamical systems, originally developed as a tool to study algebras of operators in Hilbert spaces, has recently become an important branch of algebra. Its most powerful results allow for understanding structural properties of algebras, both in the purely algebraic and in the C*-contexts, in terms of the dynamical properties of certain systems which are often hiding behind algebraic structures. The first indication that the study of an algebra using partial dynamical systems may be helpful is the presence of a grading. While the usual theory of graded algebras often requires gradings to be saturated, the theory of partial dynamical systems is especially well suited to treat nonsaturated graded algebras which are in fact the source of the notion of "partiality". One of the main results of the book states that every graded algebra satisfying suitable conditions may be reconstructed from a partial dynamical system via a process called the partial crossed product. Running in parallel with partial dynamica...

  18. Receptor-receptor interactions within receptor mosaics. Impact on neuropsychopharmacology.

    Science.gov (United States)

    Fuxe, K; Marcellino, D; Rivera, A; Diaz-Cabiale, Z; Filip, M; Gago, B; Roberts, D C S; Langel, U; Genedani, S; Ferraro, L; de la Calle, A; Narvaez, J; Tanganelli, S; Woods, A; Agnati, L F

    2008-08-01

    Future therapies for diseases associated with altered dopaminergic signaling, including Parkinson's disease, schizophrenia and drug addiction or drug dependence may substantially build on the existence of intramembrane receptor-receptor interactions within dopamine receptor containing receptor mosaics (RM; dimeric or high-order receptor oligomers) where it is believed that the dopamine D(2) receptor may operate as the 'hub receptor' within these complexes. The constitutive adenosine A(2A)/dopamine D(2) RM, located in the dorsal striato-pallidal GABA neurons, are of particular interest in view of the demonstrated antagonistic A(2A)/D(2) interaction within these heteromers; an interaction that led to the suggestion and later demonstration that A(2A) antagonists could be used as novel anti-Parkinsonian drugs. Based on the likely existence of A(2A)/D(2)/mGluR5 RM located both extrasynaptically on striato-pallidal GABA neurons and on cortico-striatal glutamate terminals, multiple receptor-receptor interactions within this RM involving synergism between A(2A)/mGluR5 to counteract D(2) signaling, has led to the proposal of using combined mGluR5 and A(2A) antagonists as a future anti-Parkinsonian treatment. Based on the same RM in the ventral striato-pallidal GABA pathways, novel strategies for the treatment of schizophrenia, building on the idea that A(2A) agonists and/or mGluR5 agonists will help reduce the increased dopaminergic signaling associated with this disease, have been suggested. Such treatment may ensure the proper glutamatergic drive from the mediodorsal thalamic nucleus to the prefrontal cortex, one which is believed to be reduced in schizophrenia due to a dominance of D(2)-like signaling in the ventral striatum. Recently, A(2A) receptors also have been shown to counteract the locomotor and sensitizing actions of cocaine and increases in A(2A) receptors have also been observed in the nucleus accumbens after extended cocaine self-administration, probably

  19. Rat hepatic β2-adrenergic receptor: structural similarities to the rat fat cell β1-adrenergic receptor

    International Nuclear Information System (INIS)

    Graziano, M.P.

    1984-01-01

    The mammalian β 2 -adrenergic receptor from rat liver has been purified by sequential cycles of affinity chromatography followed by steric-exclusion high performance liquid chromatography. Electrophoresis of highly purified receptor preparations on polyacrylamide gels in the presence of sodium dodecyl sulfate under reducing conditions reveals a single peptide M/sub r/ = 67,000, as judged by silver staining. Purified β 2 -adrenergic receptor migrates on steric-exclusion high performance liquid chromatography in two peaks, with M/sub r/ = 140,000 and 67,000. Specific binding of the high affinity, β-adrenergic receptor antagonists (-)[ 3 H]dihydroalprenolol and (-)[ 125 I]iodocyanopindolol to purified rat liver β-adrenergic receptor preparations displays stereoselectivity for (-)isomers of agonists and a rank order of potencies for agonists characteristics of a β 2 -adrenergic receptor. Radioiodinated, β 1 -adrenergic receptors from rat fat cells and β 2 -adrenergic receptors from rat liver purified in the presence of protease inhibitors comigrate in electrophoretic separations on polyacrylamide gels in the presence of sodium dodecyl sulfate as 67,000-M/sub r/ peptides. Autoradiograms of two dimensional partial proteolytic digests of the purified, radioiodinated rat liver β 2 -adrenergic receptor, generated with α-chymotrypsin, S. aureus V8 protease and elastase reveal a pattern of peptide fragments essentially identical to those generated by partial proteolytic digests of the purified, radioiodinated β 1 -adrenergic receptor from rat fat cells, by these same proteases. These data indicate that a high degree of homology exists between these two pharmacologically distinct mammalian β-adrenergic receptor proteins

  20. The collagen receptor uPARAP/Endo180

    DEFF Research Database (Denmark)

    Engelholm, Lars H; Ingvarsen, Signe; Jürgensen, Henrik J

    2009-01-01

    The uPAR-associated protein (uPARAP/Endo180), a type-1 membrane protein belonging to the mannose receptor family, is an endocytic receptor for collagen. Through this endocytic function, the protein takes part in a previously unrecognized mechanism of collagen turnover. uPARAP/Endo180 can bind...... and internalize both intact and partially degraded collagens. In some turnover pathways, the function of the receptor probably involves an interplay with certain matrix-degrading proteases whereas, in other physiological processes, redundant mechanisms involving both endocytic and pericellular collagenolysis seem...... in collagen breakdown seems to be involved in invasive tumor growth Udgivelsesdato: 2009...

  1. Acetylcholine receptor antibody

    Science.gov (United States)

    ... medlineplus.gov/ency/article/003576.htm Acetylcholine receptor antibody To use the sharing features on this page, please enable JavaScript. Acetylcholine receptor antibody is a protein found in the blood of ...

  2. NMDA Receptor Modulators in the Treatment of Drug Addiction.

    Science.gov (United States)

    Tomek, Seven E; Lacrosse, Amber L; Nemirovsky, Natali E; Olive, M Foster

    2013-02-06

    Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

  3. NMDA Receptor Modulators in the Treatment of Drug Addiction

    Directory of Open Access Journals (Sweden)

    M. Foster Olive

    2013-02-01

    Full Text Available Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

  4. Cooperative ethylene receptor signaling

    OpenAIRE

    Liu, Qian; Wen, Chi-Kuang

    2012-01-01

    The gaseous plant hormone ethylene is perceived by a family of five ethylene receptor members in the dicotyledonous model plant Arabidopsis. Genetic and biochemical studies suggest that the ethylene response is suppressed by ethylene receptor complexes, but the biochemical nature of the receptor signal is unknown. Without appropriate biochemical measures to trace the ethylene receptor signal and quantify the signal strength, the biological significance of the modulation of ethylene responses ...

  5. Differential suppression of seizures via Y2 and Y5 neuropeptide Y receptors

    DEFF Research Database (Denmark)

    Woldbye, David P D; Nanobashvili, Avtandil; Sørensen, Andreas Vehus

    2005-01-01

    Neuropeptide Y (NPY) prominently inhibits epileptic seizures in different animal models. The NPY receptors mediating this effect remain controversial partially due to lack of highly selective agonists and antagonists. To circumvent this problem, we used various NPY receptor knockout mice with the...

  6. Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists.

    Directory of Open Access Journals (Sweden)

    Gunnar Kleinau

    Full Text Available Trace amine-associated receptors (TAAR are rhodopsin-like G-protein-coupled receptors (GPCR. TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines tyramine (TYR, phenylethylamine (PEA, octopamine (OA, but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous β-adrenergic receptors 1 (ADRB1 and 2 (ADRB2 have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, tyramine (TAR octopamine (OAR, ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular β-adrenergic receptor subtypes.

  7. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn

    2011-01-01

    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered......: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...

  8. Dimer-based model for heptaspanning membrane receptors.

    Science.gov (United States)

    Franco, Rafael; Casadó, Vicent; Mallol, Josefa; Ferré, Sergi; Fuxe, Kjell; Cortés, Antonio; Ciruela, Francisco; Lluis, Carmen; Canela, Enric I

    2005-07-01

    The existence of intramembrane receptor-receptor interactions for heptaspanning membrane receptors is now fully accepted, but a model considering dimers as the basic unit that binds to two ligand molecules is lacking. Here, we propose a two-state-dimer model in which the ligand-induced conformational changes from one component of the dimer are communicated to the other. Our model predicts cooperativity in binding, which is relevant because the other current models fail to address this phenomenon satisfactorily. Our two-state-dimer model also predicts the variety of responses elicited by full or partial agonists, neutral antagonists and inverse agonists. This model can aid our understanding of the operation of heptaspanning receptors and receptor channels, and, potentially, be important for improving the treatment of cardiovascular, neurological and neuropsychyatric diseases.

  9. Partial differential equations of mathematical physics

    CERN Document Server

    Sobolev, S L

    1964-01-01

    Partial Differential Equations of Mathematical Physics emphasizes the study of second-order partial differential equations of mathematical physics, which is deemed as the foundation of investigations into waves, heat conduction, hydrodynamics, and other physical problems. The book discusses in detail a wide spectrum of topics related to partial differential equations, such as the theories of sets and of Lebesgue integration, integral equations, Green's function, and the proof of the Fourier method. Theoretical physicists, experimental physicists, mathematicians engaged in pure and applied math

  10. [Removable partial dentures. Oral functions and types

    OpenAIRE

    Creugers, N.H.J.; Baat, C. de

    2009-01-01

    A removable partial denture enables the restoration or improvement of 4 oral functions: aesthetics, mandibular stability, mastication, and speech. However, wearing a removable partial denture should not cause oral comfort to deteriorate. There are 3 types of removable partial dentures: acrylic tissue-supported dentures, dentures with cast metal frameworks en dentures with cast metal frameworks and (semi)precision attachments. Interrupted tooth arches,free-ending tooth arches, and a combinatio...

  11. Partial vaginismus : definition, symptoms and treatment

    OpenAIRE

    Engman, Maria

    2007-01-01

    Vaginismus is a sexual pain disorder, where spasm of musculature of the outer third of the vagina interferes with intercourse. Vaginismus exists in two forms: total vaginismus, where intercourse is impossible, and the more seldom described partial vaginismus, in which intercourse is possible but painful. The aim of the thesis was to develop a useful definition of partial vaginismus for both clinical and scientific purposes; to describe the prevalence of partial vaginismus among women with sup...

  12. Partial Evaluation of the Euclidian Algorithm

    DEFF Research Database (Denmark)

    Danvy, Olivier; Goldberg, Mayer

    1997-01-01

    -like behavior. Each of them presents a challenge for partial evaluation. The Euclidian algorithm is one of them, and in this article, we make it amenable to partial evaluation. We observe that the number of iterations in the Euclidian algorithm is bounded by a number that can be computed given either of the two...... arguments. We thus rephrase this algorithm using bounded recursion. The resulting program is better suited for automatic unfolding and thus for partial evaluation. Its specialization is efficient....

  13. Partial distance correlation with methods for dissimilarities

    OpenAIRE

    Székely, Gábor J.; Rizzo, Maria L.

    2014-01-01

    Distance covariance and distance correlation are scalar coefficients that characterize independence of random vectors in arbitrary dimension. Properties, extensions, and applications of distance correlation have been discussed in the recent literature, but the problem of defining the partial distance correlation has remained an open question of considerable interest. The problem of partial distance correlation is more complex than partial correlation partly because the squared distance covari...

  14. In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2.

    Science.gov (United States)

    Jamil, Khurram; Pappas, Stephen Chris; Devarakonda, Krishna R

    2018-01-01

    Terlipressin, a synthetic, systemic vasoconstrictor with selective activity at vasopressin-1 (V 1 ) receptors, is a pro-drug for the endogenous/natural porcine hormone [Lys 8 ]-vasopressin (LVP). We investigated binding and receptor-mediated cellular activities of terlipressin, LVP, and endogenous human hormone [Arg 8 ]-vasopressin (AVP) at V 1 and vasopressin-2 (V 2 ) receptors. Cell membrane homogenates of Chinese hamster ovary cells expressing human V 1 and V 2 receptors were used in competitive binding assays to measure receptor-binding activity. These cells were used in functional assays to measure receptor-mediated cellular activity of terlipressin, LVP, and AVP. Binding was measured by [ 3 H]AVP counts, and the activity was measured by fluorometric detection of intracellular calcium mobilization (V 1 ) and cyclic adenosine monophosphate (V 2 ). Binding potency at V 1 and V 2 was AVP>LVP>terlipressin. LVP and terlipressin had approximately sixfold higher affinity for V 1 than for V 2 . Cellular activity potency was also AVP>LVP>terlipressin. Terlipressin was a partial agonist at V 1 and a full agonist at V 2 ; LVP was a full agonist at both V 1 and V 2 . The in vivo response to terlipressin is likely due to the partial V 1 agonist activity of terlipressin and full V 1 agonist activity of its metabolite, LVP. These results provide supportive evidence for previous findings and further establish terlipressin pharmacology for vasopressin receptors.

  15. Differential trafficking of AMPA receptors following activation of NMDA receptors and mGluRs

    Directory of Open Access Journals (Sweden)

    Sanderson Thomas M

    2011-07-01

    Full Text Available Abstract The removal of AMPA receptors from synapses is a major component of long-term depression (LTD. How this occurs, however, is still only partially understood. To investigate the trafficking of AMPA receptors in real-time we previously tagged the GluA2 subunit of AMPA receptors with ecliptic pHluorin and studied the effects of NMDA receptor activation. In the present study we have compared the effect of NMDA receptor and group I mGluR activation, using GluA2 tagged with super ecliptic pHluorin (SEP-GluA2 expressed in cultured hippocampal neurons. Surprisingly, agonists of the two receptors, which are both able to induce chemical forms of LTD, had clearly distinct effects on AMPA receptor trafficking. In agreement with our previous work we found that transient NMDA receptor activation results in an initial decrease in surface GluA2 from extrasynaptic sites followed by a delayed reduction in GluA2 from puncta (putative synapses. In contrast, transient activation of group I mGluRs, using DHPG, led to a pronounced but more delayed decrease in GluA2 from the dendritic shafts. Surprisingly, there was no average change in the fluorescence of the puncta. Examination of fluorescence at individual puncta, however, indicated that alterations did take place, with some puncta showing an increase and others a decrease in fluorescence. The effects of DHPG were, like DHPG-induced LTD, prevented by treatment with a protein tyrosine phosphatase (PTP inhibitor. The electrophysiological correlate of the effects of DHPG in the SEP-GluA2 infected cultures was a reduction in mEPSC frequency with no change in amplitude. The implications of these findings for the initial mechanisms of expression of both NMDA receptor- and mGluR-induced LTD are discussed.

  16. Nature and regulation of the insulin receptor: structure and function

    International Nuclear Information System (INIS)

    Czech, M.P.

    1985-01-01

    Native, cell-surface insulin receptor consists of two glycoprotein subunit types with apparent masses of about 125,000 daltons (alpha subunit) and 90,000 daltons (beta subunit). The alpha and beta insulin-receptor subunits seem to have distinct functions such that alpha appears to bind hormone whereas beta appears to possess intrinsic tyrosine kinase activity. In detergent extracts, insulin activates receptor autophosphorylation of tyrosine residues on its beta subunit, whereas in the presence of reductant, the alpha subunit is also phosphorylated. In intact cells, insulin activates serine/threonine phosphorylation of insulin receptor beta subunit as well as tyrosine phosphorylation. The biological role of the receptor-associated tyrosine kinase is not known. The insulin receptor kinase is regulated by beta-adrenergic agonists and other agents that elevate cAMP in adipocytes, presumably via the cAMP-dependent protein kinase. Such agents decrease receptor affinity for insulin and partially uncouple receptor tyrosine kinase activity from activation by insulin. These effects appear to contribute to the biological antagonism between insulin and beta-agonists. These data suggest the hypothesis that a complex network of tyrosine and serine/threonine phosphorylations on the insulin receptor modulate its binding and kinase activities in an antagonistic manner

  17. Is tapentadol different from classical opioids? A review of the evidence.

    Science.gov (United States)

    Langford, Richard M; Knaggs, Roger; Farquhar-Smith, Paul; Dickenson, Anthony H

    2016-11-01

    Tapentadol is a single molecule able to deliver analgesia by two distinct mechanisms, a feature which differentiates it from many other analgesics. Pre-clinical data demonstrate two mechanisms of action: mu-opioid receptor agonist activity and noradrenaline re-uptake inhibition. From these, one may predict that tapentadol would be applicable across a broad spectrum of pain from nociceptive to neuropathic. The evidence in animal models suggests that norepinephrine re-uptake inhibition (NRI) is a key mechanism and may even predominate over opioid actions in chronic (and especially neuropathic) pain states, reinforcing that tapentadol is different to classical opioids and may, therefore, be an a priori choice for the treatment of neuropathic and mixed pain. The clinical studies and subsequent practice experience and surveillance support the concept of opioid and non-opioid mechanisms of action. The reduced incidence of some of the typical opioid-induced side effects, compared to equianalgesic doses of classical opioids, supports the hypothesis that tapentadol analgesia is only partially mediated by opioid agonist mechanisms. Both the pre-clinical and clinical profiles appear to be differentiated from those of classical opioids.

  18. Delayed liver regeneration after partial hepatectomy in adiponectin knockout mice

    International Nuclear Information System (INIS)

    Ezaki, Hisao; Yoshida, Yuichi; Saji, Yukiko; Takemura, Takayo; Fukushima, Juichi; Matsumoto, Hitoshi; Kamada, Yoshihiro; Wada, Akira; Igura, Takumi; Kihara, Shinji; Funahashi, Tohru; Shimomura, Iichiro; Tamura, Shinji; Kiso, Shinichi; Hayashi, Norio

    2009-01-01

    We previously demonstrated that adiponectin has anti-fibrogenic and anti-inflammatory effects in the liver of mouse models of various liver diseases. However, its role in liver regeneration remains unclear. The aim of this study was to determine the role of adiponectin in liver regeneration. We assessed liver regeneration after partial hepatectomy in wild-type (WT) and adiponectin knockout (KO) mice. We analyzed DNA replication and various signaling pathways involved in cell proliferation and metabolism. Adiponectin KO mice exhibited delayed DNA replication and increased lipid accumulation in the regenerating liver. The expression levels of peroxisome proliferator-activated receptor (PPAR) α and carnitine palmitoyltransferase-1 (CPT-1), a key enzyme in mitochondrial fatty acid oxidation, were decreased in adiponectin KO mice, suggesting possible contribution of altered fat metabolism to these phenomena. Collectively, the present results highlight a new role for adiponectin in the process of liver regeneration.

  19. Positron emission tomography in pre-surgical evaluation of partial epilepsy in adults

    International Nuclear Information System (INIS)

    Semah, F.; Dupont, S.

    1999-01-01

    Positron emission tomography (PET) may be used to map regional cerebral glucose metabolism using 18 F-deoxyglucose in patients with partial epilepsy. An area of reduced glucose metabolism, that is commonly more extensive than the underlying anatomical abnormality, is found in most of the patients with medically refractory partial epilepsy. These functional lesions are very useful in the delineation of the epileptogenic focus prior to surgery. PET may also be used to demonstrate abnormalities in the binding of specific ligands, such as 11 C-flumazenil, to the central benzodiazepine-GABA A receptor complex. Focal decreases in benzodiazepine receptor binding is commonly seen at an epileptic focus, in a more restricted distribution than the area of hypo-metabolism. (author)

  20. Partial discharges and bulk dielectric field enhancement

    DEFF Research Database (Denmark)

    McAllister, Iain Wilson; Johansson, Torben

    2000-01-01

    A consequence of partial discharge activity within a gaseous void is the production of a field enhancement in the solid dielectric in the proximity of the void. This situation arises due to the charge created by the partial discharges accumulating at the void wall. The influence of the spatial...

  1. Laparoscopic partial nephrectomy for endophytic hilar tumors

    DEFF Research Database (Denmark)

    Di Pierro, G B; Tartaglia, N; Aresu, L

    2014-01-01

    To analyze feasibility and outcomes of laparoscopic partial nephrectomy (LPN) for endophytic hilar tumors in low-intermediate (ASA I-II) risk patients.......To analyze feasibility and outcomes of laparoscopic partial nephrectomy (LPN) for endophytic hilar tumors in low-intermediate (ASA I-II) risk patients....

  2. Removable partial overdentures for the irradiated patient

    International Nuclear Information System (INIS)

    Rosenberg, S.W.

    1990-01-01

    Patients who have received radiotherapy to the head and neck area must avoid dental extractions and seek simplicity in treatment and home care follow-up. For partially edentulous patients, removable partial overdenture therapy can fulfill these goals while maintaining the high level of function and aesthetics desired by patients.11 references

  3. Coordinating choice in partial cooperative equilibrium

    NARCIS (Netherlands)

    Mallozzi, L.; Tijs, S.H.

    2009-01-01

    In this paper we consider symmetric aggregative games and investigate partial cooperation between a portion of the players that sign a cooperative agreement and the rest of the players. Existence results of partial cooperative equilibria are obtained when the players who do not sign the agreement

  4. Memoization in Type-Directed Partial Evaluation

    DEFF Research Database (Denmark)

    Balat, Vincent; Danvy, Olivier

    2002-01-01

    the functions and type-directed partial evaluation provides a convenient setting to obtain the normal form of their composition. However, off-the-shelf type-directed partial evaluation turns out to yield gigantic normal forms. We identify that this gigantism is due to redundancies, and that these redundancies...

  5. Mathematical Modelling of Intraretinal Oxygen Partial Pressure ...

    African Journals Online (AJOL)

    Purpose: The aim of our present work is to develop a simple steady state model for intraretinal oxygen partial pressure distribution and to investigate the effect of various model parameters on the partial pressure distribution under adapted conditions of light and darkness.. Method: A simple eight-layered mathematical model ...

  6. Zero ischemia laparoscopic partial thulium laser nephrectomy.

    LENUS (Irish Health Repository)

    Thomas, Arun Z

    2013-11-01

    Laser technology presents a promising alternative to achieve tumor excision and renal hemostasis with or without hilar occlusion, yet its use in partial nephrectomy has not been significantly evaluated. We prospectively evaluated the thulium:yttrium-aluminum-garnet laser in laparoscopic partial nephrectomy (LPN) in our institution over a 1-year period.

  7. Esthetic Rehabilitation with a Cast Partial Denture

    Directory of Open Access Journals (Sweden)

    Suraksha Shrestha

    2017-01-01

    Full Text Available Removable partial denture is a treatment option where fixed prosthesis is not indicated. Due to its esthetic problems in the anterior region various modifications have been designed for its fabrication. This article describes an esthetic alternative using a round rest distal depression clasp for maxillary anterior teeth abutment while restoring the missing teeth with a cast partial denture.

  8. Heat deposition on the partial limiter

    International Nuclear Information System (INIS)

    Itoh, Kimitaka; Itoh, Sanae-I; Nagasaki, Kazunobu.

    1990-01-01

    The effect of the partial limiter in the outermost magnetic surface of toroidal plasmas is studied. The power deposition on the partial limiter and its effect on the temperature profile are analysed. Interpretation in terms of the perpendicular heat conductivity is also discussed. (author)

  9. Partial purification and biochemical characterization of acid ...

    African Journals Online (AJOL)

    Mung bean (Vigna radiata) is one of the important crops of the North Eastern Region of India. In the present study, acid phosphatase enzyme was isolated and partially purified from germinated local mung bean seeds. The sequential partial purification process was performed using ammonium sulphate precipitation method.

  10. Partial Safety Factors for Rubble Mound Breakwaters

    DEFF Research Database (Denmark)

    Sørensen, John Dalsgaard; Burcharth, H. F.; Christiani, E.

    1995-01-01

    On the basis of the failure modes formulated in the various subtasks calibration of partial safety factors are described in this paper. The partial safety factors can be used to design breakwaters under quite different design conditions, namely probabilities of failure from 0.01 to 0.4, design...... lifetimes from 20 to 100 years and different qualities of wave data. A code of practice where safety is taken into account using partial safety factors is called a level I code. The partial safety factors are calibrated using First Order Reliability Methods (FORM, see Madsen et al. [1]) where...... in section 3. First Order Reliability Methods are described in section 4, and in section 5 it is shown how partial safety factors can be introduced and calibrated. The format of a code for design and analysis of rubble mound breakwaters is discussed in section 6. The mathematical formulation of the limit...

  11. Development of Partial Discharging Simulation Test Equipment

    Science.gov (United States)

    Kai, Xue; Genghua, Liu; Yan, Jia; Ziqi, Chai; Jian, Lu

    2017-12-01

    In the case of partial discharge training for recruits who lack of on-site work experience, the risk of physical shock and damage of the test equipment may be due to the limited skill level and improper operation by new recruits. Partial discharge simulation tester is the use of simulation technology to achieve partial discharge test process simulation, relatively true reproduction of the local discharge process and results, so that the operator in the classroom will be able to get familiar with and understand the use of the test process and equipment.The teacher sets up the instrument to display different partial discharge waveforms so that the trainees can analyze the test results of different partial discharge types.

  12. GABA receptor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Doo [Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA{sub A}-receptor that allows chloride to pass through a ligand gated ion channel and GABA{sub B}-receptor that uses G-proteins for signaling. The GABA{sub A}-receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA{sub A}-receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with {sup 11}C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, {sup 18}F-fluoroflumazenil (FFMZ) has been developed to overcome {sup 11}C's short half-life. {sup 18}F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1{sup 1}C-FMZ PET instead of {sup 18}F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA{sub A} receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas.

  13. GABA receptor imaging

    International Nuclear Information System (INIS)

    Lee, Jong Doo

    2007-01-01

    GABA is primary an inhibitory neurotransmitter that is localized in inhibitory interneurons. GABA is released from presynaptic terminals and functions by binding to GABA receptors. There are two types of GABA receptors, GABA A -receptor that allows chloride to pass through a ligand gated ion channel and GABA B -receptor that uses G-proteins for signaling. The GABA A -receptor has a GABA binding site as well as a benzodiazepine binding sites, which modulate GABA A -receptor function. Benzodiazepine GABAA receptor imaging can be accomplished by radiolabeling derivates that activates benzodiazepine binding sites. There has been much research on flumazenil (FMZ) labeled with 11 C-FMZ, a benzodiazepine derivate that is a selective, reversible antagonist to GABAA receptors. Recently, 18 F-fluoroflumazenil (FFMZ) has been developed to overcome 11 C's short half-life. 18 F-FFMZ shows high selective affinity and good pharmacodynamics, and is a promising PET agent with better central benzodiazepine receptor imaging capabilities. In an epileptic focus, because the GABA/benzodiazepine receptor amount is decreased, using '1 1 C-FMZ PET instead of 18 F-FDG, PET, restrict the foci better and may also help find lesions better than high resolution MR. GABA A receptors are widely distributed in the cerebral cortex, and can be used as an viable neuronal marker. Therefore it can be used as a neuronal cell viability marker in cerebral ischemia. Also, GABA-receptors decrease in areas where neuronal plasticity develops, therefore, GABA imaging can be used to evaluate plasticity. Besides these usages, GABA receptors are related with psychological diseases, especially depression and schizophrenia as well as cerebral palsy, a motor-related disorder, so further in-depth studies are needed for these areas

  14. Partially Observed Mixtures of IRT Models: An Extension of the Generalized Partial-Credit Model

    Science.gov (United States)

    Von Davier, Matthias; Yamamoto, Kentaro

    2004-01-01

    The generalized partial-credit model (GPCM) is used frequently in educational testing and in large-scale assessments for analyzing polytomous data. Special cases of the generalized partial-credit model are the partial-credit model--or Rasch model for ordinal data--and the two parameter logistic (2PL) model. This article extends the GPCM to the…

  15. Partial clinical response to anakinra in severe palmoplantar pustular psoriasis.

    Science.gov (United States)

    Tauber, M; Viguier, M; Alimova, E; Petit, A; Lioté, F; Smahi, A; Bachelez, H

    2014-09-01

    Palmoplantar pustular psoriasis is a clinical psoriasis variant characterised by a high impact on quality of life and poor response to biologics approved for plaque type psoriasis.The recombinant interleukin-1 (IL-1) receptor antagonist anakinra has been recently used for the treatment of isolated refractory cases of generalised pustular psoriasis with contrasted results. To report the clinical response in two patients treated with anakinra as salvage therapy in two patients with severe palmoplantar pustular psoriasis refractory to currently available antipsoriatic systemic therapies. Anakinra was given subcutaneously at the daily dose of 100 mg, and clinical response was evaluated using the palmoplantar psoriasis area and severity index (PPPASI). Only partial and transient responses were observed in both patients, who had to stop anakinra due to lack of efficacy and to side effects. Anakinra appears to provide only partial clinical improvement in refractory palmoplantar pustular psoriasis. Prospective clinical studies on larger populations are warranted to investigate more accurately both efficacy and safety of IL-1-inhibiting strategies in pustular psoriasis. © 2014 British Association of Dermatologists.

  16. Glucocorticoid receptor modulators.

    Science.gov (United States)

    Meijer, Onno C; Koorneef, Lisa L; Kroon, Jan

    2018-06-01

    The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  17. Dengue virus receptor

    OpenAIRE

    Hidari, Kazuya I.P.J.; Suzuki, Takashi

    2011-01-01

    Dengue virus is an arthropod-borne virus transmitted by Aedes mosquitoes. Dengue virus causes fever and hemorrhagic disorders in humans and non-human primates. Direct interaction of the virus introduced by a mosquito bite with host receptor molecule(s) is crucial for virus propagation and the pathological progression of dengue diseases. Therefore, elucidation of the molecular mechanisms underlying the interaction between dengue virus and its receptor(s) in both humans and mosquitoes is essent...

  18. Partial transposition on bi-partite system

    OpenAIRE

    Han, Y. -J.; Ren, X. J.; Wu, Y. C.; Guo, G. -C.

    2006-01-01

    Many of the properties of the partial transposition are not clear so far. Here the number of the negative eigenvalues of K(T)(the partial transposition of K) is considered carefully when K is a two-partite state. There are strong evidences to show that the number of negative eigenvalues of K(T) is N(N-1)/2 at most when K is a state in Hilbert space N*N. For the special case, 2*2 system(two qubits), we use this result to give a partial proof of the conjecture sqrt(K(T))(T)>=0. We find that thi...

  19. Numerical Analysis of Partial Differential Equations

    CERN Document Server

    Lui, S H

    2011-01-01

    A balanced guide to the essential techniques for solving elliptic partial differential equations Numerical Analysis of Partial Differential Equations provides a comprehensive, self-contained treatment of the quantitative methods used to solve elliptic partial differential equations (PDEs), with a focus on the efficiency as well as the error of the presented methods. The author utilizes coverage of theoretical PDEs, along with the nu merical solution of linear systems and various examples and exercises, to supply readers with an introduction to the essential concepts in the numerical analysis

  20. Partial differential equations for scientists and engineers

    CERN Document Server

    Farlow, Stanley J

    1993-01-01

    Most physical phenomena, whether in the domain of fluid dynamics, electricity, magnetism, mechanics, optics, or heat flow, can be described in general by partial differential equations. Indeed, such equations are crucial to mathematical physics. Although simplifications can be made that reduce these equations to ordinary differential equations, nevertheless the complete description of physical systems resides in the general area of partial differential equations.This highly useful text shows the reader how to formulate a partial differential equation from the physical problem (constructing th

  1. Partial Deconvolution with Inaccurate Blur Kernel.

    Science.gov (United States)

    Ren, Dongwei; Zuo, Wangmeng; Zhang, David; Xu, Jun; Zhang, Lei

    2017-10-17

    Most non-blind deconvolution methods are developed under the error-free kernel assumption, and are not robust to inaccurate blur kernel. Unfortunately, despite the great progress in blind deconvolution, estimation error remains inevitable during blur kernel estimation. Consequently, severe artifacts such as ringing effects and distortions are likely to be introduced in the non-blind deconvolution stage. In this paper, we tackle this issue by suggesting: (i) a partial map in the Fourier domain for modeling kernel estimation error, and (ii) a partial deconvolution model for robust deblurring with inaccurate blur kernel. The partial map is constructed by detecting the reliable Fourier entries of estimated blur kernel. And partial deconvolution is applied to wavelet-based and learning-based models to suppress the adverse effect of kernel estimation error. Furthermore, an E-M algorithm is developed for estimating the partial map and recovering the latent sharp image alternatively. Experimental results show that our partial deconvolution model is effective in relieving artifacts caused by inaccurate blur kernel, and can achieve favorable deblurring quality on synthetic and real blurry images.Most non-blind deconvolution methods are developed under the error-free kernel assumption, and are not robust to inaccurate blur kernel. Unfortunately, despite the great progress in blind deconvolution, estimation error remains inevitable during blur kernel estimation. Consequently, severe artifacts such as ringing effects and distortions are likely to be introduced in the non-blind deconvolution stage. In this paper, we tackle this issue by suggesting: (i) a partial map in the Fourier domain for modeling kernel estimation error, and (ii) a partial deconvolution model for robust deblurring with inaccurate blur kernel. The partial map is constructed by detecting the reliable Fourier entries of estimated blur kernel. And partial deconvolution is applied to wavelet-based and learning

  2. PARTIAL REINFORCEMENT (ACQUISITION) EFFECTS WITHIN SUBJECTS.

    Science.gov (United States)

    AMSEL, A; MACKINNON, J R; RASHOTTE, M E; SURRIDGE, C T

    1964-03-01

    Acquisition performance of 22 rats in a straight alley runway was examined. The animals were subjected to partial reinforcement when the alley was black (B+/-) and continuous reinforcement when it was white (W+). The results indicated (a) higher terminal performance, for partial as against continuous reinforcement conditions, for starting-time and running-time measures, and (b) lower terminal performance under partial conditions for a goal-entry-time measure. These results confirm within subjects an effect previously demonstrated, in the runway, only in between-groups tests, where one group is run under partial reinforcement and a separate group is run under continuous reinforcement in the presence of the same external stimuli. Differences between the runway situation, employing a discrete-trial procedure and performance measures at three points in the response chain, and the Skinner box situation, used in its free-operant mode with a single performance measure, are discussed in relation to the present findings.

  3. Introduction to partial differential equations with applications

    CERN Document Server

    Zachmanoglou, E C

    1988-01-01

    This text explores the essentials of partial differential equations as applied to engineering and the physical sciences. Discusses ordinary differential equations, integral curves and surfaces of vector fields, the Cauchy-Kovalevsky theory, more. Problems and answers.

  4. Dual Component Removable Partial Denture shows improved ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-02-18

    Feb 18, 2009 ... 2Faculty of Dentistry, the University of Hong Kong, Hong Kong. 3Department of ... an example of poor oral condition caused mainly by periodontitis, and ... working model of the Dual Component Removable Partial Denture.

  5. Evaluation of Prothrombin Time and Activated Partial ...

    African Journals Online (AJOL)

    and activated partial thromboplastin time (APTT) were investigated in treated and untreated diabetics as well as ... decrease the availability of these proteins which affect the clotting ... calcum rabbit brain thromboplastin reagent placed in.

  6. chemical composition and sensory acceptability of partially ...

    African Journals Online (AJOL)

    Pasta products were produced from partially gelatinized blends of wheat, ... products were significantly different in height, thickness and expansion ratio but, not significantly different ... protein and no less than 30% of wet gluten (protein.

  7. Hospital Outpatient PPS Partial Hospitalization Program LDS

    Data.gov (United States)

    U.S. Department of Health & Human Services — Hospital Outpatient Prospective Payment System (OPPS) Partial Hospitalization Program LDS This file contains select claim level data and is derived from 2010 claims...

  8. On construction of partial association rules

    KAUST Repository

    Moshkov, Mikhail; Piliszczuk, Marcin; Zielosko, Beata Marta

    2009-01-01

    This paper is devoted to the study of approximate algorithms for minimization of partial association rule length. It is shown that under some natural assumptions on the class NP, a greedy algorithm is close to the best polynomial approximate

  9. Partial Duplication of Chromosome 8p

    African Journals Online (AJOL)

    rme

    The partial chromosome 8p duplication is a rare syndrome and is ... abnormality of maternal origin that ... second trimester by vaginal bleeding and ... echocardiography, brain CT scan and. MRI. Fig. 1:Conventional karyotype of case 3 showing.

  10. Clustering stocks using partial correlation coefficients

    Science.gov (United States)

    Jung, Sean S.; Chang, Woojin

    2016-11-01

    A partial correlation analysis is performed on the Korean stock market (KOSPI). The difference between Pearson correlation and the partial correlation is analyzed and it is found that when conditioned on the market return, Pearson correlation coefficients are generally greater than those of the partial correlation, which implies that the market return tends to drive up the correlation between stock returns. A clustering analysis is then performed to study the market structure given by the partial correlation analysis and the members of the clusters are compared with the Global Industry Classification Standard (GICS). The initial hypothesis is that the firms in the same GICS sector are clustered together since they are in a similar business and environment. However, the result is inconsistent with the hypothesis and most clusters are a mix of multiple sectors suggesting that the traditional approach of using sectors to determine the proximity between stocks may not be sufficient enough to diversify a portfolio.

  11. Partial Actions, Paradoxicality and Topological full Groups

    DEFF Research Database (Denmark)

    Scarparo, Eduardo

    uniform Roe algebra is finite. In Article C, we analyze the C*-algebra generated by the Koopman representation of a topological full group, showing, in particular, that it is not AF andhas real rank zero. We also prove that if G is a finitely generated, elementary amenable group, and C*(G) has real rank......We study how paradoxicality properties affect the way groups partially acton topological spaces and C*-algebras. We also investigate the real rank zero and AF properties for certain classes of group C*-algebras. Specifically, in article A, we characterize supramenable groups in terms of existence...... of invariant probability measures for partial actions on compact Hausdorff spaces and existence of tracial states on partial crossed products. These characterizations show that, in general, one cannot decompose a partial crossed product of a C*-algebra by a semidirect product of groups as two iterated...

  12. Higher-order rewriting and partial evaluation

    DEFF Research Database (Denmark)

    Danvy, Olivier; Rose, Kristoffer H.

    1998-01-01

    We demonstrate the usefulness of higher-order rewriting techniques for specializing programs, i.e., for partial evaluation. More precisely, we demonstrate how casting program specializers as combinatory reduction systems (CRSs) makes it possible to formalize the corresponding program...

  13. Mathematical Modelling of Intraretinal Oxygen Partial Pressure

    African Journals Online (AJOL)

    Erah

    oxygen availability) is required for retinal oxidative metabolism. .... retina was described using Hill's equation and Fick's law. ... ganglion cell / nerve fiber layer and the superficial ..... parameter values producing the best. Figure 2: Partial ...

  14. Partial Differential Equations Modeling and Numerical Simulation

    CERN Document Server

    Glowinski, Roland

    2008-01-01

    This book is dedicated to Olivier Pironneau. For more than 250 years partial differential equations have been clearly the most important tool available to mankind in order to understand a large variety of phenomena, natural at first and then those originating from human activity and technological development. Mechanics, physics and their engineering applications were the first to benefit from the impact of partial differential equations on modeling and design, but a little less than a century ago the Schrödinger equation was the key opening the door to the application of partial differential equations to quantum chemistry, for small atomic and molecular systems at first, but then for systems of fast growing complexity. Mathematical modeling methods based on partial differential equations form an important part of contemporary science and are widely used in engineering and scientific applications. In this book several experts in this field present their latest results and discuss trends in the numerical analy...

  15. Partial discharge transients: The field theoretical approach

    DEFF Research Database (Denmark)

    McAllister, Iain Wilson; Crichton, George C

    1998-01-01

    Up until the mid-1980s the theory of partial discharge transients was essentially static. This situation had arisen because of the fixation with the concept of void capacitance and the use of circuit theory to address what is in essence a field problem. Pedersen rejected this approach and instead...... began to apply field theory to the problem of partial discharge transients. In the present paper, the contributions of Pedersen using the field theoretical approach will be reviewed and discussed....

  16. A Model for Partial Kantian Cooperation

    OpenAIRE

    Kordonis, Ioannis

    2016-01-01

    This work presents a game theoretic model to describe game situations in which there is a partial cooperation among the players. Specifically, we assume that the players partially follow Kant's "Categorical Imperative". The model is stated for games with a continuum of players and the basic assumption made is that the participants consider that they belong to virtual groups in which they optimize their actions as if they were bound to follow the same strategy. The relation with the Nash, (Ben...

  17. On the Partiality of Procreative Beneficence

    DEFF Research Database (Denmark)

    Petersen, Thomas Søbirk

    2015-01-01

    The aim of this paper is to criticise the well-discussed principle of Procreative Beneficence (PB) lately refined by Julian Savulescu and Guy Kahane. First, it is argued that advocates of PB leave us with an implausible justification for the moral partiality towards the child (or children) which...... the target. Finally, a genuine counterexample to PB is developed in order to show that the partiality of PB leads to the wrong answer in a specific case....

  18. Pancharatnam geometric phase originating from successive partial ...

    Indian Academy of Sciences (India)

    Pancharatnam connection [1,2] dictates that ψp is in phase ψ0. The partial projection effects a ... up to a real multiplier. Here again, ψf is in phase with ψp but relative to ψ0, has a .... For the third partial projection of strength t3 and an azimuth angle φ13 to effect a triangle closure for both initial states |z〉 and | − z〉, we derive ...

  19. Spreading paths in partially observed social networks

    Science.gov (United States)

    Onnela, Jukka-Pekka; Christakis, Nicholas A.

    2012-03-01

    Understanding how and how far information, behaviors, or pathogens spread in social networks is an important problem, having implications for both predicting the size of epidemics, as well as for planning effective interventions. There are, however, two main challenges for inferring spreading paths in real-world networks. One is the practical difficulty of observing a dynamic process on a network, and the other is the typical constraint of only partially observing a network. Using static, structurally realistic social networks as platforms for simulations, we juxtapose three distinct paths: (1) the stochastic path taken by a simulated spreading process from source to target; (2) the topologically shortest path in the fully observed network, and hence the single most likely stochastic path, between the two nodes; and (3) the topologically shortest path in a partially observed network. In a sampled network, how closely does the partially observed shortest path (3) emulate the unobserved spreading path (1)? Although partial observation inflates the length of the shortest path, the stochastic nature of the spreading process also frequently derails the dynamic path from the shortest path. We find that the partially observed shortest path does not necessarily give an inflated estimate of the length of the process path; in fact, partial observation may, counterintuitively, make the path seem shorter than it actually is.

  20. Spreading paths in partially observed social networks.

    Science.gov (United States)

    Onnela, Jukka-Pekka; Christakis, Nicholas A

    2012-03-01

    Understanding how and how far information, behaviors, or pathogens spread in social networks is an important problem, having implications for both predicting the size of epidemics, as well as for planning effective interventions. There are, however, two main challenges for inferring spreading paths in real-world networks. One is the practical difficulty of observing a dynamic process on a network, and the other is the typical constraint of only partially observing a network. Using static, structurally realistic social networks as platforms for simulations, we juxtapose three distinct paths: (1) the stochastic path taken by a simulated spreading process from source to target; (2) the topologically shortest path in the fully observed network, and hence the single most likely stochastic path, between the two nodes; and (3) the topologically shortest path in a partially observed network. In a sampled network, how closely does the partially observed shortest path (3) emulate the unobserved spreading path (1)? Although partial observation inflates the length of the shortest path, the stochastic nature of the spreading process also frequently derails the dynamic path from the shortest path. We find that the partially observed shortest path does not necessarily give an inflated estimate of the length of the process path; in fact, partial observation may, counterintuitively, make the path seem shorter than it actually is.

  1. Angiotensin type 2 receptors

    DEFF Research Database (Denmark)

    Sumners, Colin; de Kloet, Annette D; Krause, Eric G

    2015-01-01

    In most situations, the angiotensin AT2-receptor (AT2R) mediates physiological actions opposing those mediated by the AT1-receptor (AT1R), including a vasorelaxant effect. Nevertheless, experimental evidence vastly supports that systemic application of AT2R-agonists is blood pressure neutral...

  2. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  3. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the f......Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player...... in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular...

  4. Functional ET(A)-ET(B) Receptor Cross-talk in Basilar Artery In Situ From ET(B) Receptor Deficient Rats.

    Science.gov (United States)

    Yoon, SeongHun; Gariepy, Cheryl E; Yanagisawa, Masashi; Zuccarello, Mario; Rapoport, Robert M

    2016-03-01

    The role of endothelin (ET)(A)-ET(B) receptor cross-talk in limiting the ET(A) receptor antagonist inhibition of ET-1 constriction is revealed by the partial or complete dependency of the ET(A) receptor antagonist inhibition on functional removal of the ET(B) receptor. Although functional removal of the ET(B) receptor is generally accomplished with ET(B) receptor antagonist, a novel approach using rats containing a naturally occurring deletion mutation in the ET(B) receptor [rescued "spotting lethal" (sl) rats; ET(B)(sl/sl)] demonstrated increased ET(A) receptor antagonist inhibition of ET-1 constriction in vena cava. We investigated whether this deletion mutation was also sufficient to remove the ET(B) receptor dependency of the ET(A) receptor antagonist inhibition of ET-1 constriction in the basilar artery. Consistent with previous reports, ET-1 plasma levels were elevated in ET(B)(sl/sl) as compared with ET(B)(+/+) rats. ET(B) receptor antagonist failed to relax the ET-1 constricted basilar artery from ET(B)(+/+) and ET(B)(sl/sl) rats. Relaxation to combined ET(A) and ET(B) receptor antagonist was greater than relaxation to ET(A) receptor antagonist in the basilar artery from ET(B)(+/+) and, unexpectedly, ET(B)(sl/sl) rats. These findings confirm the presence of ET(A)-ET(B) receptor cross-talk in the basilar artery. We speculate that mutant ET(B) receptor expression produced by alternative splicing may be sufficient to allow cross-talk.

  5. 77 FR 64737 - Partial Approval and Partial Disapproval of Air Quality State Implementation Plans; Nevada...

    Science.gov (United States)

    2012-10-23

    ... the Transport TSD ``appears to talk about nonattainment areas rather than maintenance areas'' while... Receptor Selection Methodology''). These criteria for selection of nonattainment and maintenance...

  6. Lipophorin Receptor: The Insect Lipoprotein Receptor

    Indian Academy of Sciences (India)

    IAS Admin

    Director of ... function of the Lp is to deliver lipids throughout the insect body for metabolism ... Lipid is used as a major energy source for development as well as other metabolic .... LpR4 receptor variant was expressed exclusively in the brain and.

  7. Hypersensitivity Induced by Activation of Spinal Cord PAR2 Receptors Is Partially Mediated by TRPV1 Receptors

    Czech Academy of Sciences Publication Activity Database

    Mrózková, Petra; Špicarová, Diana; Paleček, Jiří

    2016-01-01

    Roč. 11, č. 10 (2016), č. článku e0163991. E-ISSN 1932-6203 R&D Projects: GA ČR(CZ) GA15-11138S; GA MŠk(CZ) LH15279; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : PAR2 * TRP * neuropathy * spinal cord Subject RIV: FH - Neurology Impact factor: 2.806, year: 2016

  8. Compatriot partiality and cosmopolitan justice: Can we justify compatriot partiality within the cosmopolitan framework?

    Directory of Open Access Journals (Sweden)

    Rachelle Bascara

    2016-10-01

    Full Text Available This paper shows an alternative way in which compatriot partiality could be justified within the framework of global distributive justice. Philosophers who argue that compatriot partiality is similar to racial partiality capture something correct about compatriot partiality. However, the analogy should not lead us to comprehensively reject compatriot partiality. We can justify compatriot partiality on the same grounds that liberation movements and affirmative action have been justified. Hence, given cosmopolitan demands of justice, special consideration for the economic well-being of your nation as a whole is justified if and only if the country it identifies is an oppressed developing nation in an unjust global order.This justification is incomplete. We also need to say why Person A, qua national of Country A, is justified in helping her compatriots in Country A over similarly or slightly more oppressed non-compatriots in Country B. I argue that Person A’s partiality towards her compatriots admits further vindication because it is part of an oppressed group’s project of self-emancipation, which is preferable to paternalistic emancipation.Finally, I identify three benefits in my justification for compatriot partiality. First, I do not offer a blanket justification for all forms of compatriot partiality. Partiality between members of oppressed groups is only a temporary effective measure designed to level an unlevel playing field. Second, because history attests that sovereign republics could arise as a collective response to colonial oppression, justifying compatriot partiality on the grounds that I have identified is conducive to the development of sovereignty and even democracy in poor countries, thereby avoiding problems of infringement that many humanitarian poverty alleviation efforts encounter. Finally, my justification for compatriot partiality complies with the implicit cosmopolitan commitment to the realizability of global justice

  9. Effects of muscarinic receptor antagonists on cocaine discrimination in wild-type mice and in muscarinic receptor M1, M2, and M4 receptor knockout mice.

    Science.gov (United States)

    Joseph, Lauren; Thomsen, Morgane

    2017-06-30

    Muscarinic M 1 /M 4 receptor stimulation can reduce abuse-related effects of cocaine and may represent avenues for treating cocaine addiction. Muscarinic antagonists can mimic and enhance effects of cocaine, including discriminative stimulus (S D ) effects, but the receptor subtypes mediating those effects are not known. A better understanding of the complex cocaine/muscarinic interactions is needed to evaluate and develop potential muscarinic-based medications. Here, knockout mice lacking M 1 , M 2 , or M 4 receptors (M 1 -/- , M 2 -/- , M 4 -/- ), as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline. Muscarinic receptor antagonists with no subtype selectivity (scopolamine), or preferential affinity at the M 1 , M 2 , or M 4 subtype (telenzepine, trihexyphenidyl; methoctramine, AQ-RA 741; tropicamide) were tested alone and in combination with cocaine. In intact animals, antagonists with high affinity at M 1 /M 4 receptors partially substituted for cocaine and increased the S D effect of cocaine, while M 2 -preferring antagonists did not substitute, and reduced the S D effect of cocaine. The cocaine-like effects of scopolamine were absent in M 1 -/- mice. The cocaine S D attenuating effects of methoctramine were absent in M 2 -/- mice and almost absent in M 1 -/- mice. The findings indicate that the cocaine-like S D effects of muscarinic antagonists are primarily mediated through M 1 receptors, with a minor contribution of M 4 receptors. The data also support our previous findings that stimulation of M 1 receptors and M 4 receptors can each attenuate the S D effect of cocaine, and show that this can also be achieved by blocking M 2 autoreceptors, likely via increased acetylcholine release. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Beta-endorphin 1-31 biotransformation and cAMP modulation in inflammation.

    Directory of Open Access Journals (Sweden)

    Naghmeh Hajarol Asvadi

    Full Text Available A large body of evidence now exists for the immune cell expression, production, and the release of beta-endorphin (BE 1-31 within inflamed tissue. The inflammatory milieu is characterised by increased acidity, temperature and metabolic activity. Within these harsh conditions BE 1-31 is even more susceptible to increased enzymatic degradation over that of plasma or other non-injured tissue. To elucidate the biotransformation pathways of BE 1-31 and provide an insight to the impact of inflamed tissue environments, BE 1-31 and three of its major N-terminal fragments (BE 1-11, BE 1-13 and BE 1-17 were incubated in inflamed tissue homogenates at pH 5.5 for 2 hrs. In addition, the potency of BE 1-31 and five main N--terminal fragments (BE 1-9, BE 1-11, BE 1-13, BE 1-17, BE 1-20 was assessed at mu-opioid receptors (MOR, delta-opioid receptors (DOR, and kappa-opioid receptors (KOR. Opioid receptor potency was investigated by examining the modulation of forskolin induced cAMP accumulation. The majority of the N-terminal fragment of BE 1-31 had similar efficacy to BE 1-31 at MOR. The shortest of the major N-terminal fragments (BE 1-9, had partial agonist activity at MOR but possessed the highest potency of all tested peptides at DOR. There was limited effect for BE 1-31 and the biotransformed peptides at KOR. Major N-terminal fragments produced within inflamed tissue have increased presence within inflamed tissue over that of the parent molecule BE 1-31 and may therefore contribute to BE 1-31 efficacy within disease states that involve inflammation.

  11. Insulin receptor binding and protein kinase activity in muscles of trained rats

    International Nuclear Information System (INIS)

    Dohm, G.L.; Sinha, M.K.; Caro, J.F.

    1987-01-01

    Exercise has been shown to increase insulin sensitivity, and muscle is quantitatively the most important tissue of insulin action. Since the first step in insulin action is the binding to a membrane receptor, the authors postulated that exercise training would change insulin receptors in muscle and in this study they have investigated this hypothesis. Female rats initially weighing ∼ 100 g were trained by treadmill running for 2 h/day, 6 days/wk for 4 wk at 25 m/min (0 grade). Insulin receptors from vastus intermedius muscles were solubilized by homogenizing in a buffer containing 1% Triton X-100 and then partially purified by passing the soluble extract over a wheat germ agglutinin column. The 4 wk training regimen resulted in a 65% increase in citrate synthase activity in red vastus lateralis muscle, indicating an adaptation to exercise [ 125 I]. Insulin binding by the partially purified receptor preparations was approximately doubled in muscle of trained rats at all insulin concentrations, suggesting an increase in the number of receptors. Training did not alter insulin receptor structure as evidenced by electrophoretic mobility under reducing and nonreducing conditions. Basal insulin receptor protein kinase activity was higher in trained than untrained animals and this was likely due to the greater number of receptors. However, insulin stimulation of the protein kinase activity was depressed by training. These results demonstrate that endurance training does alter receptor number and function in muscle and these changes may be important in increasing insulin sensitivity after exercise training

  12. Serotonin Receptors in Hippocampus

    Science.gov (United States)

    Berumen, Laura Cristina; Rodríguez, Angelina; Miledi, Ricardo; García-Alcocer, Guadalupe

    2012-01-01

    Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system. PMID:22629209

  13. A novel technique for partial discharge measurement

    International Nuclear Information System (INIS)

    Farrokh, Fattahi; Navid, Tagizadegan; Ahmad, Zentabchi; Mehdi, Rashidi

    2005-01-01

    Full text : Partial discharges are a sensitive measure of local electrical stress and therefore the measurements is very often used as a quality check of the insulation. The inception of partial discharges gives information on the limit of the electrical strength of the insulating material before a complete discharge between the conductors takes place. Therefore the insulating material can be tested with high stress but without damaging or reducing the performance of the insulation. Also, for partial discharge measurements it should be taken into account that every stress of the insulation will have an influence on the life expectancy of the material, but a reasonable compromise between the stress during the measurement in order to get reliable results and the influence of he lifetime should be found and established in the relevant standard for the particular equipment, for example transformers, cables and so on

  14. Thin film oxygen partial pressure sensor

    Science.gov (United States)

    Wortman, J. J.; Harrison, J. W.; Honbarrier, H. L.; Yen, J.

    1972-01-01

    The development is described of a laboratory model oxygen partial pressure sensor using a sputtered zinc oxide thin film. The film is operated at about 400 C through the use of a miniature silicon bar. Because of the unique resistance versus temperature relation of the silicon bar, control of the operational temperature is achieved by controlling the resistance. A circuit for accomplishing this is described. The response of sputtered zinc oxide films of various thicknesses to oxygen, nitrogen, argon, carbon dioxide, and water vapor caused a change in the film resistance. Over a large range, film conductance varied approximately as the square root of the oxygen partial pressure. The presence of water vapor in the gas stream caused a shift in the film conductance at a given oxygen partial pressure. A theoretical model is presented to explain the characteristic features of the zinc oxide response to oxygen.

  15. Particle Systems and Partial Differential Equations I

    CERN Document Server

    Gonçalves, Patricia

    2014-01-01

    This book presents the proceedings of the international conference Particle Systems and Partial Differential Equations I, which took place at the Centre of Mathematics of the University of Minho, Braga, Portugal, from the 5th to the 7th of December, 2012.  The purpose of the conference was to bring together world leaders to discuss their topics of expertise and to present some of their latest research developments in those fields. Among the participants were researchers in probability, partial differential equations and kinetics theory. The aim of the meeting was to present to a varied public the subject of interacting particle systems, its motivation from the viewpoint of physics and its relation with partial differential equations or kinetics theory, and to stimulate discussions and possibly new collaborations among researchers with different backgrounds.  The book contains lecture notes written by François Golse on the derivation of hydrodynamic equations (compressible and incompressible Euler and Navie...

  16. Partial Thickness Rotator Cuff Tears: Current Concepts

    Science.gov (United States)

    Matthewson, Graeme; Beach, Cara J.; Nelson, Atiba A.; Woodmass, Jarret M.; Ono, Yohei; Boorman, Richard S.; Lo, Ian K. Y.; Thornton, Gail M.

    2015-01-01

    Partial thickness rotator cuff tears are a common cause of pain in the adult shoulder. Despite their high prevalence, the diagnosis and treatment of partial thickness rotator cuff tears remains controversial. While recent studies have helped to elucidate the anatomy and natural history of disease progression, the optimal treatment, both nonoperative and operative, is unclear. Although the advent of arthroscopy has improved the accuracy of the diagnosis of partial thickness rotator cuff tears, the number of surgical techniques used to repair these tears has also increased. While multiple repair techniques have been described, there is currently no significant clinical evidence supporting more complex surgical techniques over standard rotator cuff repair. Further research is required to determine the clinical indications for surgical and nonsurgical management, when formal rotator cuff repair is specifically indicated and when biologic adjunctive therapy may be utilized. PMID:26171251

  17. Partially massless graviton on beyond Einstein spacetimes

    Science.gov (United States)

    Bernard, Laura; Deffayet, Cédric; Hinterbichler, Kurt; von Strauss, Mikael

    2017-06-01

    We show that a partially massless graviton can propagate on a large set of spacetimes which are not Einstein spacetimes. Starting from a recently constructed theory for a massive graviton that propagates the correct number of degrees of freedom on an arbitrary spacetime, we first give the full explicit form of the scalar constraint responsible for the absence of a sixth degree of freedom. We then spell out generic conditions for the constraint to be identically satisfied, so that there is a scalar gauge symmetry which makes the graviton partially massless. These simplify if one assumes that spacetime is Ricci symmetric. Under this assumption, we find explicit non-Einstein spacetimes (some, but not all, with vanishing Bach tensors) allowing for the propagation of a partially massless graviton. These include in particular the Einstein static Universe.

  18. Partial Thickness Rotator Cuff Tears: Current Concepts

    Directory of Open Access Journals (Sweden)

    Graeme Matthewson

    2015-01-01

    Full Text Available Partial thickness rotator cuff tears are a common cause of pain in the adult shoulder. Despite their high prevalence, the diagnosis and treatment of partial thickness rotator cuff tears remains controversial. While recent studies have helped to elucidate the anatomy and natural history of disease progression, the optimal treatment, both nonoperative and operative, is unclear. Although the advent of arthroscopy has improved the accuracy of the diagnosis of partial thickness rotator cuff tears, the number of surgical techniques used to repair these tears has also increased. While multiple repair techniques have been described, there is currently no significant clinical evidence supporting more complex surgical techniques over standard rotator cuff repair. Further research is required to determine the clinical indications for surgical and nonsurgical management, when formal rotator cuff repair is specifically indicated and when biologic adjunctive therapy may be utilized.

  19. Partial Cavity Flows at High Reynolds Numbers

    Science.gov (United States)

    Makiharju, Simo; Elbing, Brian; Wiggins, Andrew; Dowling, David; Perlin, Marc; Ceccio, Steven

    2009-11-01

    Partial cavity flows created for friction drag reduction were examined on a large-scale. Partial cavities were investigated at Reynolds numbers up to 120 million, and stable cavities with frictional drag reduction of more than 95% were attained at optimal conditions. The model used was a 3 m wide and 12 m long flat plate with a plenum on the bottom. To create the partial cavity, air was injected at the base of an 18 cm backwards-facing step 2.1 m from the leading edge. The geometry at the cavity closure was varied for different flow speeds to optimize the closure of the cavity. Cavity gas flux, thickness, frictional loads, and cavity pressures were measured over a range of flow speeds and air injection fluxes. High-speed video was used extensively to investigate the unsteady three dimensional cavity closure, the overall cavity shape and oscillations.

  20. Partial discharges in ellipsoidal and spheroidal voids

    DEFF Research Database (Denmark)

    Crichton, George C; Karlsson, P. W.; Pedersen, Aage

    1989-01-01

    Transients associated with partial discharges in voids can be described in terms of the charges induced on the terminal electrodes of the system. The relationship between the induced charge and the properties which are usually measured is discussed. The method is illustrated by applying it to a s......Transients associated with partial discharges in voids can be described in terms of the charges induced on the terminal electrodes of the system. The relationship between the induced charge and the properties which are usually measured is discussed. The method is illustrated by applying...

  1. arXiv Minimal Fundamental Partial Compositeness

    CERN Document Server

    Cacciapaglia, Giacomo; Sannino, Francesco; Thomsen, Anders Eller

    Building upon the fundamental partial compositeness framework we provide consistent and complete composite extensions of the standard model. These are used to determine the effective operators emerging at the electroweak scale in terms of the standard model fields upon consistently integrating out the heavy composite dynamics. We exhibit the first effective field theories matching these complete composite theories of flavour and analyse their physical consequences for the third generation quarks. Relations with other approaches, ranging from effective analyses for partial compositeness to extra dimensions as well as purely fermionic extensions, are briefly discussed. Our methodology is applicable to any composite theory of dynamical electroweak symmetry breaking featuring a complete theory of flavour.

  2. Higher-Order Rewriting and Partial Evaluation

    DEFF Research Database (Denmark)

    Danvy, Olivier; Rose, Kristoffer H.

    1997-01-01

    transformations as meta-reductions, i.e., reductions in the internal “substitution calculus.” For partial-evaluation problems, this means that instead of having to prove on a case-by-case basis that one's “two-level functions” operate properly, one can concisely formalize them as a combinatory reduction system...... and obtain as a corollary that static reduction does not go wrong and yields a well-formed residual program. We have found that the CRS substitution calculus provides an adequate expressive power to formalize partial evaluation: it provides sufficient termination strength while avoiding the need...

  3. Flexible removable partial dentures: a basic overview.

    Science.gov (United States)

    Hill, Edward E; Rubel, Barry; Smith, John B

    2014-01-01

    For many years, flexible resin materials have been available for fabricating removable partial denture (RPD) prostheses. Using a nonrigid material for the major connector or other components of an RPD may be a consideration for certain patients. Except for the promotional literature that has been written for flexible resin dentures, there is very little information available in the dental literature concerning nonrigid RPDs. As a result, the decision to use this treatment option depends on the judgment and experience of the dentist and fabricating laboratory. This article summarizes clinically pertinent information about flexible, nonrigid partial dentures.

  4. DEVICE FOR CONTROL OF OXYGEN PARTIAL PRESSURE

    Science.gov (United States)

    Bradner, H.; Gordon, H.S.

    1957-12-24

    A device is described that can sense changes in oxygen partial pressure and cause a corresponding mechanical displacement sufficient to actuate meters, valves and similar devices. A piston and cylinder arrangement contains a charge of crystalline metal chelate pellets which have the peculiar property of responding to variations in the oxygen content of the ambient atmosphere by undergoing a change in dimension. A lever system amplifies the relative displacement of the piston in the cylinder, and actuates the controlled valving device. This partial pressure oxygen sensing device is useful in controlled chemical reactions or in respiratory devices such as the oxygen demand meters for high altitude aircraft.

  5. Partial gravity - Human impacts on facility design

    Science.gov (United States)

    Capps, Stephen; Moore, Nathan

    1990-01-01

    Partial gravity affects the body differently than earth gravity and microgravity environments. The main difference from earth gravity is human locomotion; while the main dfference from microgravity is the specific updown orientation and reach envelopes which increase volume requirements. Much data are available on earth gravity and microgravity design; however, very little information is available on human reactions to reduced gravity levels in IVA situations (without pressure suits). Therefore, if humans commit to permanent lunar habitation, much research should be conducted in the area of partial gravity effects on habitat design.

  6. Proximal Hamstring Tendinosis and Partial Ruptures.

    Science.gov (United States)

    Startzman, Ashley N; Fowler, Oliver; Carreira, Dominic

    2017-07-01

    Proximal hamstring tendinosis and partial hamstring origin ruptures are painful conditions of the proximal thigh and hip that may occur in the acute, chronic, or acute on chronic setting. Few publications exist related to their diagnosis and management. This systematic review discusses the incidence, treatment, and prognosis of proximal hamstring tendinosis and partial hamstring ruptures. Conservative treatment measures include nonsteroidal anti-inflammatory drugs, physical therapy, rest, and ice. If these measures fail, platelet-rich plasma or shockwave therapy may be considered. When refractory to conservative management, these injuries may be treated with surgical debridement and hamstring reattachment. [Orthopedics. 2017; 40(4):e574-e582.]. Copyright 2017, SLACK Incorporated.

  7. Partial oxidation of 2-propanol on perovskites

    Energy Technology Data Exchange (ETDEWEB)

    Sumathi, R.; Viswanathan, B.; Varadarajan, T.K. [Indian Inst. of Tech., Madras (India). Dept. of Chemistry

    1998-12-31

    Partial oxidation of 2-propanol was carried out on AB{sub 1-x}B`{sub x}O{sub 3} (A=Ba, B=Pb, Ce, Ti; B`=Bi, Sb and Cu) type perovskite oxides. Acetone was the major product observed on all the catalysts. All the catalysts underwent partial reduction during the reaction depending on the composition of the reactant, nature of the B site cation and the extent of substitution at B site. The catalytic activity has been correlated with the reducibility of the perovskite oxides determined from Temperature Programmed Reduction (TPR) studies. (orig.)

  8. Generalized solutions of nonlinear partial differential equations

    CERN Document Server

    Rosinger, EE

    1987-01-01

    During the last few years, several fairly systematic nonlinear theories of generalized solutions of rather arbitrary nonlinear partial differential equations have emerged. The aim of this volume is to offer the reader a sufficiently detailed introduction to two of these recent nonlinear theories which have so far contributed most to the study of generalized solutions of nonlinear partial differential equations, bringing the reader to the level of ongoing research.The essence of the two nonlinear theories presented in this volume is the observation that much of the mathematics concernin

  9. Characterization of beta-adrenergic receptors through the replicative life span of IMR-90 cells

    International Nuclear Information System (INIS)

    Scarpace, P.J.

    1987-01-01

    Beta-adrenergic receptor number and receptor affinity for isoproterenol were assessed at various in vitro ages of the human diploid fibroblast cell line IMR-90. From population doubling level (PDL) 33 to 44, there was a positive correlation between beta-adrenergic receptor density and PDL. Beta-adrenergic receptors, assessed by Scatchard analysis of [ 125 I]-iodocyanopindolol (ICYP) binding, increased from 15 fmol/mg protein at PDL 33 to 36 fmol/mg protein at PDL 44. In contrast, from PDL 44 to 59, there was a negative correlation between beta-adrenergic receptor density and PDL. Receptor density declined to 12 fmol/mg protein at PDL 59. When the density of beta-adrenergic receptors was expressed as receptor per cell, the findings were similar. Receptor agonist affinity for isoproterenol was determined from Hill plots of [ 125 I]-ICYP competition with isoproterenol. There was no change in the dissociation constant for isoproterenol with in vitro age. In humans, serum norepinephrine concentrations increase with age. This increase in serum norepinephrine may be partially responsible for the decreased beta-adrenergic receptor-agonist affinity observed with age in human lymphocytes and rat heart and lung. The present findings are consistent with the hypothesis that the decreases in receptor agonist affinity in rat and man with age are secondary to increases in catecholamine concentrations

  10. Functional expression of the 5-HT1c receptor in neuronal and nonneuronal cells

    International Nuclear Information System (INIS)

    Julius, D.; MacDermott, A.B.; Jessel, T.M.; Huang, K.; Molineaux, S.; Schieren, I.; Axel, R.

    1988-01-01

    The isolation of the genes encoding the multiple serotonin receptor subtypes and the ability to express these receptors in new cellular environments will help to elucidate the molecular mechanisms of action of serotonin in the mammalian brain. The cloning of most neurotransmitter receptors has required the purification of receptor, the determination of partial protein sequence, and the synthesis of oligonucleotide probes with which to obtain cDNA or genomic clones. However, the serotonin receptors have not been purified and antibodies have not been generated. The authors therefore designed a cDNA expression system that permits the identification of functional cDNA clones encoding serotonin receptors in the absence of protein sequence information. They have combined cloning in RNA expression vectors with an electrophysiological assay in oocytes to isolate a functional cDNA clone encoding the entire 5-HT 1c receptor. The sequence of this clone reveals that the 5-HT 1c receptor belongs to a family of G-protein-coupled receptors that are thought to traverse the membrane seven times. Mouse fibroblasts transformed with this clone bind serotonergic ligands and respond to serotonin with an elevation in intracellular calcium. Moreover, in situ hybridization and Northern blot analysis indicate that the 5-HT 1c receptor mRNA is expressed in a wide variety of neurons in the rat central nervous system, suggesting that this receptor plays a prominent role in neuronal function

  11. Phytoconstituents from Vitex agnus-castus fruits.

    Science.gov (United States)

    Chen, Shao-Nong; Friesen, J Brent; Webster, Donna; Nikolic, Dejan; van Breemen, Richard B; Wang, Z Jim; Fong, Harry H S; Farnsworth, Norman R; Pauli, Guido F

    2011-06-01

    A new labdane-diterpene, viteagnusin I (1), together with 23 known phytoconstituents were isolated from the fruits of Vitex agnus-castus L, and their structures characterized by spectroscopic methods (NMR and MS). The known compounds include ten flavonoids, five terpenoids, three neolignans, and four phenolic compounds, as well as one glyceride. Biological evaluation identified apigenin, 3-methylkaempferol, luteolin, and casticin as weak ligands of delta and mu opioid receptors, exhibiting dose-dependent receptor binding. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Effects of morphine and naloxone on feline colonic transit

    International Nuclear Information System (INIS)

    Krevsky, B.; Libster, B.; Maurer, A.H.; Chase, B.J.; Fisher, R.S.

    1989-01-01

    The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of the other opioid receptors is inferred

  13. Effects of morphine and naloxone on feline colonic transit

    Energy Technology Data Exchange (ETDEWEB)

    Krevsky, B.; Libster, B.; Maurer, A.H.; Chase, B.J.; Fisher, R.S.

    1989-01-01

    The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of the other opioid receptors is inferred.

  14. Solubilization, partial purification, and reconstitution of glutamate- and N-methyl-D-aspartate-activated cation channels from brain synaptic membranes

    International Nuclear Information System (INIS)

    Ly, A.M.; Michaelis, E.K.

    1991-01-01

    L-Glutamate-activated cation channel proteins from rat brain synaptic membranes were solubilized, partially purified, and reconstituted into liposomes. Optimal conditions for solubilization and reconstitution included treatment of the membranes with nonionic detergents in the presence of neutral phospholipids plus glycerol. Quench-flow procedures were developed to characterize the rapid kinetics of ion flux induced by receptor agonists. [ 14 C]Methylamine, a cation that permeates through the open channel of both vertebrate and invertebrate glutamate receptors, was used to measure the activity of glutamate receptor-ion channel complexes in reconstituted liposomes. L-Glutamate caused an increase in the rate of [ 14 C]methylamine influx into liposomes reconstituted with either solubilized membrane proteins or partially purified glutamate-binding proteins. Of the major glutamate receptor agonists, only N-methyl-D-aspartate activated cation fluxes in liposomes reconstituted with glutamate-binding proteins. In liposomes reconstituted with glutamate-binding proteins, N-methyl-D-aspartate- or glutamate-induced influx of NA + led to a transient increase in the influx of the lipid-permeable anion probe S 14 CN - . These results indicate the functional reconstitution of N-methyl-D-aspartate-sensitive glutamate receptors and the role of the ∼69-kDa protein in the function of these ion channels

  15. Maintenance on naltrexone+amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys.

    Science.gov (United States)

    Moerke, Megan J; Banks, Matthew L; Cheng, Kejun; Rice, Kenner C; Negus, S Stevens

    2017-12-01

    Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0-0.1mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032-0.32mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Opiate-induced suppression of rat hypoglossal motoneuron activity and its reversal by ampakine therapy.

    Directory of Open Access Journals (Sweden)

    Amanda R Lorier

    2010-01-01

    Full Text Available Hypoglossal (XII motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of mu-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s. We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity.A medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the mu-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717 alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons.The inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract mu-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron activity and resultant impairment of airway patency.

  17. Barrelet zeros in partial wave analysis

    International Nuclear Information System (INIS)

    Baker, R.D.

    1976-01-01

    The formalism of Barrelet zeros is discussed. Spinless scattering is described to introduce the idea, then the more usual case of 0 - 1/2 + → 0 - 1/2 + scattering. The zeros are regarded here only as a means to an end, viz the partial waves. The extraction of these is given in detail, and ambiguities are discussed at length. (author)

  18. Partial discharges in spheroidal voids: Void orientation

    DEFF Research Database (Denmark)

    McAllister, Iain Wilson

    1997-01-01

    Partial discharge transients can be described in terms of the charge induced on the detecting electrode. The influence of the void parameters upon the induced charge is examined and discussed for spheroidal voids. It is shown that a quantitative interpretation of the induced charge requires...

  19. Partial splenectomy in children with Gaucher's disease

    International Nuclear Information System (INIS)

    Bar-Maor, J.A.; Govrin-Yehudain, J.

    1985-01-01

    Because of hypersplenism and mechanical problems, partial splenectomy was performed in four children with Gaucher's disease. Subsequently, one of the patients underwent a total splenectomy due to bleeding from the remnant of the spleen. At the follow-up of the other three patients, an isotope scan showed that the remaining spleen was functioning well

  20. Partial Hospitalization Programs: A Current Perspective.

    Science.gov (United States)

    Whitelaw, Carolyn A.; Perez, Edgardo L.

    1987-01-01

    Reviews the historical background, standards, the issue of day treatment versus day care, functional issues, specialization, efficacy and cost effectiveness, utilization issues, and alternative models of care of partial hospitalization programs in North America. Emphasizes issues of relevance when planning alternative programs to inpatient…

  1. Partial chord diagrams and matrix models

    DEFF Research Database (Denmark)

    Andersen, Jørgen Ellegaard; Fuji, Hiroyuki; Manabe, Masahide

    In this article, the enumeration of partial chord diagrams is discussed via matrix model techniques. In addition to the basic data such as the number of backbones and chords, we also consider the Euler characteristic, the backbone spectrum, the boundary point spectrum, and the boundary length spe...

  2. [Elderly people and removable partial dentures

    NARCIS (Netherlands)

    Baat, C. de

    2009-01-01

    The most frequently reported disadvantages of removable partial dentures are the more demanding daily oral hygiene self-care, especially for people who already experience difficulties in self-care, and the possible harmful influence on the remaining dentition. These disadvantages can be expressed in

  3. Dual Component Removable Partial Denture shows improved ...

    African Journals Online (AJOL)

    Dual Component Removable Partial Denture (DuCo RPD) is composed of a double base; lower and upper. The lower base, where the artificial teeth are attached, acts as a support and is in contact with the alveolar ridges and oral mucosa. Clasps are designed on the upper base, which acts towards the retention and ...

  4. Flow visualization via partial differential equations

    NARCIS (Netherlands)

    Preusser, T.; Rumpf, M.; Telea, A.C.; Möller, T.; Hamann, B.; Russell, R.D.

    2009-01-01

    The visualization of stationary and time-dependent flow is an important and chaltenging topic in scientific visualization. lts aim is 10 represent transport phenomena govemed by vector fjelds in an intuitively understandable way. In this paper. we review the use of methods based on partial

  5. [Resin-bonded fixed partial dentures

    NARCIS (Netherlands)

    Kreulen, C.M.; Creugers, N.H.J.

    2013-01-01

    A resin-bonded fixed partial denture is a prosthetic construction which can replace I or several teeth in an occlusal system and which comprises a pontic element which is adhesively attached to 1 or more abutment teeth. To compensate for the limited shear strength of the adhesive layer, the Jixed

  6. Permissive Subsorted Partial Logic in CASL

    DEFF Research Database (Denmark)

    Cerioli, Maura; Haxthausen, Anne Elisabeth; Krieg-Brückner, Bernd

    1997-01-01

    This paper presents a permissive subsorted partial logic used in the CoFI Algebraic Specification Language. In contrast to other order-sorted logics, subsorting is not modeled by set inclusions, but by injective embeddings allowing for more general models in which subtypes can have different data...

  7. Canonical coordinates for partial differential equations

    Science.gov (United States)

    Hunt, L. R.; Villarreal, Ramiro

    1988-01-01

    Necessary and sufficient conditions are found under which operators of the form Sigma (m, j=1) x (2) sub j + X sub O can be made constant coefficient. In addition, necessary and sufficient conditions are derived which classify those linear partial differential operators that can be moved to the Kolmogorov type.

  8. Canonical coordinates for partial differential equations

    Science.gov (United States)

    Hunt, L. R.; Villarreal, Ramiro

    1987-01-01

    Necessary and sufficient conditions are found under which operators of the form Sigma(m, j=1) X(2)sub j + X sub 0 can be made constant coefficient. In addition, necessary and sufficient conditions are derived which classify those linear partial differential operators that can be moved to the Kolmogorov type.

  9. Monitoring as a partially observable decision problem

    Science.gov (United States)

    Paul L. Fackler; Robert G. Haight

    2014-01-01

    Monitoring is an important and costly activity in resource man-agement problems such as containing invasive species, protectingendangered species, preventing soil erosion, and regulating con-tracts for environmental services. Recent studies have viewedoptimal monitoring as a Partially Observable Markov Decision Pro-cess (POMDP), which provides a framework for...

  10. Atomic disintegrations for partially hyperbolic diffeomorphisms

    NARCIS (Netherlands)

    Homburg, Ale Jan

    2017-01-01

    Shub and Wilkinson and Ruelle and Wilkinson studied a class of volume preserving diffeomorphisms on the three dimensional torus that are stably ergodic. The diffeomorphisms are partially hyperbolic and admit an invariant central foliation of circles. The foliation is not absolutely continuous; in

  11. First symposium accelerated partial breast irradiation

    International Nuclear Information System (INIS)

    2012-01-01

    The First symposium accelerated partial breast irradiation, was organized by the Marie Curie Foundation, between the 14 to 16 june 2012, in the Cordoba city of Argentina. In this event were presented some papers on the following topics: radiotherapy in breast cancer; interaction between systemic treatments and radiotherapy; interstitial brachytherapy.

  12. Crichton ambiguities with infinitely many partial waves

    International Nuclear Information System (INIS)

    Atkinson, D.; Kok, L.P.; de Roo, M.

    1978-01-01

    We construct families of spinless two-particle unitary cross sections that possess a nontrivial discrete phase-shift ambiguity, with in general an infinite number of nonvanishing partial waves. A numerical investigation reveals that some of the previously known finite Crichton ambiguities are merely special cases of the newly constructed examples

  13. Group-wise partial least square regression

    NARCIS (Netherlands)

    Camacho, José; Saccenti, Edoardo

    2018-01-01

    This paper introduces the group-wise partial least squares (GPLS) regression. GPLS is a new sparse PLS technique where the sparsity structure is defined in terms of groups of correlated variables, similarly to what is done in the related group-wise principal component analysis. These groups are

  14. Partial axillary dissection in early breast cancer

    African Journals Online (AJOL)

    Tarek Abdel Halim El-Fayoumi

    ORIGINAL ARTICLE. Partial axillary dissection in early breast cancer. Tarek Abdel Halim El-Fayoumi *. Department of General Surgery, Faculty of Medicine, Alexandria University, Egypt. Received 16 October 2012; accepted 7 January 2013. Available online 7 March 2013. KEYWORDS. Breast cancer;. Axillary lymph nodes.

  15. New applications of partial residual methodology

    International Nuclear Information System (INIS)

    Uslu, V.R.

    1999-12-01

    The formulation of a problem of interest in the framework of a statistical analysis starts with collecting the data, choosing a model, making certain assumptions as described in the basic paradigm by Box (1980). This stage is is called model building. Then the estimation stage is in order by pretending as if the formulation of the problem was true to obtain estimates, to make tests and inferences. In the final stage, called diagnostic checking, checking of whether there are some disagreements between the data and the model fitted is done by using diagnostic measures and diagnostic plots. It is well known that statistical methods perform best under the condition that all assumptions related to the methods are satisfied. However it is true that having the ideal case in practice is very difficult. Diagnostics are therefore becoming important so are diagnostic plots because they provide a immediate assessment. Partial residual plots that are the main interest of the present study are playing the major role among the diagnostic plots in multiple regression analysis. In statistical literature it is admitted that partial residual plots are more useful than ordinary residual plots in detecting outliers, nonconstant variance, and especially discovering curvatures. In this study we consider the partial residual methodology in statistical methods rather than multiple regression. We have shown that for the same purpose as in the multiple regression the use of partial residual plots is possible particularly in autoregressive time series models, transfer function models, linear mixed models and ridge regression. (author)

  16. [Designing metal frame removable partial dentures

    NARCIS (Netherlands)

    Witter, D.J.; Barel, J.C.; Keltjens, H.M.A.M.; Creugers, N.H.J.

    2011-01-01

    Oral health care providers have the full responsibility for designing metal frame removable partial dentures and making all of the necessary preparations. Important principles of design are that the denture should hamper natural cleaning and daily oral hygiene as little as possible and that it

  17. psychrometry: from partial pressures to mole fractions

    African Journals Online (AJOL)

    ES Obe

    1980-03-01

    Mar 1, 1980 ... as an ideal gas mixture. Partial pressures then become identical: to mole fractions and sets of psychometric parameters result from rather elementary thermodynamic relations. Search for more accurate data has long led to the realization that neither dry air nor pure water vapour behaves like an ideal gas,.

  18. Partial purification and characterization of metalloprotease of ...

    African Journals Online (AJOL)

    USER

    2013-07-31

    Jul 31, 2013 ... The supplementation of partially purified enzyme preparation in detergents such as Rin and Wheel significantly improved their cleansing efficiency as blood and fish curry stains on the cloth disappeared within 15 min (Figure 6). Our finding go hand in hand with earlier findings on Bacillus licheniformis ...

  19. Partial purification, characterization and hydrolytic activities of ...

    African Journals Online (AJOL)

    α-Amylase and amyloglucosidase produced by amylolytic Bacillus licheniformis and Aspergillus niger isolated from plantain and yam peels media were partially purified and characterized. Following cultivation of the microbial isolates on the agricultural residue media, crude enzyme solutions were obtained by filtration and ...

  20. Partial Evaluation of the Euclidian Algorithm

    DEFF Research Database (Denmark)

    Danvy, Olivier; Goldberg, Mayer

    1997-01-01

    Some programs are easily amenable to partial evaluation because their control flow clearly depends on one of their parameters. Specializing such programs with respect to this parameter eliminates the associated interpretive overhead. Some other programs, however, do not exhibit this interpreter-l...

  1. Exergy of partially coherent thermal radiation

    International Nuclear Information System (INIS)

    Wijewardane, S.; Goswami, Yogi

    2012-01-01

    Exergy of electromagnetic radiation has been studied by a number of researchers for well over four decades in order to estimate the maximum conversion efficiencies of thermal radiation. As these researchers primarily dealt with solar and blackbody radiation, which have a low degree of coherence, they did not consider the partial coherence properties of thermal radiation. With the recent development of surface structures, which can emit radiation with high degree of coherence, the importance of considering the partial coherent properties in exergy calculation has become a necessity as the coherence properties directly influence the entropy of the wave field. Here in this paper we derive an expression for the exergy of quasi-monochromatic radiation using statistical thermodynamics and show that it is identical with the expressions derived using classical thermodynamics. We also present a method to calculate the entropy, thereby the exergy of partially coherent radiation using statistical thermodynamics and a method called matrix treatment of wave field. -- Highlights: ► Considered partial coherence of radiation for the first time to calculate exergy. ► The importance of this method is emphasized with energy conversion examples. ► Derived an expression for the exergy of radiation using statistical thermodynamics. ► Adopted a method to calculate intensity of statistically independent principle wave.

  2. Crichton ambiguities with infinitely many partial waves

    NARCIS (Netherlands)

    Atkinson, D.; Kok, L.P.; de Roo, M.

    We construct families of spin less two-particle unitary cross sections that possess a nontrivial discrete phase-shift ambiguity, with in general an infinite number of nonvanishing partial waves. A numerical investigation reveals that some of the previously known finite Crichton ambiguities are

  3. Partial differential equations in several complex variables

    CERN Document Server

    Chen, So-Chin

    2001-01-01

    This book is intended both as an introductory text and as a reference book for those interested in studying several complex variables in the context of partial differential equations. In the last few decades, significant progress has been made in the fields of Cauchy-Riemann and tangential Cauchy-Riemann operators. This book gives an up-to-date account of the theories for these equations and their applications. The background material in several complex variables is developed in the first three chapters, leading to the Levi problem. The next three chapters are devoted to the solvability and regularity of the Cauchy-Riemann equations using Hilbert space techniques. The authors provide a systematic study of the Cauchy-Riemann equations and the \\bar\\partial-Neumann problem, including L^2 existence theorems on pseudoconvex domains, \\frac 12-subelliptic estimates for the \\bar\\partial-Neumann problems on strongly pseudoconvex domains, global regularity of \\bar\\partial on more general pseudoconvex domains, boundary ...

  4. Partial wave analysis using graphics processing units

    Energy Technology Data Exchange (ETDEWEB)

    Berger, Niklaus; Liu Beijiang; Wang Jike, E-mail: nberger@ihep.ac.c [Institute of High Energy Physics, Chinese Academy of Sciences, 19B Yuquan Lu, Shijingshan, 100049 Beijing (China)

    2010-04-01

    Partial wave analysis is an important tool for determining resonance properties in hadron spectroscopy. For large data samples however, the un-binned likelihood fits employed are computationally very expensive. At the Beijing Spectrometer (BES) III experiment, an increase in statistics compared to earlier experiments of up to two orders of magnitude is expected. In order to allow for a timely analysis of these datasets, additional computing power with short turnover times has to be made available. It turns out that graphics processing units (GPUs) originally developed for 3D computer games have an architecture of massively parallel single instruction multiple data floating point units that is almost ideally suited for the algorithms employed in partial wave analysis. We have implemented a framework for tensor manipulation and partial wave fits called GPUPWA. The user writes a program in pure C++ whilst the GPUPWA classes handle computations on the GPU, memory transfers, caching and other technical details. In conjunction with a recent graphics processor, the framework provides a speed-up of the partial wave fit by more than two orders of magnitude compared to legacy FORTRAN code.

  5. A Partial Theory of Executive Succession.

    Science.gov (United States)

    Thiemann, Francis C.

    This study has two purposes: (1) To construct a partial theory of succession, and (2) to utilize a method of theory construction which combines some of the concepts of Hans Zetterberg with the principles of formal symbolic logic. A bibliography on succession in complex organizations with entries on descriptive and empirical studies from various…

  6. Microbial Flora of Partially Processed Periwinkles (Tympantotonus ...

    African Journals Online (AJOL)

    A survey of microbial flora of partially processed periwinkles (Tympanotonus fuscatus) sold in six markets in Port Harcourt was undertaken for twelve weeks. Results show that all samples of periwinkles were contaminated with Staphylococcus aureus, Bacillus sp., Escherichia coil, Staphepidermidis sp., Micrococcus sp., ...

  7. A computational formalization for partial evaluation

    DEFF Research Database (Denmark)

    Hatcliff, John; Danvy, Olivier

    1997-01-01

    We formalize a partial evaluator for Eugenio Moggi's computational metalanguage. This formalization gives an evaluation-order independent view of binding-time analysis and program specialization, including a proper treatment of call unfolding. It also enables us to express the essence of `control...

  8. A note on partial vertical integration

    NARCIS (Netherlands)

    G.W.J. Hendrikse (George); H.J.M. Peters (Hans)

    1989-01-01

    textabstractA simple model is constructed to show how partial vertical integration may emerge as an equilibrium market structure in a world characterized by rationing, differences in the reservation prices of buyers, and in the risk attitudes of buyers and sellers. The buyers with the high

  9. Memorization in Type-Directed Partial Evaluation

    DEFF Research Database (Denmark)

    Balat, Vincent; Danvy, Olivier

    2002-01-01

    We use a code generator—type-directed partial evaluation— to verify conversions between isomorphic types, or more precisely to verify that a composite function is the identity function at some complicated type. A typed functional language such as ML provides a natural support to express the funct...

  10. Testing the generalized partial credit model

    NARCIS (Netherlands)

    Glas, Cornelis A.W.

    1996-01-01

    The partial credit model (PCM) (G.N. Masters, 1982) can be viewed as a generalization of the Rasch model for dichotomous items to the case of polytomous items. In many cases, the PCM is too restrictive to fit the data. Several generalizations of the PCM have been proposed. In this paper, a

  11. Some Considerations on the Partial Credit Model

    Science.gov (United States)

    Verhelst, N. D.; Verstralen, H. H. F. M.

    2008-01-01

    The Partial Credit Model (PCM) is sometimes interpreted as a model for stepwise solution of polytomously scored items, where the item parameters are interpreted as difficulties of the steps. It is argued that this interpretation is not justified. A model for stepwise solution is discussed. It is shown that the PCM is suited to model sums of binary…

  12. How to test for partially predictable chaos.

    Science.gov (United States)

    Wernecke, Hendrik; Sándor, Bulcsú; Gros, Claudius

    2017-04-24

    For a chaotic system pairs of initially close-by trajectories become eventually fully uncorrelated on the attracting set. This process of decorrelation can split into an initial exponential decrease and a subsequent diffusive process on the chaotic attractor causing the final loss of predictability. Both processes can be either of the same or of very different time scales. In the latter case the two trajectories linger within a finite but small distance (with respect to the overall extent of the attractor) for exceedingly long times and remain partially predictable. Standard tests for chaos widely use inter-orbital correlations as an indicator. However, testing partially predictable chaos yields mostly ambiguous results, as this type of chaos is characterized by attractors of fractally broadened braids. For a resolution we introduce a novel 0-1 indicator for chaos based on the cross-distance scaling of pairs of initially close trajectories. This test robustly discriminates chaos, including partially predictable chaos, from laminar flow. Additionally using the finite time cross-correlation of pairs of initially close trajectories, we are able to identify laminar flow as well as strong and partially predictable chaos in a 0-1 manner solely from the properties of pairs of trajectories.

  13. Pragmatics of type-directed partial evaluation

    DEFF Research Database (Denmark)

    Danvy, Olivier

    1996-01-01

    Type-directed partial evaluation stems from the residualization of static values in dynamic contexts, given their type and the type of their free variables. Its algorithm coincides with the algorithm for coercing a subtype value into a supertype value, which itself coincides with Berger and Schwi...

  14. Complete destructive interference of partially coherent fields

    NARCIS (Netherlands)

    Gbur, G.J.; Visser, T.D.; Wolf, E.

    2004-01-01

    A three-point source model is used to study the interference of wavefields which are mutually partially coherent. It is shown that complete destructive interference of the fields is possible in such a "three-pinhole interferometer" even if the sources are not fully coherent with respect to each

  15. Partial Polarization in Interfered Plasmon Fields

    Directory of Open Access Journals (Sweden)

    P. Martínez Vara

    2014-01-01

    Full Text Available We describe the polarization features for plasmon fields generated by the interference between two elemental surface plasmon modes, obtaining a set of Stokes parameters which allows establishing a parallelism with the traditional polarization model. With the analysis presented, we find the corresponding coherence matrix for plasmon fields incorporating to the plasmon optics the study of partial polarization effects.

  16. Partial Automated Alignment and Integration System

    Science.gov (United States)

    Kelley, Gary Wayne (Inventor)

    2014-01-01

    The present invention is a Partial Automated Alignment and Integration System (PAAIS) used to automate the alignment and integration of space vehicle components. A PAAIS includes ground support apparatuses, a track assembly with a plurality of energy-emitting components and an energy-receiving component containing a plurality of energy-receiving surfaces. Communication components and processors allow communication and feedback through PAAIS.

  17. Design of multistable systems via partial synchronization

    Indian Academy of Sciences (India)

    Mohammad Ali Khan

    2017-07-05

    Jul 5, 2017 ... The basic idea of the scheme is to design partial synchronization of states between the coupled systems and ... Numerical simulation results consisting of ... systems of the same order via active control is discussed. In §3, the ...

  18. Partially Decentralized Control Architectures for Satellite Formations

    Science.gov (United States)

    Carpenter, J. Russell; Bauer, Frank H.

    2002-01-01

    In a partially decentralized control architecture, more than one but less than all nodes have supervisory capability. This paper describes an approach to choosing the number of supervisors in such au architecture, based on a reliability vs. cost trade. It also considers the implications of these results for the design of navigation systems for satellite formations that could be controlled with a partially decentralized architecture. Using an assumed cost model, analytic and simulation-based results indicate that it may be cheaper to achieve a given overall system reliability with a partially decentralized architecture containing only a few supervisors, than with either fully decentralized or purely centralized architectures. Nominally, the subset of supervisors may act as centralized estimation and control nodes for corresponding subsets of the remaining subordinate nodes, and act as decentralized estimation and control peers with respect to each other. However, in the context of partially decentralized satellite formation control, the absolute positions and velocities of each spacecraft are unique, so that correlations which make estimates using only local information suboptimal only occur through common biases and process noise. Covariance and monte-carlo analysis of a simplified system show that this lack of correlation may allow simplification of the local estimators while preserving the global optimality of the maneuvers commanded by the supervisors.

  19. A partial account of presupposition projection

    NARCIS (Netherlands)

    Beaver, D.; Krahmer, E.J.

    2001-01-01

    In this paper it is shown how a partial semantics for presuppositions can be given which is empirically more satisfactory than its predecessors, and how this semantics can be integrated with a technically sound, compositional grammar in the Montagovian fashion. Additionally, it is argued that the

  20. Pipeline transportation of emerging partially upgraded bitumen

    International Nuclear Information System (INIS)

    Luhning, R.W.; Anand, A.; Blackmore, T.; Lawson, D.S.

    2002-01-01

    The recoverable reserves of Canada's vast oil deposits is estimated to be 335 billion barrels (bbl), most of which are in the Alberta oil sands. Canada was the largest import supplier of crude oil to the United States in 2001, followed by Saudi Arabia. By 2011, the production of oil sands is expected to increase to 50 per cent of Canada's oil, and conventional oil production will decline as more production will be provided by synthetic light oil and bitumen. This paper lists the announced oil sands projects. If all are to proceed, production would reach 3,445,000 bbl per day by 2011. The three main challenges regarding the transportation and marketing of this new production were described. The first is to expand the physical capacity of existing pipelines. The second is the supply of low viscosity diluent (such as natural gas condensate or synthetic diluent) to reduce the viscosity and density of the bitumen as it passes through the pipelines. The current pipeline specifications and procedures to transport partially upgraded products are presented. The final challenge is the projected refinery market constraint to process the bitumen and synthetic light oil into consumer fuel products. These challenges can be addressed by modifying refineries and increasing Canadian access in Petroleum Administration Defense District (PADD) II and IV. The technology for partial upgrading of bitumen to produce pipeline specification oil, reduce diluent requirements and add sales value, is currently under development. The number of existing refineries to potentially accept partially upgraded product is listed. The partially upgraded bitumen will be in demand for additional upgrading to end user products, and new opportunities will be presented as additional pipeline capacity is made available to transport crude to U.S. markets and overseas. The paper describes the following emerging partial upgrading methods: the OrCrude upgrading process, rapid thermal processing, CPJ process for

  1. Treatment planning: implant-supported partial overdentures.

    Science.gov (United States)

    Chee, Winston W L

    2005-04-01

    When multiple anterior teeth are missing, many options of replacement are available. Traditionally, the choice was between a fixed or removable prostheses. Today, with the predictability of dental implants, the options of tooth replacement range from removable partial dentures to implant-supported fixed prostheses. The choice of which restoration that will best provide occlusion and esthetics depends on multiple factors including the number and location of missing teeth, the residual ridge form in relation to the replacement teeth, the relationship of the maxillary and mandibular anterior teeth, the condition of teeth adjacent to the edentulous span, the amount of bone available for implant placement, the patients "smile line" and display of teeth, lip support, and financial constraints. When there is minimal loss of the ridge contour, restorations that emerge from the ridge are the most functional and esthetic restorations, adhesive-type fixed partial dentures, conventional fixed partial dentures, and implant-supported restorations can be indicated with the choice of restoration dependent on a risk benefit and cost benefit analysis. When there is a loss of ridge contour due to residual ridge resorption or trauma, the decision becomes more complex as not only does the tooth structure need to be replaced, the ridge form also has to be replaced. (Figures 1 and 2). This can be assessed clinically as illustrated by Figures 1 and 2 where a dis crepancy in arch form and ridge form in relation to the adjacent teeth and/or opposing arch can be observed. Other considerations are lip support and display of the teeth when smiling. This article presents a case and rationale for implant-supported par tial overdentures. Many authors have written on the merits of com plete overdentures. The complete overdenture has proven to be an improvement over conventional complete prostheses with respect to chewing efficiency, patient comfort and satisfaction. In partial edentulism, the

  2. [Partial splenectomy in sickle cell disease].

    Science.gov (United States)

    Gutiérrez Díaz, A I; Svarch, E; Arencibia Núñez, A; Sabournin Ferrier, V; Machín García, S; Menendez Veitía, A; Ramón Rodriguez, L; Serrano Mirabal, J; García Peralta, T; López Martin, L G

    2015-04-01

    Total splenectomy in sickle cell disease is related to a high risk of fulminant sepsis and increased incidence of other events, which have not been reported in patients with partial splenectomy. In this study we examined the patients with sickle cell disease and partial splenectomy and compared the clinical and laboratory results with non-splenectomized patients. We studied 54 patients with sickle cell disease who underwent partial splenectomy in childhood from 1986 until 2011 at the Institute of Hematology and Immunology. They were compared with 54 non-splenectomized patients selected by random sampling with similar characteristics. Partial splenectomy was performed at a mean age of 4.1 years, with a higher frequency in homozygous hemoglobin S (70.4%), and the most common cause was recurrent splenic sequestration crisis. The most common postoperative complications were fever of unknown origin (14.8%) and acute chest syndrome (11.1%). After splenectomy there was a significant increase in leukocytes, neutrophils, and platelets, the latter two parameters remained significantly elevated when compared with non-splenectomized patients. There was no difference in the incidence of clinical events, except hepatic sequestration, which was more common in splenectomized patients. Partial splenectomy was a safe procedure in patients with sickle cell disease. There were no differences in the clinical picture in children splenectomized and non-splenectomized except the greater frequency of hepatic sequestration crisis in the first group. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  3. Monotherapy for partial epilepsy: focus on levetiracetam

    Directory of Open Access Journals (Sweden)

    Antonio Gambardella

    2008-03-01

    Full Text Available Antonio Gambardella1,2, Angelo Labate1,2, Eleonora Colosimo1, Roberta Ambrosio1, Aldo Quattrone1,21Institute of Neurology, University Magna Græcia, Catanzaro, Italy; 2Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Cosenza, ItalyAbstract: Levetiracetam (LEV, the S-enantiomer of alpha-ethyl-2-oxo-1-pyrollidine acetamide, is a recently licensed antiepileptic drug (AED for adjunctive therapy of partial seizures. Its mechanism of action is uncertain but it exhibits a unique profile of anticonvulsant activity in models of chronic epilepsy. Five randomized, double-blind, placebo-controlled trials enrolling adult or pediatric patients with refractory partial epilepsy have demonstrated the efficacy of LEV as adjunctive therapy, with a responder rate (≥50% reduction in seizure frequency of 28%–45%. Long-term efficacy studies suggest retention rates of 60% after one year, with 13% of patients seizure-free for 6 months of the study and 8% seizure-free for 1 year. More recent studies illustrated successful conversion to monotherapy in patients with refractory epilepsy, and its effectiveness as a single agent in partial epilepsy. LEV has also efficacy in generalized epilepsies. Adverse effects of LEV, including somnolence, lethargy, and dizziness, are generally mild and their occurrence rate seems to be not significantly different from that observed in placebo groups. LEV also has no clinically significant pharmacokinetic interactions with other AEDs, or with commonly prescribed medications. The combination of effective antiepileptic properties with a relatively mild adverse effect profile makes LEV an attractive therapy for partial seizures.Keywords: levetiracetam, partial epilepsy, antiepileptic drugs

  4. NMDA receptors are not required for pattern completion during associative memory recall.

    Directory of Open Access Journals (Sweden)

    Bing Mei

    2011-04-01

    Full Text Available Pattern completion, the ability to retrieve complete memories initiated by subsets of external cues, has been a major focus of many computation models. A previously study reports that such pattern completion requires NMDA receptors in the hippocampus. However, such a claim was derived from a non-inducible gene knockout experiment in which the NMDA receptors were absent throughout all stages of memory processes as well as animal's adult life. This raises the critical question regarding whether the previously described results were truly resulting from the requirement of the NMDA receptors in retrieval. Here, we have examined the role of the NMDA receptors in pattern completion via inducible knockout of NMDA receptors limited to the memory retrieval stage. By using two independent mouse lines, we found that inducible knockout mice, lacking NMDA receptor in either forebrain or hippocampus CA1 region at the time of memory retrieval, exhibited normal recall of associative spatial reference memory regardless of whether retrievals took place under full-cue or partial-cue conditions. Moreover, systemic antagonism of NMDA receptor during retention tests also had no effect on full-cue or partial-cue recall of spatial water maze memories. Thus, both genetic and pharmacological experiments collectively demonstrate that pattern completion during spatial associative memory recall does not require the NMDA receptor in the hippocampus or forebrain.

  5. Neomycin is a platelet-derived growth factor (PDGF) antagonist that allows discrimination of PDGF alpha- and beta-receptor signals in cells expressing both receptor types.

    Science.gov (United States)

    Vassbotn, F S; Ostman, A; Siegbahn, A; Holmsen, H; Heldin, C H

    1992-08-05

    The aminoglycoside neomycin has recently been found to affect certain platelet-derived growth factor (PDGF) responses in C3H/10T1/2 C18 fibroblasts. Using porcine aortic endothelial cells transfected with PDGF alpha- or beta-receptors, we explored the possibility that neomycin interferes with the interaction between the different PDGF isoforms and their receptors. We found that neomycin (5 mM) inhibited the binding of 125I-PDGF-BB to the alpha-receptor with only partial effect on the binding of 125I-PDGF-AA; in contrast, the binding of 125I-PDGF-BB to the beta-receptor was not affected by the aminoglycoside. Scatchard analyses showed that neomycin (5 mM) decreased the number of binding sites for PDGF-BB on alpha-receptor-expressing cells by 87%. Together with cross-competition studies with 125I-labeled PDGF homodimers, the effect of neomycin indicates that PDGF-AA and PDGF-BB bind to both common and unique structures on the PDGF alpha-receptor. Neomycin specifically inhibited the autophosphorylation of the alpha-receptor by PDGF-BB, with less effect on the phosphorylation induced by PDGF-AA and no effect on the phosphorylation of the beta-receptor by PDGF-BB. Thus, neomycin is a PDGF isoform- and receptor-specific antagonist that provides a possibility to compare the signal transduction pathways of alpha- and beta-receptors in cells expressing both receptor types. This approach was used to show that activation of PDGF beta-receptors by PDGF-BB mediated a chemotactic response in human fibroblasts, whereas activation of alpha-receptors by the same ligand inhibited chemotaxis.

  6. PARTIAL TRISOMY 4p AND PARTIAL MONOSOMY 13q: CASE REPORT AND A LITERATURE REVIEW.

    Science.gov (United States)

    Puvabanditsin, S; Herrera-Garcia, G; Gengel, N; Hussein, K; February, M; Mayne, J; Mehta, R

    2016-01-01

    We report on a term first born dichorionic-diamniotic twin with deletion of the distal long arm of chromosome 13, partial trisomy of the short arm of chromosome 4, intrauterine growth retardation, and multiple anomalies including microcephaly, colpocephaly, absent corpus callosum, bulbous tip of the nose, large and low set ears, macroglossia, thin upper lip, double outlet right ventricle, atria/ventricular septal defect, cleft mitral valve, pulmonary stenosis, single umbilical artery, multicystic dysplastic left kidney, sacral dimple, anterior displacement of anus, simian creases, abnormal thumb (congenital clasped thumb), overlapping toes, and congenital hypothyroidism. This is the first report of a patient with partial trisomy 4p and partial monosomy 13q.

  7. 40 CFR Table 7 to Subpart Vvvvvv... - Partially Soluble HAP

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 14 2010-07-01 2010-07-01 false Partially Soluble HAP 7 Table 7 to... Pt. 63, Subpt. VVVVVV, Table 7 Table 7 to Subpart VVVVVV of Part 63—Partially Soluble HAP As required... partially soluble HAP listed in the following table. Partially soluble HAP name CAS No. 1. 1,1,1...

  8. Partial rectangular metric spaces and fixed point theorems.

    Science.gov (United States)

    Shukla, Satish

    2014-01-01

    The purpose of this paper is to introduce the concept of partial rectangular metric spaces as a generalization of rectangular metric and partial metric spaces. Some properties of partial rectangular metric spaces and some fixed point results for quasitype contraction in partial rectangular metric spaces are proved. Some examples are given to illustrate the observed results.

  9. Kennedy's disease and partial androgen insensitivity syndrome. Report of 4 cases and literature review.

    Science.gov (United States)

    Valera Yepes, Rocío; Virgili Casas, Maria; Povedano Panades, Monica; Guerrero Gual, Mireia; Villabona Artero, Carles

    2015-05-01

    Kennedy's disease, also known as bulbospinal muscular atrophy, is a rare, X-linked recessive neurodegenerative disorder affecting adult males. It is caused by expansion of an unstable cytosine-adenine-guanine tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12, and is characterized by spinal motor neuron progressive degeneration. Endocrinologically, these patients often have the features of hypogonadism associated to the androgen insensitivity syndrome, particularly its partial forms. We report 4 cases with the typical neurological presentation, consisting of slowly progressing generalized muscle weakness with atrophy and bulbar muscle involvement; these patients also had several endocrine manifestations; the most common non-neurological manifestation was gynecomastia. In all cases reported, molecular analysis showed an abnormal cytosine-adenine-guanine triplet repeat expansion in the androgen receptor gene. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

  10. Ionotropic crustacean olfactory receptors.

    Directory of Open Access Journals (Sweden)

    Elizabeth A Corey

    Full Text Available The nature of the olfactory receptor in crustaceans, a major group of arthropods, has remained elusive. We report that spiny lobsters, Panulirus argus, express ionotropic receptors (IRs, the insect chemosensory variants of ionotropic glutamate receptors. Unlike insects IRs, which are expressed in a specific subset of olfactory cells, two lobster IR subunits are expressed in most, if not all, lobster olfactory receptor neurons (ORNs, as confirmed by antibody labeling and in situ hybridization. Ligand-specific ORN responses visualized by calcium imaging are consistent with a restricted expression pattern found for other potential subunits, suggesting that cell-specific expression of uncommon IR subunits determines the ligand sensitivity of individual cells. IRs are the only type of olfactory receptor that we have detected in spiny lobster olfactory tissue, suggesting that they likely mediate olfactory signaling. Given long-standing evidence for G protein-mediated signaling in activation of lobster ORNs, this finding raises the interesting specter that IRs act in concert with second messenger-mediated signaling.

  11. Successful treatment of dopamine dysregulation syndrome with dopamine D2 partial agonist antipsychotic drug

    Directory of Open Access Journals (Sweden)

    Mizushima Jin

    2012-07-01

    Full Text Available Abstract Dopamine dysregulation syndrome (DDS consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson’s disease (PD. Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system.

  12. Stimulation of phosphoinositide hydrolysis by a novel substance partially purified from rat and bovine brain

    International Nuclear Information System (INIS)

    Schoepp, D.; Wilson, T.; Elliott, C.; Wright, G.; McCumbee, W.

    1986-01-01

    This study demonstrates the partial purification of a potentially novel substance from rat and bovine brain. Whole brains were homogenized in distilled water, then heated at 100 0 C for 30 min. The water extract was dialyzed and the 3 H-inositol monophosphate ( 3 H-IP) using lithium-treated slices of rat cerebral cortex prelabelled with 3 H-myo-inositol. A major peak of activity was observed in fractions from the molecular weight range of 800-1300 daltons. Stimulation of phosphoinositide hydrolysis by this material was time-dependent and dose-related. Maximal stimulation of 3 H-IP (323% of control) required 10mg/ml of bovine material and was observed at 30 minutes. These effects could not be mimicked by a number of substances of similar molecular weight (e.g. substance P, neurotensin, angiotensin II, bradykinin). Furthermore, the effects of this material were not blocked by antagonist drugs which act at the alpha-adrenoceptor, muscarinic cholinoceptor, 5-HT2 receptor, substance P receptor, or neurotensin receptor. These results indicate that the substance isolated may be a novel neuroactive molecule which has receptors coupled to phosphoinositide hydrolysis in brain

  13. Decreased autophosphorylation of EGF receptor in insulin-deficient diabetic rats

    International Nuclear Information System (INIS)

    Okamoto, M.; Kahn, C.R.; Maron, R.; White, M.F.

    1988-01-01

    The authors have previously reported that despite an increase in receptor concentration, there is a decrease in autophosphorylation and tyrosine kinase activity of the insulin receptor in insulin-deficient diabetic rats. To determine if other tyrosine kinases might be altered, they have studied the epidermal growth factor (EGF) receptor kinase in wheat germ agglutinin-purified, Triton X-100-solubilized liver membranes from streptozotocin (STZ)-induced diabetic rats and the insulin-deficient BB rat. They find that autophosphorylation of EGF receptor is decreased in proportion to the severity of the diabetic state in STZ rats with a maximal decrease of 67%. A similar decrease in autophosphorylation was observed in diabetic BB rats that was partially normalized by insulin treatment. Separation of tryptic phosphopeptides by reverse-phase high-performance liquid chromatography revealed a decrease in labeling at all sites of autophosphorylation. A parallel decrease in EGF receptor phosphorylation was also found by immunoblotting with an antiphosphotyrosine antibody. EGF receptor concentration, determined by Scatchard analysis of 125 I-labeled EGF binding, was decreased by 39% in the STZ rat and 27% in the diabetic BB rat. Thus autophosphorylation of EGF receptor, like that of the insulin receptor, is decreased in insulin-deficient rat liver. In the case of EGF receptor, this is due in part to a decrease in receptor number and in part to a decrease in the specific activity of the kinase

  14. Identification of novel selective V2 receptor non-peptide agonists.

    Science.gov (United States)

    Del Tredici, Andria L; Vanover, Kim E; Knapp, Anne E; Bertozzi, Sine M; Nash, Norman R; Burstein, Ethan S; Lameh, Jelveh; Currier, Erika A; Davis, Robert E; Brann, Mark R; Mohell, Nina; Olsson, Roger; Piu, Fabrice

    2008-10-30

    Peptides with agonist activity at the vasopressin V(2) receptor are used clinically to treat fluid homeostasis disorders such as polyuria and central diabetes insipidus. Of these peptides, the most commonly used is desmopressin, which displays poor bioavailability as well as potent activity at the V(1b) receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V(2) receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT((R))), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V(2) receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V(2) receptor compared to related vasopressin and oxytocin receptors and no activity at 28 other G protein-coupled receptors (GPCRs). All three compounds also showed partial agonist activity at the V(2) receptor in a cAMP accumulation assay. In addition, in a rat model of central diabetes insipidus, AC-94544 was able to significantly reduce urine output in a dose-dependent manner. Thus, AC-94544, AC-88324, and AC-110484 represent novel opportunities for the treatment of disorders associated with V(2) receptor agonist deficiency.

  15. An unusual protein kinase phosphorylates the chemotactic receptor of Dictystelium discoideum

    International Nuclear Information System (INIS)

    Meier, K.; Klein, C.

    1988-01-01

    The authors report the cAMP-dependent phosphorylation of the chemotactic receptor of Dictyostelium discoideum in partially purified plasma membranes. The protein kinase responsible for receptor phosphorylation is associated with this fraction and preferentially phosphorylates the ligand-occupied form of the receptor. 8-Azido[ 32 P]cAMP labeling of the cell surface has shown that the cAMP receptor exists in two forms. A 45-kDa protein is predominant on unstimulated cells. cAMP stimulation results in an increased receptor phosphorylation such that the receptor migrates on NaDodSO 4 /PAGE as a 47-kDa protein. Phosphorylation of the chemotactic receptor is not detected in membrane preparations unless cAMP is added to the incubation mixture. Only under those conditions is the phosphorylated 47-kDa form observed. The requirement for cAMP reflects the fact that the kinase involved preferentially uses the ligand-occupied receptor as a substrate. In vitro phosphorylation of the receptor does not involve tyrosine residues. The enzyme does not appear to be a cAMP- or cGMP-dependent protein kinase nor is it sensitive to guanine nucleotides, Ca 2+ /calmodulin, Ca 2+ /phospholipid, or EGTA. Similarities with the β-adrenergic receptor protein kinase are discussed

  16. Receptor protection studies comparing recombinant and native nicotinic receptors: Evidence for a subpopulation of mecamylamine-sensitive native alpha3beta4* nicotinic receptors.

    Science.gov (United States)

    Free, R Benjamin; Kaser, Daniel J; Boyd, R Thomas; McKay, Dennis B

    2006-01-09

    Studies involving receptor protection have been used to define the functional involvement of specific receptor subtypes in tissues expressing multiple receptor subtypes. Previous functional studies from our laboratory demonstrate the feasibility of this approach when applied to neuronal tissues expressing multiple nicotinic acetylcholine receptors (nAChRs). In the current studies, the ability of a variety of nAChR agonists and antagonists to protect native and recombinant alpha3beta4 nAChRs from alkylation were investigated using nAChR binding techniques. Alkylation of native alpha3beta4* nAChRs from membrane preparations of bovine adrenal chromaffin cells resulted in a complete loss of specific [(3)H]epibatidine binding. This loss of binding to native nAChRs was preventable by pretreatment with the agonists, carbachol or nicotine. The partial agonist, cytisine, produced partial protection. Several nAChR antagonists were also tested for their ability to protect. Hexamethonium and decamethonium were without protective activity while mecamylamine and tubocurarine were partially effective. Addition protection studies were performed on recombinant alpha3beta4 nAChRs. As with native alpha3beta4* nAChRs, alkylation produced a complete loss of specific [(3)H]epibatidine binding to recombinant alpha3beta4 nAChRs which was preventable by pretreatment with nicotine. However, unlike native alpha3beta4* nAChRs, cytisine and mecamylamine, provide no protection for alkylation. These results highlight the differences between native alpha3beta4* nAChRs and recombinant alpha3beta4 nAChRs and support the use of protection assays to characterize native nAChR subpopulations.

  17. Repeated potentiation of the metabotropic glutamate receptor 5 and the alpha 7 nicotinic acetylcholine receptor modulates behavioural and GABAergic deficits induced by early postnatal phencyclidine (PCP) treatment

    DEFF Research Database (Denmark)

    Kjaerby, Celia; Bundgaard, Christoffer; Fejgin, Kim

    2013-01-01

    GluR5), ADX47273, and the partial agonist of the α7 nicotinic acetylcholine receptor (α7 nAChR), SSR180711. Adolescent rats (4-5 weeks) subjected to PCP treatment during the second postnatal week displayed a consistent deficit in prepulse inhibition (PPI), which was reversed by a one-week treatment...

  18. Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti-parkinsonian drug receptor signaling

    DEFF Research Database (Denmark)

    Klewe, Ib V; Nielsen, Søren M; Tarpø, Louise

    2008-01-01

    , SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating beta-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine...

  19. Magnetic properties of partially oxidized Fe films

    Science.gov (United States)

    Garcia, Miguel Angel; Lopez-Dominguez, Victor; Hernando, Antonio

    Hybrid magnetic nanostructures exhibit appealing properties due to interface and proximity effects. A simple and interesting system of hybrid magnetic nanomaterials are partially oxidized ferromagnetic films. We have fabricated Fe films by thermal evaporation and performed a partial oxidation to magnetite (Fe3O4) by annealing in air at different times and temperatures. The magnetic properties of the films evolve from those of pure metallic iron to pure magnetite, showing intermediate states where the proximity effects control the magnetic behavior. At some stages, the magnetization curves obtained by SQUID and MOKE magnetometry exhibit important differences due to the dissimilar contribution of both phases to the magneto-optical response of the system This work has been supported by the Ministerio Español de Economia y Competitividad (MINECO) MAT2013-48009-C4-1. V.L.D and M.A.G. acknowledges financial support from BBVA foundation.

  20. Local cerebral metabolism during partial seizures

    International Nuclear Information System (INIS)

    Engel, J. Jr.; Kuhl, D.E.; Phelps, M.E.; Rausch, R.; Nuwer, M.

    1983-01-01

    Interictal and ictal fluorodeoxyglucose scans were obtained with positron CT from four patients with spontaneous recurrent partial seizures, one with epilepsia partialis continua, and one with a single partial seizure induced by electrical stimulation of the hippocampus. Ictal metabolic patterns were different for each patient studied. Focal and generalized increased and decreased metabolism were observed. Ictal hypermetabolism may exceed six times the interictal rate and could represent activation of excitatory or inhibitory synapses in the epileptogenic region and its projection fields. Hypometabolism seen on ictal scans most likely reflects postictal depression and may indicate projection fields of inhibited neurons. No quantitative relationship between alterations in metabolism and EEG or behavioral measurements of ictal events could be demonstrated