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Sample records for non-nitrogenous kappa-opioid selective

  1. A unique binding epitope for salvinorin A, a non-nitrogenous kappa opioid receptor agonist.

    Science.gov (United States)

    Kane, Brian E; Nieto, Marcelo J; McCurdy, Christopher R; Ferguson, David M

    2006-05-01

    Salvinorin A is a potent kappa opioid receptor (KOP) agonist with unique structural and pharmacological properties. This non-nitrogenous ligand lacks nearly all the structural features commonly associated with opioid ligand binding and selectivity. This study explores the structural basis to salvinorin A binding and selectivity using a combination of chimeric and single-point mutant opioid receptors. The experiments were designed based on previous models of salvinorin A that locate the ligand within a pocket formed by transmembrane (TM) II, VI, and VII. More traditional sites of opioid recognition were also explored, including the highly conserved aspartate in TM III (D138) and the KOP selectivity site E297, to determine the role, if any, that these residues play in binding and selectivity. The results indicate that salvinorin A recognizes a cluster of residues in TM II and VII, including Q115, Y119, Y312, Y313, and Y320. Based on the position of these residues within the receptor, and prior study on salvinorin A, a model is proposed that aligns the ligand vertically, between TM II and VII. In this orientation, the ligand spans residues that are spaced one to two turns down the face of the helices within the receptor cavity. The ligand is also in close proximity to EL-2 which, based on chimeric data, is proposed to play an indirect role in salvinorin A binding and selectivity.

  2. Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists

    DEFF Research Database (Denmark)

    Sasmal, Pradip K; Krishna, C Vamsee; Sudheerkumar Adabala, S

    2015-01-01

    Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR...

  3. Synthesis of [{sup 3}]DIPPA: a potent irreversible antagonist selective for the {kappa} opioid receptor

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Anchih; Portoghese, P.S. [Minnesota Univ., Minneapolis, MN (United States). College of Pharmacy; Trometer, J.D. [E.I. Du Pont de Nemours and Co., Inc., Boston, MA (United States)

    1995-06-01

    2-(3,4-Dichlorophenyl)-N-methyl-N-[(1S)-1-(3-isothiocyanatophe nyl)-2-(1-pyrrolidinyl)ethyl]acetamide (1,DIPPA) has been previously reported to be an opioid receptor affinity label that produces selective and long-lasting {kappa} opioid receptor antagonism in mice. High specific activity [{sup 3}H]DIPPA (39.7 Ci/mmol) was prepared by bromination and catalytic tritiation of the amino precursor of DIPPA followed by conversion to the isothiocyanate with thiophosgene. (Author).

  4. The crystal structure of a bimorphinan with highly selective kappa opioid receptor antagonist activity

    Science.gov (United States)

    Urbańczyk-Lipkowska, Zofia; Etter, Margaret C.; Lipkowski, Andrzej W.; Portoghese, Philip S.

    1987-07-01

    The crystal structure of the dihydrobromide heptahydrate of nor-binaltorphimine (17, 17'-bis(cyclopropylmethyl)-6,6',7,7'-tetrahydro-4,5α: 4',5'α-diepoxy-6,6'-imino[7,7' bimorphinan]-3,3',14,14'-tetraol)is presented. This structure is the first reported structure of a rigid bivalent opioid ligand. Two morphinan pharmacophores are connected by a rigid spacer, the pyrrole ring. The nor-binaltorphimine structure itself shows unique, high selectivity as a kappa opioid receptor antagonist. Crystal data: P3 2, Z = 3, a = b = 20.223 (4), c = 9.541(7) Å, α = β = 90°, γ = 120°; R = 0.079 (1765 reflections, Fobs > 1σ( F)).

  5. Effects of kappa opioid receptor-selective agonists on responses of pelvic nerve afferents to noxious colorectal distension.

    Science.gov (United States)

    Su, X; Sengupta, J N; Gebhart, G F

    1997-08-01

    The aim of this study was to examine the effects of kappa-opioid receptor selective agonists on responses of mechanosensitive afferent fibers in the pelvic nerve. Single-fiber recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root of the rat. A total of 572 afferent fibers in the S1 dorsal root were identified by electrical stimulation of the pelvic nerve; 252 (44%) responded to noxious colorectal distension (CRD; 80 mmHg). Of these 252 fibers that responded to CRD, 100 were studied further. All 100 fibers gave monotonic increases in firing to increasing pressures of CRD. Eighty-eight fibers had low thresholds for response (mean: 3 mmHg) and 12 fibers had high-thresholds for response (mean: 28 mmHg). Responses of 17 fibers also were tested after instillation of 5% mustard oil (MO) into the colon. The resting activity of 16/17 fibers significantly increased after MO instillation; 13 (77%) also exhibited sensitization of responses to graded CRD when tested 30 min after intracolonic MO instillation. The effects of kappa1-opioid receptor preferring agonists (U50,488H, U69,593 and U62,066), the kappa2-opioid receptor preferring agonist bremazocine, and the kappa3-opioid receptor preferring agonist naloxone benzoylhydrazone (nalBzoH) were tested on responses of 64 mechanosensitive afferent fibers to noxious CRD. All five agonists dose-dependently inhibited afferent fiber responses to noxious CRD. Doses producing inhibition to 50% of the control response to CRD did not differ among the five agonists, ranging from approximately 4 to 15 mg/kg. The effects of kappa1, kappa2, and kappa3 receptor agonists were attenuated by naloxone; two kappa-opioid receptor-selective antagonists were ineffective. There were no differences in the dose-response relationships of these drugs for fibers recorded from untreated and irritant-treated colons. Conduction velocities of the fibers remained unaffected after high doses of all tested agonists. In an in vitro

  6. Functional Selectivity of Kappa Opioid Receptor Agonists in Peripheral Sensory Neurons

    Science.gov (United States)

    Jamshidi, Raehannah J.; Jacobs, Blaine A.; Sullivan, Laura C.; Chavera, Teresa A.; Saylor, Rachel M.; Prisinzano, Thomas E.; Clarke, William P.

    2015-01-01

    Activation of kappa opioid receptors (KORs) expressed by peripheral sensory neurons that respond to noxious stimuli (nociceptors) can reduce neurotransmission of pain stimuli from the periphery to the central nervous system. We have previously shown that the antinociception dose-response curve for peripherally restricted doses of the KOR agonist (–)-(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50488) has an inverted U shape. Here, we found that the downward phase of the U50488 dose-response curve was blocked by an inhibitor of extracellular signal-regulated kinase (ERK) activation U0126. Local administration of the selective KOR agonist salvinorin A (Sal-A), also resulted in an inverted U-shaped curve; however, the downward phase was insensitive to U0126. By contrast, inhibition of c-Jun N-terminal kinase (JNK) partially blocked the downward phase of the dose-response curve to Sal-A, suggesting a role for JNK. In cultures of peripheral sensory neurons, U50488 and Sal-A inhibited adenylyl cyclase activity with similar efficacies; however, their ability to activate ERK and JNK differed. Whereas U50488 activated ERK but not JNK, Sal-A activated JNK but not ERK. Moreover, although both U50488 and Sal-A produced homologous desensitization, desensitization to U50488 was blocked by inhibition of ERK activation, whereas desensitization to Sal-A was blocked by inhibition of JNK. Substitution of an ethoxymethyl ether for the C2 position acetyl group of Sal-A reduced stimulation of JNK, prevented desensitization by ethoxymethyl ether for the C2 position acetyl group of Sal-A, and resulted in a monotonic antinociception dose-response curve. Collectively, these data demonstrate the functional selectivity of KOR ligands for signaling in peripheral sensory neurons, which results in differential effects on behavioral responses in vivo. PMID:26297384

  7. Biochemical and functional interactions of a selective kappa opioid agonist with calcium

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    VonVoigtlander, P.F.; Ochoa, M.C.; Lewis, R.A.

    1987-01-01

    The discovery of the selective kappa opioid receptor agonist, U-50488H, has provided a tool for the study of the mechanisms and function of the kappa receptor-effector. We have investigated the interactions of this compound with calcium in several biochemical and functional studies to assess the involvement of calcium mechanisms in the kappa receptor-linked effector. In rat brain synaptosomes, U-50488H attenuated the uptake of /sup 45/Ca++ induced by K+ (40 mM) depolarization. This effect was concentration-related (U-50488H 10(-5) to 10(-7) M), was apparent in short (8-second) but not longer (1-minute) term incubations, and did not occur in the presence of a non-polarizing concentration (5.6 mM) of K+. Naloxone (10(-7) M) did not block this effect of U-50488H (10(-6) M), and higher concentrations (10(-5) M) alone blocked calcium uptake. We have found that the binding of the depolarizing amino acid analog, kainic acid, is enhanced by CaCl2. U-50488H (10(-4) to 10(-6) M) blocks this enhancement of /sup 3/H-kainic acid binding in vitro and also blocks the in vivo effects of kainic acid. In mice, intravenous injection of kainic acid causes scratching, convulsions, and death, depending on the dose administered. U-50488H blocks all of these effects (ED50 = 4.5 mg/kg for antagonism of convulsions induced by 27.5 mg/kg kainic acid). The convulsions induced by intracerebroventricularly administered kainic acid are also blocked by U-50488H as are those induced by similarly administered Bay K 8644, a calcium channel activator. All of these anticonvulsant effects of U-50488H were antagonized by naltrexone. Together these data indicate that the kappa agonist U-50488H has functionally relevant interactions with depolarization-related Ca++ mechanisms in the central nervous system.

  8. Evaluation of the kappa-opioid receptor-selective tracer [{sup 11}C]GR103545 in awake rhesus macaques

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    Schoultz, Bent W. [University of Oslo, Department of Chemistry, Oslo (Norway); Hjornevik, Trine; Willoch, Frode [University of Oslo, Centre for Molecular Biology and Neuroscience and Institute of Basic Medical Sciences, Oslo (Norway); Akershus University Hospital, Department of Nuclear Medicine, Loerenskog (Norway); Marton, Janos [ABX Advanced Biochemical Compounds GmbH, Radeberg (Germany); Noda, Akihiro; Murakami, Yoshihiro; Miyoshi, Sosuke; Nishimura, Shintaro [Medical and Pharmacological Research Center Foundation, Basic Research Department, Hakui City, Ishikawa (Japan); Aarstad, Erik [University College of London, Institute of Nuclear Medicine, London (United Kingdom); Drzezga, Alexander [Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany); Matsunari, Ichiro [Medical and Pharmacological Research Center Foundation, Clinical Research Department, Hakui City, Ishikawa (Japan); Henriksen, Gjermund [University of Oslo, Department of Chemistry, Oslo (Norway); Technische Universitaet Muenchen, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany)

    2010-06-15

    The recent development in radiosynthesis of the {sup 11}C-carbamate function increases the potential of [{sup 11}C]GR103545, which for the last decade has been regarded as promising for imaging the kappa-opioid receptor ({kappa}-OR) with PET. In the present study, [{sup 11}C]GR103545 was evaluated in awake rhesus macaques. Separate investigations were performed to clarify the OR subtype selectivity of this compound. Regional brain uptake kinetics of [{sup 11}C]GR103545 was studied 0-120 min after injection. The binding affinity and opioid subtype selectivity of [{sup 11}C]GR103545 was determined in cells transfected with cloned human opioid receptors. In vitro binding assays demonstrated a high affinity of GR103545 for {kappa}-OR (K{sub i} = 0.02 {+-}0.01 nM) with excellent selectivity over {mu}-OR (6 x 10{sup 2}-fold) and {delta}-OR (2 x 10{sup 4}-fold). PET imaging revealed a volume of distribution (V{sub T}) pattern consistent with the known distribution of {kappa}-OR, with striatum = temporal cortex > cingulate cortex > frontal cortex > parietal cortex > thalamus > cerebellum. [{sup 11}C]GR103545 is selective for {kappa}-OR and holds promise for use to selectively depict and quantify this receptor in humans by means of PET. (orig.)

  9. A unique natural selective kappa-opioid receptor agonist, salvinorin A, and its roles in human therapeutics.

    Science.gov (United States)

    Cruz, André; Domingos, Sara; Gallardo, Eugenia; Martinho, Ana

    2017-05-01

    Until the mid-60s, only the Mazatecs, an indigenous group from Oaxaca, Mexico, used Salvia Divinorum (S. divinorum) due to its hallucinogen properties. Later it was found that the hallucinogen effects of this plant were caused by the presence of a neoclerodane diterpene Salvinorin A (salvinorin A), which is a highly selective agonist of kappa-opioid receptor (KOR) that cause more intense hallucinations than the common hallucinogens as lysergic acid, mushrooms, ecstasy and others. In fact, smoking of only 200-500 μg of S. divinorum leaves is enough to produce these effects thus making it the most potent natural occurring hallucinogen known. Due to its legal status in various countries, this compound has gained a worldwide popularity as a drug of abuse with an easy access through smartshops and internet. Furthermore, salvinorin A gathered an increased interest in the scientific community thanks to its unique structure and properties, and various studies demonstrated that salvinorin A has antinociceptive, antidepressant, in some circumstances pro-depressant and anti-addictive effects that have yielded potential new avenues for research underlying salvinorin A and its semi-synthetic analogs as therapeutic agents.

  10. Synthesis and pharmacological evaluation of [(3)H]HS665, a novel, highly selective radioligand for the kappa opioid receptor.

    Science.gov (United States)

    Guerrieri, Elena; Mallareddy, Jayapal Reddy; Tóth, Géza; Schmidhammer, Helmut; Spetea, Mariana

    2015-03-18

    Herein we report the radiolabeling and pharmacological investigation of a novel radioligand, the N-cyclobutylmethyl substituted diphenethylamine [(3)H]HS665, designed to bind selectively to the kappa opioid peptide (KOP) receptor, a target of therapeutic interest for the treatment of a variety of human disorders (i.e., pain, affective disorders, drug addiction, and psychotic disorders). HS665 was prepared in tritium-labeled form by a dehalotritiated method resulting in a specific activity of 30.65 Ci/mmol. Radioligand binding studies were performed to establish binding properties of [(3)H]HS665 to the recombinant human KOP receptor in membranes from Chinese hamster ovary cells stably expressing human KOP receptors (CHOhKOP) and to the native neuronal KOP receptor in guinea pig brain membranes. Binding of [(3)H]HS665 was specific and saturable in both tissue preparations. A single population of high affinity binding sites was labeled by [(3)H]HS665 in membranes from CHOhKOP cells and guinea pig brain with similar equilibrium dissociation constants, Kd, 0.45 and 0.64 nM, respectively. Average receptor density of [(3)H]HS665 recognition sites were 5564 and 154 fmol/mg protein in CHOhKOP cells and guinea pig brain, respectively. This study shows that the new radioligand distinguishes and labels KOP receptors specifically in neuronal and cellular systems expressing KOP receptors, making this molecule a valuable tool in probing structural and functional mechanisms governing ligand-KOP receptor interactions in both a recombinant and native in vitro setting.

  11. Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands.

    Science.gov (United States)

    Polepally, Prabhakar R; White, Kate; Vardy, Eyal; Roth, Bryan L; Ferreira, Daneel; Zjawiony, Jordan K

    2013-05-15

    Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen and is a selective κ-opioid receptor agonist. To better understand the ligand-receptor interactions, a series of dicarboxylic ester-type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at κ-, δ- and μ-opioid receptors. Most of the analogues show high affinity to the κ-opioid receptor. Methyl malonyl derivative 4 shows the highest binding affinity (Ki=2nM), analogues 5, 7, and 14 exhibit significant affinity for the κ-receptor (Ki=21, 36 and 39nM).

  12. Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations.

    Science.gov (United States)

    Chavkin, Charles; Sud, Sumit; Jin, Wenzhen; Stewart, Jeremy; Zjawiony, Jordan K; Siebert, Daniel J; Toth, Beth Ann; Hufeisen, Sandra J; Roth, Bryan L

    2004-03-01

    The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective kappa-opioid receptor agonist (Roth et al., 2002). Salvinorin A and selected derivatives were found to be potent and efficacious agonists in several measures of agonist activity using cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells. Thus, salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2-heptanoate were found to be either full (salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolin-stimulated cAMP production. Additional studies of agonist potency and efficacy of salvinorin A, performed by cotransfecting either the chimeric G proteins Gaq-i5 or the universal G protein Ga16 and quantification of agonist-evoked intracellular calcium mobilization, affirmed that salvinorin A was a potent and effective kappa-opioid agonist. Results from structure-function studies suggested that the nature of the substituent at the 2-position of salvinorin A was critical for kappa-opioid receptor binding and activation. Because issues of receptor reserve complicate estimates of agonist efficacy and potency, we also examined the agonist actions of salvinorin A by measuring potassium conductance through G protein-gated K(+) channels coexpressed in Xenopus oocytes, a system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U50488) or (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593) (two standard kappa-opioid agonists) and similar in efficacy to dynorphin A (the naturally occurring peptide ligand for kappa-opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors.

  13. Differential helical orientations among related G protein-coupled receptors provide a novel mechanism for selectivity. Studies with salvinorin A and the kappa-opioid receptor.

    Science.gov (United States)

    Vortherms, Timothy A; Mosier, Philip D; Westkaemper, Richard B; Roth, Bryan L

    2007-02-02

    Salvinorin A, the active component of the hallucinogenic sage Salvia divinorum, is an apparently selective and highly potent kappa-opioid receptor (KOR) agonist. Salvinorin A is unique among ligands for peptidergic G protein-coupled receptors in being nonnitrogenous and lipid-like in character. To examine the molecular basis for the subtype-selective binding of salvinorin A, we utilized an integrated approach using chimeric opioid receptors, site-directed mutagenesis, the substituted cysteine accessibility method, and molecular modeling and dynamics studies. We discovered that helix 2 is required for salvinorin A binding to KOR and that two residues (Val-108(2.53) and Val-118(2.63)) confer subtype selectivity. Intriguingly, molecular modeling studies predicted that these loci exhibit an indirect effect on salvinorin A binding, presumably through rotation of helix 2. Significantly, and in agreement with our in silico predictions, substituted cysteine accessibility method analysis of helix 2 comparing KOR and the delta-opioid receptor, which has negligible affinity for salvinorin A, revealed that residues known to be important for salvinorin A binding exhibit a differential pattern of water accessibility. These findings imply that differences in the helical orientation of helix 2 are critical for the selectivity of salvinorin A binding to KOR and provide a structurally novel basis for ligand selectivity.

  14. CoMFA analyses of C-2 position salvinorin A analogs at the kappa-opioid receptor provides insights into epimer selectivity.

    Science.gov (United States)

    McGovern, Donna L; Mosier, Philip D; Roth, Bryan L; Westkaemper, Richard B

    2010-04-01

    The highly potent and kappa-opioid (KOP) receptor-selective hallucinogen Salvinorin A and selected analogs have been analyzed using the 3D quantitative structure-affinity relationship technique Comparative Molecular Field Analysis (CoMFA) in an effort to derive a statistically significant and predictive model of salvinorin affinity at the KOP receptor and to provide additional statistical support for the validity of previously proposed structure-based interaction models. Two CoMFA models of Salvinorin A analogs substituted at the C-2 position are presented. Separate models were developed based on the radioligand used in the kappa-opioid binding assay, [(3)H]diprenorphine or [(125)I]6 beta-iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan ([(125)I]IOXY). For each dataset, three methods of alignment were employed: a receptor-docked alignment derived from the structure-based docking algorithm GOLD, another from the ligand-based alignment algorithm FlexS, and a rigid realignment of the poses from the receptor-docked alignment. The receptor-docked alignment produced statistically superior results compared to either the FlexS alignment or the realignment in both datasets. The [(125)I]IOXY set (Model 1) and [(3)H]diprenorphine set (Model 2) gave q(2) values of 0.592 and 0.620, respectively, using the receptor-docked alignment, and both models produced similar CoMFA contour maps that reflected the stereoelectronic features of the receptor model from which they were derived. Each model gave significantly predictive CoMFA statistics (Model 1 PSET r(2)=0.833; Model 2 PSET r(2)=0.813). Based on the CoMFA contour maps, a binding mode was proposed for amine-containing Salvinorin A analogs that provides a rationale for the observation that the beta-epimers (R-configuration) of protonated amines at the C-2 position have a higher affinity than the corresponding alpha-epimers (S-configuration).

  15. The Differential Effects of a Selective Kappa-Opioid Receptor Agonist, U50488, in Guinea Pig Heart Tissues

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    Chi-Feng Hung

    2015-01-01

    Full Text Available The differential effects of a selective kappa- (κ- opioid receptor agonist, U50488, were elucidated by monitoring the contraction of isolated guinea pig atrial and ventricular muscles. In electrically driven left atria, U50488 in nanomolar concentration range decreased the contractile force. Norbinaltorphimine (norBNI, a selective κ-receptor antagonist, and pertussis toxin (PTX abolished the negative inotropic effect of U50488. In contrast, the inhibitory effect was not affected by the pretreatment of atropine or propranolol. Even though U50488 exerted a negative inotropic effect in the left atrium, it did not affect the contractile force of the right atrium and ventricles paced at 2 Hz. Similarly, the beating rate of the spontaneously beating right atrium was also unaffected by U50488. These results indicate that the activation of κ-opioid receptors can only produce negative inotropic effect in left atria via activation of PTX-sensitive G protein in guinea pigs. The absence of negative inotropic effects in right atria and ventricles suggests that there may be a greater distribution of functional κ-opioid receptors in guinea pig left atria than in right atria and ventricles, and the distribution of the receptors may be species-specific.

  16. Schild (apparent pA2) analysis of a kappa-opioid antagonist in Planaria.

    Science.gov (United States)

    Raffa, Robert B; Baron, David A; Tallarida, Ronald J

    2006-07-01

    Previous investigators have provided radioimmunological and immunocytochemical evidence for an enkephalinergic (opioid) system in Planaria and described naloxone-sensitive qualitative behavioral responses to kappa-opioid receptor agonists. We report the application of Schild-analysis to the antagonism of a selective kappa agonist (U-50,488H) by a selective kappa antagonist (nor-BNI) in a quantitative in vivo endpoint. The results provide further evidence of a kappa-opioid-like receptor in planarians.

  17. Synaptic localization of. kappa. opioid receptors in guinea pig neostriatum

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    Jomary, C.; Beaudet, A. (McGill Univ., Montreal, Quebec (Canada)); Gairin, J.E. (Centre National de la Recherche Scientifique, Toulouse (France))

    1992-01-15

    Distribution of {kappa} opioid receptors was examined by EM radioautography in sections of guinea pig neostriatum with the selective {sup 125}I-labeled dynorphin analog (D-Pro{sup 10})dynorphin-(1-11). Most specifically labeled binding sites were found by probability circle analysis to be associated with neuronal membrane appositions. Because of limitations in resolution of the method, the radioactive sources could not be ascribed directly to either one of the apposed plasma membranes. Nevertheless, three lines of evidence favored a predominant association of ligand with dendrites of intrinsic striatal neurons: (1) the high frequency with which labeled interfaces implicated a dendrite, (2) the enrichment of dendrodendritic interfaces, and (3) the occurrence of dendritic profiles labeled at several contact points along their plasma membranes. A small proportion of labeled sites was associated with axo-axonic interfaces, which may subserve the {kappa} opioid-induced regulation of presynaptic dopamine and acetylcholine release documented in guinea pig neostriatum. These results support the hypothesis that in mammalian brain {kappa} opioid receptors are conformationally and functionally distinct from {mu} and {delta} types.

  18. Selective involvement of kappa opioid and phencyclidine receptors in the analgesic and motor effects of dynorphin-A-(1-13)-Tyr-Leu-Phe-Asn-Gly-Pro.

    Science.gov (United States)

    Shukla, V K; Bansinath, M; Dumont, M; Lemaire, S

    1992-09-18

    Dynorphin A-(1-13)-Tyr-Leu-Phe-Asn-Gly-Pro (Dyn Ia; 1-8 nmol) injected intracerebroventricularly in the mouse produces two independent behavioral effects: (1) a norbinaltorphimine (kappa opioid antagonist)-reversible analgesia in the acetic acid-induced writhing test and (2) motor dysfunction characterized by wild running, pop-corn jumping, hindlimb jerking and barrel rolling and antagonized by the irreversible phencyclidine (PCP) and sigma (sigma) receptor antagonist, metaphit and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan and ketamine. The specific involvement of the PCP receptor in the motor effects of Dyn Ia is supported by the direct competitive interaction of the peptide with the binding of [3H]MK-801 (Ki: 0.63 microM) and [3H]TCP (Ki: 4.6 microM) to mouse brain membrane preparations.

  19. Cardiorenal Effects of Kappa Opioid Peptides During Ontogeny

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    Wei Qi

    2011-01-01

    Full Text Available This review focuses on the physiological roles for kappa opioid receptors (KORs in adult animals and humans, as well as in the developing newborn animal. Our recent findings have provided new information that under physiological conditions in conscious newborn animals, activation of KORs with the selective agonist, U-50488H, results in an aquaresis, as previously observed in adult animals and humans. In addition, we have shown in conscious lambs that KORs modulate systemic and renal haemodynamics as well as the arterial baroreflex control of heart rate, providing a previously unidentified role for KORs.

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

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    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.

  1. Effect of GNTI,a kappa opioid receptor antagonist, on MK-801-induced hyperlocomotion and stereotypy in mice

    Institute of Scientific and Technical Information of China (English)

    Chun-ting QI; Hong ZOU; Chen-hao ZHANG; Qing-lian XIE; Mei-lei JIN; Lei YU

    2006-01-01

    Aim:To examine the effect of GNTI[5'-guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,-5α-epoxy-3-14-dihydroxy-6,7-2',3'-indolomorphinan],a selective antagonist for the kappa opioid receptor,in the MK-801 (dizocilpine maleate)-induced behavioral model of psychosis in schizophrenia as a way to explore the involvement of the kappa opioid receptor in modulating psychotic symptoms of schizophrenia.Methods:Two doses 0f MK-801 (0.3 mg/kg and 0.6 mg/kg) were administered by systemic injection in mice to induce psychosis-like behavior as a rodent schizophrenia model, preceded by an injection of different doses of GNTI. Both locomotion and stereotypy were measured as the behavioral endpoints for quantitative analysis.Results:GNTI inhibited MK-801-induced hyperlocomotion and stereotypy.In particular,GNTI showed differential modulation of stereotypy induced by 0.3 mg/kg VS 0.6 mg/kg MK-801.Conclusion:Antagonism of kappa opioid receptors attenuates MK-801-induced behavior,suggesting a potential involvement of the kappa opioid receptor in psychosis-like symptoms of schizophrenia.GNTI aDpears to be a useful pharmacological tool to explore the kappa opioid receptor function in vivo.

  2. [{sup 11}C]-MeJDTic: a novel radioligand for {kappa}-opioid receptor positron emission tomography imaging

    Energy Technology Data Exchange (ETDEWEB)

    Poisnel, Geraldine; Oueslati, Farhana; Dhilly, Martine; Delamare, Jerome [Groupe de Developpements Methodologiques en Tomographie par Emission de Positons, DSV/DRM UMR CEA 2E, Universite de Caen-Basse Normandie, Centre Cyceron, 14074 Caen Cedex (France); Perrio, Cecile [Groupe de Developpements Methodologiques en Tomographie par Emission de Positons, DSV/DRM UMR CEA 2E, Universite de Caen-Basse Normandie, Centre Cyceron, 14074 Caen Cedex (France)], E-mail: perrio@cyceron.fr; Debruyne, Daniele [Groupe de Developpements Methodologiques en Tomographie par Emission de Positons, DSV/DRM UMR CEA 2E, Universite de Caen-Basse Normandie, Centre Cyceron, 14074 Caen Cedex (France)], E-mail: debruyne@cyceron.fr; Barre, Louisa [Groupe de Developpements Methodologiques en Tomographie par Emission de Positons, DSV/DRM UMR CEA 2E, Universite de Caen-Basse Normandie, Centre Cyceron, 14074 Caen Cedex (France)

    2008-07-15

    Introduction: Radiopharmaceuticals that can bind selectively the {kappa}-opioid receptor may present opportunities for staging clinical brain disorders and evaluating the efficiency of new therapies related to stroke, neurodegenerative diseases or opiate addiction. The N-methylated derivative of JDTic (named MeJDTic), which has been recently described as a potent and selective antagonist of {kappa}-opioid receptor in vitro, was labeled with carbon-11 and evaluated for in vivo imaging the {kappa}-opioid receptor in mice. Methods: [{sup 11}C]-MeJDTic was prepared by methylation of JDTic with [{sup 11}C]-methyl triflate. The binding of [{sup 11}C]-MeJDTic to {kappa}-opioid receptor was investigated ex vivo by biodistribution and competition studies using nonfasted male CD1 mice. Results: [{sup 11}C]-MeJDTic exhibited a high and rapid distribution in peripheral organs. The uptake was maximal in lung where the {kappa} receptor is largely expressed. [{sup 11}C]-MeJDTic rapidly crossed the blood-brain barrier and accumulated in the brain regions of interest (hypothalamus). The parent ligand remained the major radioactive compound in brain during the experiment. Chase studies with U50,488 (a {kappa} referring agonist), morphine (a {mu} agonist) and naltrindole (a {delta} antagonist) demonstrated that this uptake was the result of specific binding to the {kappa}-opioid receptor. Conclusion: These findings suggested that [{sup 11}C]-MeJDTic appeared to be a promising selective 'lead' radioligand for {kappa}-opioid receptor PET imaging.

  3. Studies Toward the Pharmacophore of Salvinorin A, a Potent Kappa Opioid Receptor Agonist

    OpenAIRE

    Munro, Thomas A.; Mark A. Rizzacasa; Roth, Bryan L.; Toth, Beth A.; Yan, Feng

    2005-01-01

    Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity, but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors.

  4. Studies toward the pharmacophore of salvinorin A, a potent kappa opioid receptor agonist.

    Science.gov (United States)

    Munro, Thomas A; Rizzacasa, Mark A; Roth, Bryan L; Toth, Beth A; Yan, Feng

    2005-01-27

    Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors.

  5. Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders

    Science.gov (United States)

    Butelman, Eduardo R.; Kreek, Mary Jeanne

    2015-01-01

    Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A. PMID:26441647

  6. Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders.

    Science.gov (United States)

    Butelman, Eduardo R; Kreek, Mary Jeanne

    2015-01-01

    Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A.

  7. The dynamic relationship between mu and kappa opioid receptors in body temperature regulation.

    Science.gov (United States)

    Chen, Xiaohong; McClatchy, Daniel B; Geller, Ellen B; Tallarida, Ronald J; Adler, Martin W

    2005-12-12

    Previous studies demonstrated that intracerebroventricular (icv) injection of a kappa opioid receptor agonist decreased, and a mu agonist increased, body temperature (Tb) in rats. A dose-response study with the selective kappa antagonist nor-binaltorphimine (nor-BNI) showed that a low dose (1.25 nmol, icv) alone had no effect, although a high dose (25 nmol, icv) increased Tb. It was hypothesized that the hyperthermia induced by nor-BNI was the result of the antagonist blocking the kappa opioid receptor and releasing its inhibition of mu opioid receptor activity. To determine whether the Tb increase caused by nor-BNI was a mu receptor-mediated effect, we administered the selective mu antagonist CTAP (1.25 nmol, icv) 15 min after nor-BNI (25 nmol, icv) and measured rectal Tb in unrestrained rats. CTAP significantly antagonized the Tb increase induced by icv injection of nor-BNI. Injection of 5 or 10 nmol of CTAP alone significantly decreased the Tb, and 1.25 nmol of nor-BNI blocked that effect, indicating that the CTAP-induced hypothermia was kappa-mediated. The findings strongly suggest that mu antagonists, in blocking the basal hyperthermia mediated by mu receptors, can unmask the endogenous kappa receptor-mediated hypothermia, and that there is a tonic balance between mu and kappa opioid receptors that serves as a homeostatic mechanism for maintaining Tb.

  8. The Central Reinforcing Properties of Ethanol Are Mediated by Endogenous Opioid Systems: Effects of Mu and Kappa Opioid Antagonists.

    Directory of Open Access Journals (Sweden)

    Norman E. Spear

    2009-09-01

    Full Text Available Endogenous opioid systems are implicated in the reinforcing effects of ethanol and may play a substantial role in modulating the central reinforcing effects of ethanol early in ontogeny. This possibility was explored in the present study through the use of an olfactory conditioning paradigm with centrally administered ethanol serving as an unconditioned stimulus (US. In Experiment 1, newborn rat pups were treated with either a selective mu antagonist CTOP or kappa selective antagonist nor-BNI prior to olfactory conditioning. Experiment 2 tested the effectiveness of an alternative, shorter-duration kappa opioid antagonist GNTI in altering ethanol reinforcement. Experiment 3 investigated whether the effectiveness of pharmacological blockade of opioid receptors was due to the disruption of learning per se using an olfactory aversive conditioning paradigm with intraoral quinine serving as a US. Central administration of either mu or kappa opioid antagonists prior to conditioning disrupted the reinforcing effects of ethanol in newborn rats. The kappa opioid antagonist GNTI was as effective as nor-BNI. These effects of opioid antagonists on ethanol reinforcement are unlikely to be due to a disruption of all types of conditioning, since CTOP did not affect aversive reinforcement to intraoral infusions of quinine. The present results support the hypothesis that in newborn rats, the reinforcing properties of ethanol are mediated by the endogenous activity at mu and kappa opioid receptors.

  9. Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice.

    Science.gov (United States)

    Ansonoff, Michael A; Zhang, Jiwen; Czyzyk, Traci; Rothman, Richard B; Stewart, Jeremy; Xu, Heng; Zjwiony, Jordan; Siebert, Daniel J; Yang, Feng; Roth, Bryan L; Pintar, John E

    2006-08-01

    Salvia divinorum is a natural occurring hallucinogen that is traditionally used by the Mazatec Indians of central Mexico. The diterpene salvinorin A was identified as an active component of S. divinorum over 20 years ago, but only recently has biochemical screening indicated that a molecular target of salvinorin A in vitro is the kappa-opioid receptor. We have examined whether salvinorin A, the C2-substituted derivative salvinorinyl-2-propionate, and salvinorin B can act as kappa-opioid receptor agonists in vivo. We found that following intracerebroventricular injection over a dose range of 1 to 30 microg of both salvinorin A and salvinorinyl-2-propionate produces antinociception in wild-type mice but not in a novel strain of kappa-opioid receptor knockout mice. Moreover, both salvinorin A and salvinorinyl-2-propionate reduce rectal body temperature, similar to conventional kappa-opioid receptor agonists, in a genotype-dependent manner. In addition, we determined that salvinorin A has high affinity for kappa 1- but not kappa 2-opioid receptors, demonstrating selectivity for this receptor subclass. Finally, treatment over the same dose range with salvinorin B, which is inactive in vitro, produced neither antinociceptive nor hypothermic effects in wild-type mice. These data demonstrate that salvinorin A is the active component of S. divinorum, selective for kappa(1)-opioid receptors, and that salvinorin A and specific structurally related analogs produce behavioral effects that require the kappa-opioid receptor.

  10. Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors.

    Science.gov (United States)

    Yan, Feng; Mosier, Philip D; Westkaemper, Richard B; Stewart, Jeremy; Zjawiony, Jordan K; Vortherms, Timothy A; Sheffler, Douglas J; Roth, Bryan L

    2005-06-21

    Salvinorin A is a naturally occurring hallucinogenic diterpenoid from the plant Salvia divinorumthat selectively and potently activates kappa-opioid receptors (KORs). Salvinorin A is unique in that it is the only known lipid-like molecule that selectively and potently activates a G-protein coupled receptor (GPCR), which has as its endogenous agonist a peptide; salvinorin A is also the only known non-nitrogenous opioid receptor agonist. In this paper, we identify key residues in KORs responsible for the high binding affinity and agonist efficacy of salvinorin A. Surprisingly, we discovered that salvinorin A was stabilized in the binding pocket by interactions with tyrosine residues in helix 7 (Tyr313 and Tyr320) and helix 2 (Tyr119). Intriguingly, activation of KORs by salvinorin A required interactions with the helix 7 tyrosines Tyr312, Tyr313, and Tyr320 and with Tyr139 in helix 3. In contrast, the prototypical nitrogenous KOR agonist U69593 and the endogenous peptidergic agonist dynorphin A (1-13) showed differential requirements for these three residues for binding and activation. We also employed a novel approach, whereby we examined the effects of cysteine-substitution mutagenesis on the binding of salvinorin A and an analogue with a free sulfhydryl group, 2-thiosalvinorin B. We discovered that residues predicted to be in close proximity, especially Tyr313, to the free thiol of 2-thiosalvinorin B when mutated to Cys showed enhanced affinity for 2-thiosalvinorin B. When these findings are taken together, they imply that the diterpenoid salvinorin A utilizes unique residues within a commonly shared binding pocket to selectively activate KORs.

  11. On the mechanisms of kappa-opioid-induced diuresis.

    Science.gov (United States)

    Blackburn, T. P.; Borkowski, K. R.; Friend, J.; Rance, M. J.

    1986-01-01

    In conscious saline loaded rats, the kappa-opioid agonists tifluadom, U50488, and ethylketocyclazocine, given subcutaneously, induced a characteristic diuresis which could be antagonized by naloxone. Bilateral adrenal demedullation significantly reduced adrenal gland catecholamine content and plasma adrenaline levels, but did not significantly affect plasma corticosterone levels, indicating that the adrenal cortex remained both intact and functional. Seven days following bilateral adrenal demedullation, the subcutaneous administration of the kappa-agonists no longer induced diuresis. However, demedullation did not affect the diuretic response to frusemide or clonidine, nor did it affect the antidiuretic response induced by the mu-opioid agonists morphine and buprenorphine. Adrenal catecholamines do not appear to be involved in kappa-opioid-induced diuresis, since pretreatment with propranolol, prazosin and idazoxan did not affect the diuretic response in intact animals. The results indicate a link between the adrenal medulla and kappa-opioid-induced diuresis and suggest that a peripheral mechanism may also be involved in mediating this effect. PMID:3542107

  12. Effects of differential modulation of mu-, delta- and kappa-opioid systems on bicuculline-induced convulsions in the mouse.

    Science.gov (United States)

    Yajima, Y; Narita, M; Takahashi-Nakano, Y; Misawa, M; Nagase, H; Mizoguchi, H; Tseng, L F; Suzuki, T

    2000-04-17

    The present study investigated the effects of micro-, delta- and kappa-opioid receptor agonists on seizures produced by blockade of gamma-aminobutyric acid (GABA)-mediated synaptic transmission in the mouse. The selective GABA(A) receptor antagonist bicuculline (1.25-3 mg/kg) given subcutaneously caused dose-dependent clonic-tonic convulsions. These convulsions were potentiated by the prototypic mu-opioid receptor agonist morphine given subcutaneously 20 min prior to a subconvulsive dose of bicuculline. The potentiation by morphine was completely reversed by pretreatment intraventricularly with the selective mu-opioid receptor antagonist beta-funaltrexamine (0.5 microgram/mouse). Pretreatment intraventricularly with the selective delta-opioid receptor agonists 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12abeta-octahydro-quinolino[2,3,3-g]isoquinoline ((-)TAN-67) or [D-Pen(2,5)]-enkephalin (DPDPE) showed a dose-dependent increase in the incidence of convulsions. Pretreatment with naltrindole (2 mg/kg, s.c.), a selective delta-opioid receptor antagonist, abolished the enhancement of the bicuculline-induced convulsions by DPDPE. In contrast, pretreatment with the selective kappa-opioid receptor agonist U-50,488H (0.6-80 mg/kg, subcutaneously or 25-100 microgram/mouse, intraventricularly) produced a dose-dependent suppression of the bicuculline-induced convulsions. The inhibitory effect of U-50,488H was completely blocked by pretreatment subcutaneously with nor-binaltorphimine (5 mg/kg), a selective kappa-opioid receptor antagonist. This study demonstrates that activation of both mu- and delta-opioid receptors increases the incidence of convulsions produced by blockade of GABA-mediated synaptic transmission, while stimulation of kappa-opioid receptors has an anticonvulsive effect.

  13. Salvinorin A, a kappa-opioid receptor (KOP-r agonist hallucinogen: Pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Eduardo eButelman

    2015-09-01

    Full Text Available Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins in higher functions, including cognition, and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A- containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and drug reinforcers (including drugs of abuse. KOPr activation (including by salvinorin A can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike all other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects, with a reduced burden of undesirable effects associated with salvinorin A.

  14. D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims.

    Science.gov (United States)

    Mash, D C; Staley, J K

    1999-06-29

    Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry, which affects motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blockade of DA uptake, reciprocal signaling between DA and endogenous opioids has important implications for understanding cocaine dependence. We have used in vitro autoradiography and ligand binding to map D3 DA and kappa opioid receptors in the human brains of cocaine-overdose victims. The number of D3 binding sites was increased one-to threefold over the nucleus accumbens and ventromedial sectors of the caudate and putamen from cocaine-overdose victims, as compared to age-matched and drug-free control subjects. D3 receptor/cyclophilin mRNA ratios in the nucleus accumbens were increased sixfold in cocaine-overdose victims over control values, suggesting that cocaine exposure also affects the expression of D3 receptor mRNA. The number of kappa opioid receptors in the nucleus accumbens and other corticolimbic areas from cocaine fatalities was increased twofold as compared to control values. Cocaine-overdose victims exhibiting preterminal excited delirium had a selective upregulation of kappa receptors measured also in the amygdala. Understanding the complex regulatory profiles of DA and opioid synaptic markers that occur with chronic misuse of cocaine may suggest multitarget strategies for treating cocaine dependence.

  15. Isolation and chemical modification of clerodane diterpenoids from Salvia species as potential agonists at the kappa-opioid receptor.

    Science.gov (United States)

    Li, Yiqiang; Husbands, Stephen M; Mahon, Mary F; Traynor, John R; Rowan, Michael G

    2007-07-01

    The clerodane diterpenoid salvinorin A (1), the main active component of the psychotropic herb Salvia divinorum, has been reported to be a potent agonist at the kappa-opioid receptor. Computer modeling suggested that splendidin (2) from S. splendens, as well as related compounds, might possess similar activities. In the present study, this hypothesis was tested by determination of the binding properties of a series of structural congeners, compounds 2-8, at the mu-, delta-, and kappa-opioid receptors. However, none of these compounds showed significant binding to any of the opioid-receptor subtypes, thus disproving the above hypothesis. The novel compounds 7 and 8 were obtained semi-synthetically by selective modification of salvifarin (5), isolated from Salvia farinacea, upon epoxide-ring opening with AcOH in the presence of indium(III) triflate. Also, the X-ray crystal structure of salvifaricin (6; Fig.), obtained from S. farinacea, was determined for the first time and used, in combination with in-depth NMR experiments, to elucidate the absolute configurations of the new products. Our experiments demonstrate that the relatively well-accessible diterpenoid 6 could be used as starting material for future studies into the structure-activity relationship at the kappa-opioid receptor.

  16. The hallucinogen derived from Salvia divinorum, salvinorin A, has kappa-opioid agonist discriminative stimulus effects in rats.

    Science.gov (United States)

    Willmore-Fordham, Catherine B; Krall, Daniel M; McCurdy, Christopher R; Kinder, David H

    2007-09-01

    Data from clinical and preclinical studies converge implicating the plant-derived hallucinogen salvinorin A as an important pharmacologic tool; this psychoactive compound may expand scientific understandings on mammalian kappa-opioid receptor systems. Human salvinorin A effects, consistent with kappa-opioid receptor agonism, include antinociception, sedation, dysphoria and distorted perceptions. The experiments reported here measured salvinorin A (1-3mg/kg, i.p.) discriminative stimulus properties in male Sprague-Dawley rats conditioned to recognize the discriminative stimulus cue generated by the well characterized kappa-opioid agonist U-69593 (0.56 mg/kg, i.p.). At three distinct active doses, salvinorin A fully substituted for U-69593 without altering response rates. The lever choice pattern in U-69593 trained animals reverted to vehicle lever responding when a kappa selective antagonist compound, nor-BNI (4.5 nM, i.c.v.) was administered 1h prior to salvinorin A, yet nor-BNI alone failed to impact the rate or pattern of subject responses. These findings confirm and extend results published after similar drug discrimination tests were performed in rhesus monkeys. The discussion section of this article highlights public concern over salvinorin A misuse and emphasizes several potential pharmacotherapeutic applications for salvinorin A or analogue compounds.

  17. Antinociceptive profile of salvinorin A, a structurally unique kappa opioid receptor agonist.

    Science.gov (United States)

    McCurdy, Christopher R; Sufka, Kenneth J; Smith, Grant H; Warnick, Jason E; Nieto, Marcelo J

    2006-01-01

    Salvinorin A, is a structurally unique, non-nitrogenous, kappa opioid receptor (KOP) agonist. Given the role of KOPs in analgesic processes, we set out to determine whether salvinorin A has antinociceptive activity in thermal and chemo-nociceptive assays. The tail-flick assay was employed to investigate 1) salvinorin A's (0.5, 1.0, 2.0, and 4.0 mg/kg) dose-response and time-course (10, 20, and 30 min) effects in a thermal nociceptive assay, and 2) the ability for the KOP antagonist norBNI (10.0 mg/kg) to prevent salvinorin A antinociception. The hotplate assay was utilized as a second thermal nociceptive measure to test salvinorin A's dose-response effects. The acetic acid abdominal constriction assay was used to study salvinorin A's dose-response and time-course (over 30 min) effects in a chemo-nociceptive assay. Together, these studies revealed that salvinorin A produces a dose-dependent antinociception that peaked at 10 min post-injection but rapidly returned to baseline. Additionally, pretreatment with the KOP antagonist norbinaltorphimine (norBNI) reversed salvinorin A-induced antinociception. These findings demonstrate that salvinorin A produces a KOP mediated antinociceptive effect with a short duration of action.

  18. Locus coeruleus kappa-opioid receptors modulate reinstatement of cocaine place preference through a noradrenergic mechanism.

    Science.gov (United States)

    Al-Hasani, Ream; McCall, Jordan G; Foshage, Audra M; Bruchas, Michael R

    2013-11-01

    Activation of kappa-opioid receptors (KORs) in monoamine circuits results in dysphoria-like behaviors and stress-induced reinstatement of drug seeking in both conditioned place preference (CPP) and self-administration models. Noradrenergic (NA) receptor systems have also been implicated in similar behaviors. Dynorphinergic projections terminate within the locus coeruleus (LC), a primary source of norepinephrine in the forebrain, suggesting a possible link between the NA and dynorphin/kappa opioid systems, yet the implications of these putative interactions have not been investigated. We isolated the necessity of KORs in the LC in kappa opioid agonist (U50,488)-induced reinstatement of cocaine CPP by blocking KORs in the LC with NorBNI (KOR antagonist). KOR-induced reinstatement was significantly attenuated in mice injected with NorBNI in the LC. To determine the sufficiency of KORs in the LC on U50,488-induced reinstatement of cocaine CPP, we virally re-expressed KORs in the LC of KOR knockout mice. We found that KORs expression in the LC alone was sufficient to partially rescue KOR-induced reinstatement. Next we assessed the role of NA signaling in KOR-induced reinstatement of cocaine CPP in the presence and absence of a α2-agonist (clonidine), β-adrenergic receptor antagonist (propranolol), and β(1)- and β(2)-antagonist (betaxolol and ICI-118,551 HCl). Both the blockade of postsynaptic β(1)-adrenergic receptors and the activation of presynaptic inhibitory adrenergic autoreceptors selectively potentiated the magnitude of KOR-induced reinstatement of cocaine CPP but not cocaine-primed CPP reinstatement. Finally, viral restoration of KORs in the LC together with β-adrenergic receptor blockade did not potentiate KOR-induced reinstatement to cocaine CPP, suggesting that adrenergic receptor interactions occur at KOR-expressing regions external to the LC. These results identify a previously unknown interaction between KORs and NA systems and suggest a NA

  19. Kappa-opioid receptor-mediated effects of the plant-derived hallucinogen, salvinorin A, on inverted screen performance in the mouse.

    Science.gov (United States)

    Fantegrossi, William E; Kugle, Kelly M; Valdes, Leander J; Koreeda, Masato; Woods, James H

    2005-12-01

    Salvinorin A is a pharmacologically active diterpene that occurs naturally in the Mexican mint Ska Maria Pastora (Salvia divinorum) and represents the first naturally occurring kappa-opioid receptor agonist. The chemical structure of salvinorin A is novel among the opioids, and thus defines a new structural class of kappa-opioid-receptor selective drugs. Few studies have examined the effects of salvinorin A in vivo, and fewer still have attempted to assess the agonist actions of this compound at mu-opioid, delta-opioid, and kappa-opioid receptors using selective antagonists. In the mouse, salvinorin A disrupted climbing behavior on an inverted screen task, indicating a rapid, but short-lived induction of sedation/motor incoordination. Similar effects were observed with the mu-agonist remifentanil and the synthetic kappa-agonist U69,593. When behaviorally equivalent doses of all three opioids were challenged with antagonists at doses selective for mu-opioid, delta-opioid, or kappa-opioid receptors, results suggested that the motoric effects of remifentanil were mediated by mu-receptors, whereas those of salvinorin A and U69,593 were mediated via kappa-receptors. Despite similar potencies and degrees of effectiveness, salvinorin A and U69,593 differed with regard to their susceptibility to antagonism by the kappa-antagonist nor-binaltorphamine. This later finding, coupled with the novel chemical structure of the compound, is consistent with recent findings that the diterpene salvinorin A may bind to the kappa-receptor in a manner that is qualitatively different from that of more traditional kappa-agonists such as the benzeneacetamide U69,593. Such pharmacological differences among these kappa-opioids raise the possibility that the development of other diterpene-based opioids may yield important therapeutic compounds.

  20. Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice.

    Science.gov (United States)

    Negus, S Stevens; Neddenriep, Bradley; Altarifi, Ahmad A; Carroll, F Ivy; Leitl, Michael D; Miller, Laurence L

    2015-06-01

    Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- × 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the μ-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.

  1. Prefrontal Cortical Kappa Opioid Receptors Attenuate Responses to Amygdala Inputs.

    Science.gov (United States)

    Tejeda, Hugo A; Hanks, Ashley N; Scott, Liam; Mejias-Aponte, Carlos; Hughes, Zoë A; O'Donnell, Patricio

    2015-12-01

    Kappa opioid receptors (KORs) have been implicated in anxiety and stress, conditions that involve activation of projections from the basolateral amygdala (BLA) to the medial prefrontal cortex (mPFC). Although KORs have been studied in several brain regions, their role on mPFC physiology and on BLA projections to the mPFC remains unclear. Here, we explored whether KORs modify synaptic inputs from the BLA to the mPFC using in vivo electrophysiological recordings with electrical and optogenetic stimulation. Systemic administration of the KOR agonist U69,593 inhibited BLA-evoked synaptic responses in the mPFC without altering hippocampus-evoked responses. Intra-mPFC U69,593 inhibited electrical and optogenetic BLA-evoked synaptic responses, an effect blocked by the KOR antagonist nor-BNI. Bilateral intra-mPFC injection of the KOR antagonist nor-BNI increased center time in the open field test, suggesting an anxiolytic effect. The data demonstrate that mPFC KORs negatively regulate glutamatergic synaptic transmission in the BLA-mPFC pathway and anxiety-like behavior. These findings provide a framework whereby KOR signaling during stress and anxiety can regulate the flow of emotional state information from the BLA to the mPFC.

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

    Directory of Open Access Journals (Sweden)

    Catherine M Cahill

    2014-11-01

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

  3. Kappa Opioids, Salvinorin A and Major Depressive Disorder.

    Science.gov (United States)

    Taylor, George T; Manzella, Francesca

    2016-01-01

    Opioids are traditionally associated with pain, analgesia and drug abuse. It is now clear, however, that the opioids are central players in mood. The implications for mood disorders, particularly clinical depression, suggest a paradigm shift from the monoamine neurotransmitters to the opioids either alone or in interaction with monoamine neurons. We have a special interest in dynorphin, the last of the major endogenous opioids to be isolated and identified. Dynorphin is derived from the Greek word for power, dynamis, which hints at the expectation that the neuropeptide held for its discoverers. Yet, dynorphin and its opioid receptor subtype, kappa, has always taken a backseat to the endogenous b-endorphin and the exogenous morphine that both bind the mu opioid receptor subtype. That may be changing as the dynorphin/ kappa system has been shown to have different, often opposite, neurophysiological and behavioral influences. This includes major depressive disorder (MDD). Here, we have undertaken a review of dynorphin/ kappa neurobiology as related to behaviors, especially MDD. Highlights include the unique features of dynorphin and kappa receptors and the special relation of a plant-based agonist of the kappa receptor salvinorin A. In addition to acting as a kappa opioid agonist, we conclude that salvinorin A has a complex pharmacologic profile, with potential additional mechanisms of action. Its unique neurophysiological effects make Salvinorina A an ideal candidate for MDD treatment research.

  4. Structure of the human [kappa]-opioid receptor in complex with JDTic

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    Wu, Huixian; Wacker, Daniel; Mileni, Mauro; Katritch, Vsevolod; Han, Gye Won; Vardy, Eyal; Liu, Wei; Thompson, Aaron A.; Huang, Xi-Ping; Carroll, F. Ivy; Mascarella, S. Wayne; Westkaemper, Richard B.; Mosier, Philip D.; Roth, Bryan L.; Cherezov, Vadim; Stevens, Raymond C. (VCU); (Scripps); (UNC); (Res. Tri. Inst.)

    2013-04-25

    Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and - in the case of {kappa}-opioid receptor ({kappa}-OR) - dysphoria and psychotomimesis. Here we report the crystal structure of the human {kappa}-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 {angstrom} resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human {kappa}-OR. Modelling of other important {kappa}-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for {kappa}-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human {kappa}-OR.

  5. Toward a structure-based model of salvinorin A recognition of the kappa-opioid receptor.

    Science.gov (United States)

    Kane, Brian E; McCurdy, Christopher R; Ferguson, David M

    2008-03-27

    The structural basis to salvinorin A recognition of the kappa-opioid receptor is evaluated using a combination of site-directed mutagenesis and molecular-modeling techniques. The results show that salvinorin A recognizes a collection of residues in transmembrane II and VII, including Q115, Y119, Y313, I316, and Y320. The mutation of one hydrophobic residue in particular, I316, was found to completely abolish salvinorin A binding. As expected, none of the residues in transmembrane III or VI commonly associated with opiate recognition (such as D138 or E297) appear to be required for ligand binding. On the basis of the results presented here and elsewhere, a binding site model is proposed that aligns salvinorin A vertically within a pocket spanning transmembrane II and VII, with the 2' substituent directed toward the extracellular domains. The model explains the role that hydrophobic contacts play in binding this lipophilic ligand and gives insight into the structural basis to the mu-opioid receptor selectivity of 2'-benzoyl salvinorin (herkinorin).

  6. Kappa Opioid Receptors Mediate where Fear Is Expressed Following Extinction Training

    Science.gov (United States)

    Cole, Sindy; Richardson, Rick; McNally, Gavan P.

    2011-01-01

    Six experiments used a within-subjects renewal design to examine the involvement of kappa opioid receptors (KORs) in regulating the expression and recovery of extinguished fear. Rats were trained to fear a tone conditioned stimulus (CS) via pairings with foot shock in a distinctive context (A). This was followed by extinction training of the CS in…

  7. Changes of mu and kappa opioid receptors in cathartic colon of rat

    Institute of Scientific and Technical Information of China (English)

    LIU Bao-hua; MO Ping; JIA Hou-jun; LI Chun-xue; ZHANG Sheng-ben

    2004-01-01

    Objective: To oberve the changes of mu and kappa opioid receptors in the cathartic colon of rat, and to clarify that whether opioid receptors accounts for the occurrence of slow trait constipation (STC). Methods: The cathartiic colon model of rat was made by feeding with laxatives. The activity of mu and kappa opioid receptors in the cathartic colon of rat was measured by radio-ligand binding assay. Results: Compared with the control group, the maximal binding capacity (Bmax) and affinity(Kd) of mu opioid receptor in cathartic colon group were significantly increased (207. 00 ± 22. 90 fmol/mg·p vs 82. 00 ± 14.23 fmol/mg· p, P < 0.01 ;3.30 ± 0.45 mmol/L vs 2.40 ± 0.57 mmol/L, P < 0.05). The maximal binding capacity of kappa opioid receptor also showed a great increase (957. 00 ± 102. 41 fmol/mg· p vs 459.00 ± 52.41 fmol/mg·p, P < 0.01 ), but no significant difference of affinity was found between the two groups. Conclsion: The mu and kappa opioid receptors may be involved in the functional disorders of cathartic colon.

  8. Kappa Opioid Receptors Mediate where Fear Is Expressed Following Extinction Training

    Science.gov (United States)

    Cole, Sindy; Richardson, Rick; McNally, Gavan P.

    2011-01-01

    Six experiments used a within-subjects renewal design to examine the involvement of kappa opioid receptors (KORs) in regulating the expression and recovery of extinguished fear. Rats were trained to fear a tone conditioned stimulus (CS) via pairings with foot shock in a distinctive context (A). This was followed by extinction training of the CS in…

  9. Studies on the adrenomedullary dependence of kappa-opioid agonist-induced diuresis in conscious rats.

    Science.gov (United States)

    Borkowski, K. R.

    1989-01-01

    1. The dependence of kappa-opioid agonist-induced diuresis, upon an intact and functional adrenal medulla in conscious rats, was investigated in order to test the hypothesis that the diuresis is mediated by a blood-borne 'diuretic factor', of adrenomedullary origin, released by kappa-opioid receptor stimulation. 2. Confirming previous observations, adrenal demedullation significantly attenuated diuretic responses to the kappa-opioid agonists U50488H, ethylketocyclazocine (EKC) and tifluadom, but did not affect basal urine output, furosemide-induced diuresis or the antidiuretic response to the mu-opioid agonist, buprenorphine. Naloxone abolished U50488H-induced diuresis, confirming an involvement of opioid receptors. 3. Transfusion studies established that blood, from intact rats treated with U50488H, induced diuresis in intact and demedullated recipient rats, whether or not the recipients had been pretreated with naloxone. However, blood from demedullated rats treated with U50448H was unable to induce diuresis when administered to intact or demedullated recipients. 4. It is concluded that kappa-opioid agonist-induced diuresis is dependent upon an intact and functional adrenal medulla and appears to be mediated by a blood-borne 'diuretic factor' of adrenomedullary origin. PMID:2558758

  10. nor-BNI Antagonism of Kappa Opioid Agonist-Induced Reinstatement of Ethanol-Seeking Behavior

    Directory of Open Access Journals (Sweden)

    Erin Harshberger

    2016-01-01

    Full Text Available Recent work suggests that the dynorphin (DYN/kappa opioid receptor (KOR system may be a key mediator in the behavioral effects of alcohol. The objective of the present study was to examine the ability of the KOR antagonist norbinaltorphimine (nor-BNI to attenuate relapse to ethanol seeking due to priming injections of the KOR agonist U50,488 at time points consistent with KOR selectivity. Male Wistar rats were trained to self-administer a 10% ethanol solution, and then responding was extinguished. Following extinction, rats were injected with U50,488 (0.1–10 mg/kg, i.p. or saline and were tested for the reinstatement of ethanol seeking. Next, the ability of the nonselective opioid receptor antagonist naltrexone (0 or 3.0 mg/kg, s.c. and nor-BNI (0 or 20.0 mg/kg, i.p. to block U50,488-induced reinstatement was examined. Priming injections U50,488 reinstated responding on the previously ethanol-associated lever. Pretreatment with naltrexone reduced the reinstatement of ethanol-seeking behavior. nor-BNI also attenuated KOR agonist-induced reinstatement, but to a lesser extent than naltrexone, when injected 24 hours prior to injections of U50,488, a time point that is consistent with KOR selectivity. While these results suggest that activation of KORs is a key mechanism in the regulation of ethanol-seeking behavior, U50,488-induced reinstatement may not be fully selective for KORs.

  11. Immediate and Persistent Effects of Salvinorin A on the Kappa Opioid Receptor in Rodents, Monitored In Vivo with PET.

    Science.gov (United States)

    Placzek, Michael S; Van de Bittner, Genevieve C; Wey, Hsiao-Ying; Lukas, Scott E; Hooker, Jacob M

    2015-12-01

    Monitoring changes in opioid receptor binding with positron emission tomography (PET) could lead to a better understanding of tolerance and addiction because altered opioid receptor dynamics following agonist exposure has been linked to tolerance mechanisms. We have studied changes in kappa opioid receptor (KOR) binding availability in vivo with PET following kappa opioid agonist administration. Male Sprague-Dawley rats (n=31) were anesthetized and treated with the (KOR) agonist salvinorin A (0.01-1.8 mg/kg, i.v.) before administration of the KOR selective radiotracer [(11)C]GR103545. When salvinorin A was administered 1 min prior to injection of the radiotracer, [(11)C]GR103545 binding potential (BPND) was decreased in a dose-dependent manner, indicating receptor binding competition. In addition, the unique pharmacokinetics of salvinorin A (half-life ~8 min in non-human primates) allowed us to study the residual impact on KOR after the drug had eliminated from the brain. Salvinorin A was administered up to 5 h prior to [(11)C]GR103545, and the changes in BPND were compared with baseline, 2.5 h, 1 h, and 1 min pretreatment times. At lower doses (0.18 mg/kg and 0.32 mg/kg) we observed no prolonged effect on KOR binding but at 0.60 mg/kg salvinorin A induced a sustained decrease in KOR binding (BPND decreased by 40-49%) which persisted up to 2.5 h post administration, long after salvinorin A had been eliminated from the brain. These data point towards an agonist-induced adaptive response by KOR, the dynamics of which have not been previously studied in vivo with PET.

  12. Kappa-opioid receptor antagonism improves recovery from myocardial stunning in chronically instrumented dogs.

    Science.gov (United States)

    Grosse Hartlage, Maike A; Theisen, Marc M; Monteiro de Oliveira, Nelson P; Van Aken, Hugo; Fobker, Manfred; Weber, Thomas P

    2006-10-01

    We tested the hypothesis that the selective kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) improves recovery from myocardial stunning. Ten dogs were chronically instrumented for measurement of heart rate, left atrial, aortic and left ventricular pressure (LVP), and the maximum rate of LVP increase (LV dP/dt(max)) and decrease (LV dP/dt(max)), coronary blood flow velocity and myocardial wall-thickening fraction. Regional myocardial blood flow was determined with fluorescent microspheres. Catecholamine plasma levels were measured by high-performance liquid chromatography, and beta-endorphin and dynorphin plasma levels by radioimmunoassay. An occluder around the left anterior descending artery (LAD) allowed induction of a reversible LAD-ischemia. Animals underwent two experiments in a randomized crossover fashion on separate days: (a) 10 min LAD-occlusion (control experiment), (b) second ischemic episode 24 h after nor-BNI (2.5 mg/kg IV) (intervention). Dogs receiving nor-BNI showed an increase in wall-thickening fraction, LV dP/dt(max) and LV dP/dt(min) before ischemia and during the whole reperfusion (P < 0.05 versus control experiment). After nor-BNI pretreatment, dynorphin levels increased after induction of ischemia to a peak level of 15.1 +/- 3.6 pg/mL (P < 0.05 versus control experiment). The increase in plasma beta-endorphin during ischemia and early reperfusion was attenuated after nor-BNI. Compared with the control experiment, nor-BNI left global hemodynamics, regional myocardial blood flow, and catecholamine levels unchanged. In conclusion, nor-BNI improves recovery from myocardial stunning after regional myocardial ischemia in chronically instrumented dogs.

  13. Tramadol reduces the 5-HTP-induced head-twitch response in mice via the activation of mu and kappa opioid receptors.

    Science.gov (United States)

    Sun, Hong-Lei; Zheng, Ji-Wang; Wang, Keng; Liu, Rui-Ke; Liang, Jian-Hui

    2003-01-31

    Tramadol, an atypical opioid analgesic, stimulates both opiatergic and serotonergic systems. Here we have investigated the effect of tramadol in mice on 5-hydroxyptrytophan (5-HTP)-induced head twitch response (HTR), which is an animal model for the activation of the CNS 5-HT(2A) receptors in mice. Tramadol attenuated 5-HTP-induced HTR in a dose-dependent manner as morphine. Furthermore, the nonselective opioid receptor antagonists, naloxone and diprenorphine (M5050), reversed the effect of tramadol on 5-HTP-induced HTR dose-dependently. Interestingly, in contrast to the selective delta opioid receptor antagonist NTI, beta-FNA, a selective mu receptor antagonist, and nor-BNI, a selective kappa opioid receptor antagonist, antagonized the attenuation of 5-HTP-induced HTR by tramadol. In conclusion, administration of tramadol systemically inhibits 5-HTP-induced HTR in mice by activating opiatergic system in the CNS. Our findings show that mu and kappa opioid receptors, but not delta opioid receptor, play an important role in the regulation of serotonergic function in the CNS.

  14. A Kappa Opioid Model of Atypical Altered Consciousness and Psychosis: U50488, DOI, AC90179 Effects on Prepulse Inhibition and Locomotion in Mice.

    Science.gov (United States)

    Ruderman, Michael A; Powell, Susan B; Geyer, Mark A

    2009-07-01

    Sensorimortor gating and locomotion are behaviors that reflect pre-attentive sensory filtering and higher order, top-down, sensory processing, respectively. These processes are thought to affect either the perception of novelty in an environment (filtering) or cognition (higher order processing), salient features of models of altered states of consciousness (ASC). Drugs with highly selective receptor affinities that produce ASC can help to establish neural correlates, pathways, and mechanisms underlying ASC. Furthermore, screening for substances that selectively reverse drug-induced sensory processing departures is valuable for development of experimental antipsychotics. This study investigated the anomalous opioid sub-type, the kappa opioid (KA) system, within the two ASC models. Significant interaction and reversal effects between KA and the serotonin/2A (5-HT2A) system - the serotonin sub-type associated with classical psychedelics - were observed in three BPM measures. These measures showed that KA activation-induced effects could be reversed by 5-HT2A deactivation. These results suggest that KA could function as an atypical antipsychotic medications and/or as a screening tool for new antipsychotic medicines. The experimental work for this study comprised dose-response and reversal experiments with drugs that activate and deactivate kappa opioid and serotonin systems in the two behavioral models for the first time in mice.

  15. Inhibition of trigemino-hypoglossal reflex in rats by oxytocin is mediated by mu and kappa opioid receptors.

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    Zubrzycka, Maria; Fichna, Jakub; Janecka, Anna

    2005-02-21

    Recent studies showed that oxytocin plays an important role in the modulation of pain at different levels of the central nervous system. The present study was undertaken to investigate the effect of oxytocin on trigemino-hypoglossal reflex in rats. With the experimental settings used in this study, we have demonstrated that oxytocin showed significant analgesic effect after intracerebroventricular administration in rats, as assayed by the amplitude of the retractory movements of the tongue after tooth pulp stimulation. Antinociceptive effect of oxytocin was inhibited by subsequent perfusion of cerebral ventricles with oxytocin antagonist, [deamino-Cys1-D-Tyr(OEt)2-Thr4-Orn8]-oxytocin, atosiban. An involvement of opioid system in the oxytocin-induced analgesia was studied after intracerebroventricular administration of different opioid antagonists: non-selective naloxone, mu-selective beta-funaltrexamine, delta-selective naltrindole, and kappa-selective nor-binaltorphimine. It was shown that inhibition of antinociceptive effects was mediated through mu and kappa opioid receptors, indicating that there is a synergy between oxytocin and opioid systems in transmitting and modulating pain stimuli. Co-administration of oxytocin and a mu-selective endogenous opioid ligand endomorphin-2 did not significantly increase the antinociceptive activity of endomorphin-2.

  16. Kappa opioid receptors stimulate phosphoinositide turnover in rat brain

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    Periyasamy, S.; Hoss, W. (Univ. of Toledo, OH (USA))

    1990-01-01

    The effects of various subtype-selective opioid agonists and antagonists on the phosphoinositide (PI) turnover response were investigated in the rat brain. The {kappa}-agonists U-50,488H and ketocyclazocine produced a concentration-dependent increase in the accumulation of IP's in hippocampal slices. The other {kappa}-agonists Dynorphin-A (1-13) amide, and its protected analog D(Ala){sup 2}-dynorphin-A (1-13) amide also produced a significant increase in the formation of ({sup 3}H)-IP's, whereas the {mu}-selective agonists (D-Ala{sup 2}-N-Me-Phe{sup 4}-Gly{sup 5}-ol)-enkephalin and morphine and the {delta}-selective agonist (D-Pen{sup 2,5})-enkephalin were ineffective. The increase in IP's formation elicited by U-50,488H was partially antagonized by naloxone and more completely antagonized by the {kappa}-selective antagonists nor-binaltorphimine and MR 2266. The formation of IP's induced by U-50,488H varies with the regions of the brain used, being highest in hippocampus and amygdala, and lowest in striatum and pons-medullar. The results indicate that brain {kappa}- but neither {mu}- nor {delta}- receptors are coupled to the PI turnover response.

  17. Salvinorin A administration after global cerebral hypoxia/ischemia preserves cerebrovascular autoregulation via kappa opioid receptor in piglets.

    Directory of Open Access Journals (Sweden)

    Zhenhong Wang

    Full Text Available BACKGROUND: Cerebral hypoxia/ischemia (HI is not uncommon during the perinatal period. If occurring, it can result in severe neurologic disabilities that persist throughout life. Salvinorin A, a non-opioid Kappa opioid receptors (KOR selective agonist, has the potential to address this devastating situation. We have demonstrated that salvinorin A administration before HI, preserves pial artery autoregulative function through both the KOR and extracellular signal-regulated kinases (ERK pathways. In the present study, we tested the hypothesis that administration of salvinorin A after HI could preserve cerebral autoregulation via KOR and ERK pathway. METHODOLOGY/PRINCIPAL FINDINGS: The response of the pial artery to hypercapnia, hypotension and isoproterenol were monitored before and 1 hour after HI in piglets equipped with a cranial window. Four groups of drug administration were performed after HI. The control group had DMSO (1 µl/kg, i.v. administrated immediately after HI. Two salvinorin A treated groups had salvinorin A (10 µg/kg, i.v. administrated 0 and 30 min after HI, respectively. The 4(th group had salvinorin A and the KOR antagonist norbinaltorphimine (Nor-BIN, 1 µM topical co-administrated 0 min after HI (n = 5. The dilation responses of the pial artery to hypercapnia and hypotension were impaired after global HI and were preserved with salvinorin A administration immediately or 30 min after HI. The preservation of autoregulation was abolished when nor-BIN was administered. Levels of phosphor-ERK(pERK/ERK in the cerebrospinal fluid (CSF were measured before and 1 hour after HI. After HI, the pERK/ERK levels significantly increased in both DMSO control group and salvinorin A and nor-BIN co-administration group. The elevated levels of pERK/ERK were not observed with salvinorin A only groups. CONCLUSIONS: Salvinorin A administration 0 and 30 min after HI preserves autoregulation of pial artery to hypercapnia and hypotension via

  18. Pharmacological and genetic manipulation of kappa opioid receptors: effects on cocaine- and pentylenetetrazol-induced convulsions and seizure kindling.

    Science.gov (United States)

    Kaminski, Rafal M; Witkin, Jeffrey M; Shippenberg, Toni S

    2007-03-01

    The present study used pharmacological and gene ablation techniques to examine the involvement of kappa opioid receptors (KOPr) in modulating the convulsant effects of two mechanistically different drugs: cocaine and pentylenetetrazol (PTZ; GABA-A receptor antagonist) in mice. Systemic administration of the selective KOPr-1 agonist, U69593 (0.16-0.6mg/kg; s.c.), failed to modify cocaine-evoked convulsions or cocaine kindling. Similarly, no alteration in responsiveness to cocaine was observed in wild-type mice that received the selective KOPr-1 antagonist, nor-binaltorphimine (nor-BNI; 5mg/kg) or in mice lacking the gene encoding KOPr-1. In contrast to cocaine, U69593 attenuated the seizures induced by acute or repeated PTZ administration. Nor-BNI decreased the threshold for PTZ-evoked seizures and increased seizure incidence during the initial induction of kindling relative to controls. Decreased thresholds for PTZ-induced seizures were also observed in KOPr-1 knock out mice. Together, these data demonstrate an involvement of endogenous KOPr systems in modulating vulnerability to the convulsant effects of PTZ but not cocaine. Furthermore, they demonstrate that KOPr-1 activation protects against acute and kindled seizures induced by this convulsant. Finally, the results of our study suggest that KOPr-1 antagonists will not have therapeutic utility against cocaine-induced seizures, while they may prove beneficial in attenuating several actions of cocaine that have been linked to its abuse.

  19. Differential signaling properties at the kappa opioid receptor of 12-epi-salvinorin A and its analogues.

    Science.gov (United States)

    Béguin, Cécile; Potuzak, Justin; Xu, Wei; Liu-Chen, Lee-Yuan; Streicher, John M; Groer, Chad E; Bohn, Laura M; Carlezon, William A; Cohen, Bruce M

    2012-01-15

    The kappa opioid receptor (KOPR) has been identified as a potential drug target to prevent or alter the course of mood, anxiety and addictive disorders or reduce response to stress. In a search for highly potent and selective KOPR partial agonists as pharmacological tools, we have modified 12-epi-salvinorin A, a compound which we have previously observed to be a KOPR partial agonist. Five analogues of 12-epi-salvinorin A were synthesized and their effects on G protein activation as well as β-arrestin2 recruitment were evaluated. Only 12-epi-salvinorin A (1) partially activated signaling through G proteins, yet acted as a full agonist in the β-arrestin 2 DiscoveRx assay. Other salvinorin analogues tested in these functional assays were full agonists in both assays of KOPR activation. By comparison, the non-selective opioid ligand nalbuphine, known to be a partial agonist for G-protein activation, was also a partial agonist for the β-arrestin mediated signaling pathway activated through KOPR.

  20. Localization of the kappa opioid receptor gene to human chromosome band 8q11. 2

    Energy Technology Data Exchange (ETDEWEB)

    Yasuda, Kazuki; Takeda, Jun; Bell, G.I.; Espinosa, R.; Le Beau, M.M. (Univ. of Chicago, IL (United States))

    1994-02-01

    Using the cloned mouse kappa opioid receptor cDNA clone as a probe, screened a human genomic library and isolated a clone containing part of the human kappa opioid receptor gene (OPRK1), designated [lambda]hSR4-1. To determine the chromosomal localization of OPRK1, [lambda]hSR4-1 DNA was labeled with biotin by nick-translation in the presence of bio-11-dUTP and hybridized to human metaphase cells prepared from phytohemagglutinin-stimulated peripheral blood lymphocytes as described previously. Hybridization of the OPRK1-specific probe [lambda]hSR4-1 DNA to normal human metaphase chromosomes resulted in specific labeling only of chromosome 8. Specific labeling of 8q11 was observed on all 4 (6 cells), 3 (9 cells), 2 (9 cells), or 1 (1 cell) chromatid of the chromosome 8 homologs in 25 cells examined. Of 72 signals observed, 70 were located at 8q11. 1 signal was located at 7q11 and at 12p11. In most cells, the signal on 8q was located at 8q11.2. 7 refs., 1 fig.

  1. Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum.

    Science.gov (United States)

    Johnson, Matthew W; MacLean, Katherine A; Reissig, Chad J; Prisinzano, Thomas E; Griffiths, Roland R

    2011-05-01

    Salvinorin A is a potent, selective nonnitrogenous kappa opioid agonist and the known psychoactive constituent of Salvia divinorum, a member of the mint family that has been used for centuries by Mazatec shamans of Mexico for divination and spiritual healing. S. divinorum has over the last several years gained increased popularity as a recreational drug. This is a double-blind, placebo controlled study of salvinorin A in 4 psychologically and physically healthy hallucinogen-using adults. Across sessions, participants inhaled 16 ascending doses of salvinorin A and 4 intermixed placebo doses under comfortable and supportive conditions. Doses ranged from 0.375 μg/kg to 21 μg/kg. Subject-rated drug strength was assessed every 2 min for 60 min after inhalation. Orderly time- and dose-related effects were observed. Drug strength ratings peaked at 2 min (first time point) and definite subjective effects were no longer present at approximately 20 min after inhalation. Dose-related increases were observed on questionnaire measures of mystical-type experience (Mysticism Scale) and subjective effects associated with classic serotonergic (5-HT2(A)) hallucinogens (Hallucinogen Rating Scale). Salvinorin A did not significantly increase heart rate or blood pressure. Participant narratives indicated intense experiences characterized by disruptions in vestibular and interoceptive signals (e.g., change in spatial orientation, pressure on the body) and unusual and sometimes recurring themes across sessions such as revisiting childhood memories, cartoon-like imagery, and contact with entities. Under these prepared and supportive conditions, salvinorin A occasioned a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type effects.

  2. Relative Timing Between Kappa Opioid Receptor Activation and Cocaine Determines the Impact on Reward and Dopamine Release

    Science.gov (United States)

    Chartoff, Elena H; Ebner, Shayla R; Sparrow, Angela; Potter, David; Baker, Phillip M; Ragozzino, Michael E; Roitman, Mitchell F

    2016-01-01

    Negative affective states can increase the rewarding value of drugs of abuse and promote drug taking. Chronic cocaine exposure increases levels of the neuropeptide dynorphin, an endogenous ligand at kappa opioid receptors (KOR) that suppresses dopamine release in the nucleus accumbens (NAc) and elicits negative affective states upon drug withdrawal. However, there is evidence that the effects of KOR activation on affective state are biphasic: immediate aversive effects are followed by delayed increases in reward. The impact of KOR-induced affective states on reward-related effects of cocaine over time is not known. We hypothesize that the initial aversive effects of KOR activation increase, whereas the delayed rewarding effects decrease, the net effects of cocaine on reward and dopamine release. We treated rats with cocaine at various times (15 min to 48 h) after administration of the selective KOR agonist salvinorin A (salvA). Using intracranial self-stimulation and fast scan cyclic voltammetry, we found that cocaine-induced increases in brain stimulation reward and evoked dopamine release in the NAc core were potentiated when cocaine was administered within 1 h of salvA, but attenuated when administered 24 h after salvA. Quantitative real-time PCR was used to show that KOR and prodynorphin mRNA levels were decreased in the NAc, whereas tyrosine hydroxylase and dopamine transporter mRNA levels and tissue dopamine content were increased in the ventral tegmental area 24 h post-salvA. These findings raise the possibility that KOR activation—as occurs upon withdrawal from chronic cocaine—modulates vulnerability to cocaine in a time-dependent manner. PMID:26239494

  3. The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse.

    Science.gov (United States)

    Wee, Sunmee; Koob, George F

    2010-06-01

    Initial hypotheses regarding the role of the kappa opioid system in drug addiction suggested that kappa receptor stimulation had anti-addictive effects. However, recent research suggests that kappa receptor antagonists may reverse motivational aspects of dependence. In the present review, we revisit the studies that measured the effects of kappa receptor ligands on the reinforcing and rewarding effects of drugs and postulate underlying neurobiological mechanisms for these effects to elaborate a more complex view of the role of kappa receptor ligands in drug addiction. The review of studies indicates that kappa receptor stimulation generally antagonizes the acute reinforcing/rewarding effects of drugs whereas kappa receptor blockade has no consistent effect. However, in a drug dependent-like state, kappa receptor blockade was effective in reducing increased drug intake. In animal models of reinstatement, kappa receptor stimulation can induce reinstatement via a stress-like mechanism. Results in conditioned place preference/aversion and intracranial self-stimulation indicate that kappa receptor agonists produce, respectively, aversive-like and dysphoric-like effects. Additionally, preclinical and postmortem studies show that administration or self-administration of cocaine, ethanol, and heroin activate the kappa opioid system. kappa receptor agonists antagonize the reinforcing/rewarding effects of drugs possibly through punishing/aversive-like effects and reinstate drug seeking through stress-like effects. Evidence suggests that abused drugs activate the kappa opioid system, which may play a key role in motivational aspects of dependence. Kappa opioid systems may have an important role in driving compulsive drug intake.

  4. The kappa-opioid receptor is involved in the stimulating effect of nicotine on adrenocortical activity but not in nicotine induced anxiety.

    Science.gov (United States)

    Marco, Eva Maria; Llorente, Ricardo; Pérez-Alvarez, Laura; Moreno, Enrique; Guaza, Carmen; Viveros, Maria Paz

    2005-09-01

    The kappa (kappa) opioid system appears to interact with nicotine in the modulation of locomotion and addiction related processes. In this study we have investigated the possible implication of the kappa-opioid system in the effects of nicotine on anxiety and adrenocortical activity. In two different experiments, we analysed the possible interaction between nicotine (0.5 mg/kg i.p.) and either the kappa-opioid receptor antagonist nor-binaltorphimine (5 mg/kg i.p.) or the kappa-opioid receptor agonist U50,488H (1 mg/kg s.c.). Behavioural and endocrine experiments were performed in different groups of animals. Animals were exposed to the holeboard immediately followed by the plus-maze. Serum corticosterone levels were determined by radioimmunoassay. Nicotine induced an anxiogenic-like effect in the plus-maze and a significant decrease of holeboard activity. The anxiogenic-like effect in the plus-maze was not modified by any of the kappa-opioid receptor ligands. Nicotine also induced a significant increase in the corticosterone levels, and the kappa antagonist, which did not exert any effect per se, antagonised this effect. The kappa-agonist U50,488H induced a significant increase in corticosterone concentration when administered alone. We provide the first evidence for the involvement of the kappa-opioid receptor in the stimulatory effect of nicotine on adrenocortical activity.

  5. Maturational alterations in constitutive activity of medial prefrontal cortex kappa-opioid receptors in Wistar rats.

    Science.gov (United States)

    Sirohi, Sunil; Walker, Brendan M

    2015-11-01

    Opioid receptors can display spontaneous agonist-independent G-protein signaling (basal signaling/constitutive activity). While constitutive κ-opioid receptor (KOR) activity has been documented in vitro, it remains unknown if KORs are constitutively active in native systems. Using [(35) S] guanosine 5'-O-[gamma-thio] triphosphate coupling assay that measures receptor functional state, we identified the presence of medial prefrontal cortex KOR constitutive activity in young rats that declined with age. Furthermore, basal signaling showed an age-related decline and was insensitive to neutral opioid antagonist challenge. Collectively, the present data are first to demonstrate age-dependent alterations in the medial prefrontal cortex KOR constitutive activity in rats and changes in the constitutive activity of KORs can differentially impact KOR ligand efficacy. These data provide novel insights into the functional properties of the KOR system and warrant further consideration of KOR constitutive activity in normal and pathophysiological behavior. Opioid receptors exhibit agonist-independent constitutive activity; however, kappa-opioid receptor (KOR) constitutive activity has not been demonstrated in native systems. Our results confirm KOR constitutive activity in the medial prefrontal cortex (mPFC) that declines with age. With the ability to presynaptically inhibit multiple neurotransmitter systems in the mPFC, maturational or patho-logical alterations in constitutive activity could disrupt corticofugal glutamatergic pyramidal projection neurons mediating executive function. Regulation of KOR constitutive activity could serve as a therapeutic target to treat compromised executive function.

  6. Subadditive withdrawal from cocaine/kappa-opioid agonist combinations in Planaria.

    Science.gov (United States)

    Raffa, Robert B; Stagliano, Gregory W; Tallarida, Ronald J

    2006-10-09

    We have previously developed and extensively characterized a convenient and sensitive metric for the quantification of withdrawal responses using Planaria. Planaria are particularly valuable for these studies because of their permeable exteriors and their relevant neurotransmitter systems (e.g., dopaminergic, opioid, and serotonergic). In the present study, we used this metric and mathematically rigorous joint-action analysis to investigate poly-drug withdrawal from fixed-ratio cocaine/kappa-opioid agonist combinations. The D50 (concentration producing half-maximal effect) for cocaine and U-50,488H was 10.3 and 1.02 microg, respectively. The D50 for 19:1 or 1:19 combinations did not differ significantly (p>0.05) from expected additive values (11.6+/-3.0 vs. 9.9+/-1.4 and 1.1+/-0.2 vs. 1.5+/-0.1, respectively), but the 3:1, 1:1, and 1:3 ratios did (34.5+/-6.9 vs. 7.7+/-1.1; 55.1+/-10.0 vs. 5.7+/-0.7; and 40.8+/-8.9 vs. 3.3+/-0.4, respectively), indicating subadditive interaction at these ratios. The finding of subadditivity in this model suggests that abstinence-induced withdrawal from the combination is less intense than that predicted from the individual drug potencies. The concept that certain combinations of drugs leads to attenuated withdrawal might generalize to humans.

  7. Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A.

    Science.gov (United States)

    Cunningham, Christopher W; Rothman, Richard B; Prisinzano, Thomas E

    2011-06-01

    Salvia divinorum is a perennial sage native to Oaxaca, Mexico, that has been used traditionally in divination rituals and as a treatment for the "semimagical" disease panzón de borrego. Because of the intense "out-of-body" experiences reported after inhalation of the pyrolized smoke, S. divinorum has been gaining popularity as a recreational hallucinogen, and the United States and several other countries have regulated its use. Early studies isolated the neoclerodane diterpene salvinorin A as the principal psychoactive constituent responsible for these hallucinogenic effects. Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of KOP receptors, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because 1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and 2) its effects are not mediated by the 5-HT(2A) receptor, the classic target of hallucinogens such as lysergic acid diethylamide and mescaline. Rigorous investigation into the structural features of salvinorin A responsible for opioid receptor affinity and selectivity has produced numerous receptor probes, affinity labels, and tools for evaluating the biological processes responsible for its observed psychological effects. Salvinorin A has therapeutic potential as a treatment for pain, mood and personality disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloids are potential scaffolds for drug development for aminergic G-protein coupled receptors.

  8. Effects of kappa-opioid receptor ligands on intracranial self-stimulation in rats.

    Science.gov (United States)

    Todtenkopf, Mark S; Marcus, Jacqueline F; Portoghese, Philip S; Carlezon, William A

    2004-04-01

    Elevations in cAMP response element binding protein (CREB) function within the mesolimbic system of rats reduce cocaine reward in place conditioning studies and increase immobility in the forced swim test. Each of these behavioral adaptations can be interpreted as a depressive-like effect (i.e., anhedonia, despair) that may reflect reduced activity of brain reward systems. Furthermore, each effect appears due to increases in CREB-mediated expression of dynorphin, since each is attenuated by intracranial injections of the kappa-opioid receptor antagonist norBNI. Intracranial self-stimulation (ICSS) studies were conducted in rats to determine whether administration of a kappa-agonist would have depressive-like effects on brain stimulation reward, and whether pretreatment with a kappa-antagonist would attenuate any such effects. Conditions that have depressive effects in people (e.g., drug withdrawal) increase the threshold amounts of stimulation required to sustain ICSS in rats. Sprague-Dawley rats with lateral hypothalamic stimulating electrodes were tested in a "curve-shift" variant of the ICSS procedure after systemic administration of the kappa-agonist U-69593 alone, the novel kappa-antagonist 5'-acetamidinoethylnaltrindole (ANTI) alone, or co-administration of both drugs. U-69593 dose dependently increased ICSS thresholds, suggesting that activation of kappa-receptors reduced the rewarding impact of the brain stimulation. ANTI had no effects on its own, but it attenuated increases in ICSS thresholds caused by the agonist. These data provide further evidence that stimulation of brain kappa-receptors may trigger certain depressive-like signs, and that kappa antagonists may have efficacy as antidepressants without having reward-related actions of their own.

  9. Regional haemodynamic effects of mu-, delta-, and kappa-opioid agonists microinjected into the hypothalamic paraventricular nuclei of conscious, unrestrained rats.

    Science.gov (United States)

    Bachelard, H; Pître, M

    1995-06-01

    1. The cardiovascular effects of bilateral injection into the hypothalamic paraventricular nuclei of selective mu-, delta-, and kappa-opioid receptor agonists were investigated in conscious, unrestrained Wistar Kyoto rats, chronically instrumented with pulsed Doppler flow probes for measurement of regional haemodynamics. 2. The selective mu-agonist [D-Ala2,MePhe4,Gly5ol]enkephalin (DAMGO), injected bilaterally into the hypothalamic paraventricular nuclei (0.01-1.0 nmol), caused increases in blood pressure, tachycardias, vasoconstriction in renal and superior mesenteric vascular beds and substantial vasodilatation in the hindquarter vascular bed. 3. The administration of increasing doses (0.01-5.0 nmol) of the selective delta-agonist [D-Phe2,5]enkephalin (DPDPE) or the selective kappa-agonist, U50488H into the paraventricular nuclei (PVN) had no significant effect on blood pressure, heart rate, or regional haemodynamics. 4. Together, the present results are further evidence of a role for opioid peptides, especially acting at mu-receptors in the PVN, in the central regulation of the cardiovascular system, whereas a role for opioid peptides, acting at delta- and kappa-receptors in the PVN, seems less obvious from the present results.

  10. 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

  11. Upregulation of the kappa opioidergic system in left ventricular rat myocardium in response to volume overload: Adaptive changes of the cardiac kappa opioid system in heart failure.

    Science.gov (United States)

    Treskatsch, Sascha; Shaqura, Mohammed; Dehe, Lukas; Feldheiser, Aarne; Roepke, Torsten K; Shakibaei, Mehdi; Spies, Claudia D; Schäfer, Michael; Mousa, Shaaban A

    2015-12-01

    Opioids have long been known for their analgesic effects and are therefore widely used in anesthesia and intensive care medicine. However, in the last decade research has focused on the opioidergic influence on cardiovascular function. This project thus aimed to detect the precise cellular localization of kappa opioid receptors (KOR) in left ventricular cardiomyocytes and to investigate putative changes in KOR and its endogenous ligand precursor peptide prodynorphin (PDYN) in response to heart failure. After IRB approval, heart failure was induced using a modified infrarenal aortocaval fistula (ACF) in male Wistar rats. All rats of the control and ACF group were characterized by their morphometrics and hemodynamics. In addition, the existence and localization as well as adaptive changes of KOR and PDYN were investigated using radioligand binding, double immunofluorescence confocal analysis, RT-PCR and Western blot. Similar to the brain and spinal cord, [(3)H]U-69593 KOR selective binding sites were detected the left ventricle (LV). KOR colocalized with Cav1.2 of the outer plasma membrane and invaginated T-tubules and intracellular with the ryanodine receptor of the sarcoplasmatic reticulum. Interestingly, KOR could also be detected in mitochondria of rat LV cardiomyocytes. As a consequence of heart failure, KOR and PDYN were up-regulated on the mRNA and protein level in the LV. These findings suggest that the cardiac kappa opioidergic system might modulate rat cardiomyocyte function during heart failure.

  12. Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa Opioid Agonist with Enhanced Metabolic Stability.

    Science.gov (United States)

    Sherwood, Alexander M; Crowley, Rachel Saylor; Paton, Kelly F; Biggerstaff, Andrew; Neuenswander, Benjamin; Day, Victor W; Kivell, Bronwyn M; Prisinzano, Thomas E

    2017-04-04

    Previous structure-activity studies on the neoclerodane diterpenoid salvinorin A have demonstrated the importance of the acetoxy functionality on the A-ring in its activity as a kappa opioid receptor agonist. Few studies have focused on understanding the role of conformation in these interactions. Herein we describe the synthesis and evaluation of both flexible and conformationally restricted compounds derived from salvinorin A. One such compound, spirobutyrolactone (14), was synthesized in a single step from salvinorin B and had similar potency and selectivity to salvinorin A (EC50 = 0.6 ± 0.2 nM at κ >10,000 nM at μ and δ). Microsomal stability studies demonstrated that 14 was more metabolically resistant than salvinorin A. Evaluation of analgesic and anti-inflammatory properties revealed similar in vivo effects between 14 and salvinorin A. To our knowledge, this study represents the first example of bioisosteric replacement of an acetate group by a spirobutyrolactone to produce a metabolically resistant derivative.

  13. Complete knockout of the nociceptin/orphanin FQ receptor in the rat does not induce compensatory changes in mu, delta and kappa opioid receptors.

    NARCIS (Netherlands)

    Homberg, J.R.; Mul, J.D.; Wit, E. de; Cuppen, E.

    2009-01-01

    The nociceptin/orphanin FQ (N/OFQ) opioid peptide receptor (NOPr) is a new member of the opioid receptor family consisting of mu, delta and kappa opioid receptors. The anti-opioid properties of its endogenous ligand, N/OFQ provide the receptor interesting potentials in symptoms and processes related

  14. Complete knockout of the nociceptin/orphanin FQ receptor in the rat does not induce compensatory changes in mu, delta and kappa opioid receptors.

    NARCIS (Netherlands)

    Homberg, J.R.; Mul, J.D.; de Wit, E.; Cuppen, E.

    2009-01-01

    The nociceptin/orphanin FQ (N/OFQ) opioid peptide receptor (NOPr) is a new member of the opioid receptor family consisting of mu, delta and kappa opioid receptors. The anti-opioid properties of its endogenous ligand, N/OFQ provide the receptor interesting potentials in symptoms and processes related

  15. Kappa opioid receptor antagonist and N-methyl-D- aspartate receptor antagonist affect dynorphin- induced spinal cord electrophysiologic impairment

    Institute of Scientific and Technical Information of China (English)

    Yu Chen; Liangbi Xiang; Jun Liu; Dapeng Zhou; Hailong Yu; Qi Wang; Wenfeng Han; Weijian Ren

    2012-01-01

    The latencies of motor- and somatosensory-evoked potentials were prolonged to different degrees, and wave amplitude was obviously decreased, after injection of dynorphin into the rat subarachnoid cavity.The wave amplitude and latencies of motor- and somatosensory-evoked potentials were significantly recovered at 7 and 14 days after combined injection of dynorphin and either the kappa opioid receptor antagonist nor-binaltorphimine or the N-methyl-D-aspartate receptor antagonist MK-801.The wave amplitude and latency were similar in rats after combined injection of dynorphin and nor-binaltorphimine or MK-801.These results suggest that intrathecal injection of dynorphin causes damage to spinal cord function.Prevention of N-methyl-D-aspartate receptor or kappa receptor activation lessened the injury to spinal cord function induced by dynorphin.

  16. New neoclerodane diterpenoids isolated from the leaves of Salvia divinorum and their binding affinities for human kappa opioid receptors.

    Science.gov (United States)

    Lee, David Y W; Ma, Zhongze; Liu-Chen, Lee-Yuan; Wang, Yulin; Chen, Yong; Carlezon, William A; Cohen, Bruce

    2005-10-01

    Bioactivity-guided fractionation of the leaves of Salvia divinorum has resulted in the isolation of three new neoclerodane diterpenoids: divinatorin D (1), divinatorin E (2), and salvinorin G (3), together with 10 known terpenoids, divinatorin C (4), hardwickiic acid (5), salvinorin-A (6), -B (7), -C (8), -D (9), -E (10), and -F (11), presqualene alcohol (12), and (E)-phytol (13). The structures of these three new compounds were characterized by spectroscopic methods. All these compounds were evaluated for their binding affinities to the human kappa opioid receptors. In comparison with divinatorin D (1), divinatorin E (2), and salvinorin G (3), salvinorin A (6) is still the most potent kappa agonist.

  17. Structure-based design, synthesis, and biochemical and pharmacological characterization of novel salvinorin A analogues as active state probes of the kappa-opioid receptor.

    Science.gov (United States)

    Yan, Feng; Bikbulatov, Ruslan V; Mocanu, Viorel; Dicheva, Nedyalka; Parker, Carol E; Wetsel, William C; Mosier, Philip D; Westkaemper, Richard B; Allen, John A; Zjawiony, Jordan K; Roth, Bryan L

    2009-07-28

    Salvinorin A, the most potent naturally occurring hallucinogen, has attracted an increasing amount of attention since the kappa-opioid receptor (KOR) was identified as its principal molecular target by us [Roth, B. L., et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 11934-11939]. Here we report the design, synthesis, and biochemical characterization of novel, irreversible, salvinorin A-derived ligands suitable as active state probes of the KOR. On the basis of prior substituted cysteine accessibility and molecular modeling studies, C315(7.38) was chosen as a potential anchoring point for covalent labeling of salvinorin A-derived ligands. Automated docking of a series of potential covalently bound ligands suggested that either a haloacetate moiety or other similar electrophilic groups could irreversibly bind with C315(7.38). 22-Thiocyanatosalvinorin A (RB-64) and 22-chlorosalvinorin A (RB-48) were both found to be extraordinarily potent and selective KOR agonists in vitro and in vivo. As predicted on the basis of molecular modeling studies, RB-64 induced wash-resistant inhibition of binding with a strict requirement for a free cysteine in or near the binding pocket. Mass spectrometry (MS) studies utilizing synthetic KOR peptides and RB-64 supported the hypothesis that the anchoring residue was C315(7.38) and suggested one biochemical mechanism for covalent binding. These studies provide direct evidence of the presence of a free cysteine in the agonist-bound state of the KOR and provide novel insights into the mechanism by which salvinorin A binds to and activates the KOR.

  18. Functional Stability of the Human Kappa Opioid Receptor Reconstituted in Nanodiscs Revealed by a Time-Resolved Scintillation Proximity Assay

    Science.gov (United States)

    Hansen, Randi Westh; Wang, Xiaole; Golab, Agnieszka; Bornert, Olivier; Oswald, Christine; Wagner, Renaud; Martinez, Karen Laurence

    2016-01-01

    Long-term functional stability of isolated membrane proteins is crucial for many in vitro applications used to elucidate molecular mechanisms, and used for drug screening platforms in modern pharmaceutical industry. Compared to soluble proteins, the understanding at the molecular level of membrane proteins remains a challenge. This is partly due to the difficulty to isolate and simultaneously maintain their structural and functional stability, because of their hydrophobic nature. Here we show, how scintillation proximity assay can be used to analyze time-resolved high-affinity ligand binding to membrane proteins solubilized in various environments. The assay was used to establish conditions that preserved the biological function of isolated human kappa opioid receptor. In detergent solution the receptor lost high-affinity ligand binding to a radiolabelled ligand within minutes at room temperature. After reconstitution in Nanodiscs made of phospholipid bilayer the half-life of high-affinity ligand binding to the majority of receptors increased 70-fold compared to detergent solubilized receptors—a level of stability that is appropriate for further downstream applications. Time-resolved scintillation proximity assay has the potential to screen numerous conditions in parallel to obtain high levels of stable and active membrane proteins, which are intrinsically unstable in detergent solution, and with minimum material consumption. PMID:27035823

  19. Neocortical prodynorphin expression is transiently increased with learning: Implications for time- and learning-dependent neocortical kappa opioid receptor activation.

    Science.gov (United States)

    Loh, Ryan; Collins, Sean; Galvez, Roberto

    2017-09-29

    There are several lines of evidence that indicate a prominent role for the opioid system in the acquisition and consolidation of learned associations. Specifically, kappa opioid receptor (KOR) modulation has been demonstrated to alter various behavioral tasks including whisker trace eyeblink conditioning (WTEB). WTEB is an associative conditioning paradigm in which a neutral conditioned stimulus (CS; Whisker stimulation) is paired following a short stimulus free trace interval with a salient unconditioned stimulus that elicits a blink response (US; Eye shock). Work from our laboratory has shown that WTEB conditioning is dependent upon and induces plasticity in primary somatosensory cortex (S1), a likely site for memory storage. Our subsequent studies have shown that WTEB acquisition or consolidation are impaired when the initial or later phase of KOR activation in S1 is respectively blocked. Interestingly, this mechanism by which KOR is activated in S1 during learning remains unexplored. Dynorphin (DYN), KOR's endogenous ligand, is synthesized from the precursor prodynorphin (PD) that is synthesized from preprodynorphin (PPD). In S1, most PPD is found in inhibitory GABAergic somatostatin interneurons (SOM), suggesting that these SOM interneurons are upstream regulators of learning induced KOR activation. Using immunofluorescence to investigate the expression of PD and SOM, the current study found that PD/SOM expression was transiently increased in S1 during learning. Interestingly, these findings have direct implications towards a time- and learning-dependent role for KOR activation in neocortical mechanisms mediating learning. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Stress-induced enhancement of ethanol intake in C57BL/6J mice with a history of chronic ethanol exposure: Involvement of kappa opioid receptors

    Directory of Open Access Journals (Sweden)

    Rachel Ivy Anderson

    2016-02-01

    Full Text Available Our laboratory has previously demonstrated that daily forced swim stress (FSS prior to ethanol drinking sessions facilitates enhanced ethanol consumption in mice with a history of chronic intermittent ethanol (CIE vapor exposure without altering ethanol intake in air-exposed controls. Because both stress and chronic ethanol exposure have been shown to activate the dynorphin/kappa opioid receptor (KOR system, the present study was designed to explore a potential role for KORs in modulating stress effects on ethanol consumption in the CIE model of dependence and relapse drinking. After stable baseline ethanol intake was established in adult male C57BL/6J mice, subjects received chronic intermittent exposure (16 hr/day x 4 days/week to ethanol vapor (CIE group or air (CTL group. Weekly cycles of inhalation exposure were alternated with 5-day limited access drinking tests (1 hour access to 15% ethanol. Experiment 1 compared effects of daily FSS and KOR activation on ethanol consumption. CIE and CTL mice were either exposed to FSS (10 min, the KOR agonist U50,488 (5 mg/kg, or a vehicle injection (non-stressed condition prior to each daily drinking session during test weeks. FSS selectively increased drinking in CIE mice. U50,488 mimicked this effect in CIE mice, but also increased drinking in CTL mice. Experiment 2 assessed effects of KOR blockade on stress-induced drinking in CIE and CTL mice. Stressed and non-stressed mice were administered the short-acting KOR antagonist LY2444296 (0 or 5 mg/kg 30 min prior to each drinking session during test weeks. FSS selectively increased ethanol consumption in CIE mice, an effect that was abolished by LY2444296 pretreatment. In Experiment 3, CIE and CTL mice were administered one of four doses of U50,488 (0,1.25, 2.5, 5.0 mg/kg one hour prior to each daily drinking test (in lieu of FSS. All doses of U50,488 increased ethanol consumption in both CIE and CTL mice. The U50,488-induced increase in drinking was

  1. Synergistic antidepressant-like effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test.

    Science.gov (United States)

    Huang, Peng; Tunis, Julia; Parry, Christopher; Tallarida, Ronald; Liu-Chen, Lee-Yuan

    2016-06-15

    Kappa opioid (KOP) receptor antagonists and delta opioid (DOP) receptor agonists have antidepressant-like effects in animal tests and may be useful for treatment-resistant depression in humans. In this study, we examined whether the combination of a KOP receptor antagonist and a DOP receptor agonist would produce a better than additive effect (i.e. synergy). LY2444296 is a short-acting selective nonpeptide KOP receptor antagonist. ADL5859 is a selective nonpeptide DOP receptor agonist which does not produce seizures and EEG disturbances. Each compound and combinations of the two were examined in the forced swim test (FST) one h post injection, a screening test for antidepressant-like effect, in male adult C57BL/6J mice (Jackson Lab). LY2444296 [subcutaneous (s.c.) injection] at 10 and 30mg/kg, but not 3mg/kg, significantly decreased immobility time in a dose-dependent manner. Intraperitoneal (i.p.) injections of ADL5859 also reduced immobility time dose-dependently at doses of 3 and 10mg/kg, but not at 1mg/kg. An analysis was conducted using the method of Tallarida and Raffa (2010), which employed dose equivalence. The relative potency of the drugs was determined to be LY2444296: ADL5859=1:0.28, which was the dose ratio for combination studies. Six combinations of the two compounds were tested in mice at a fixed dose ratio. We found that LY2444296 and ADL5859 yielded significant synergistic effects for the antidepressant-like effect at the combined dose ranging from 3.84mg/kg to 9.0mg/kg. ADL5859 (10mg/kg), LY2444296 (30mg/kg) and their combined dose (3.84mg/kg) had no effects on locomotor activities. Since the two drugs have distinct pharmacological profiles, such a synergism will allow use of lower doses of both drugs to achieve desired antidepressant effects with fewer side effects.

  2. Switch from excitatory to inhibitory actions of ethanol on dopamine levels after chronic exposure: Role of kappa opioid receptors.

    Science.gov (United States)

    Karkhanis, Anushree N; Huggins, Kimberly N; Rose, Jamie H; Jones, Sara R

    2016-11-01

    Acute ethanol exposure is known to stimulate the dopamine system; however, chronic exposure has been shown to downregulate the dopamine system. In rodents, chronic intermittent exposure (CIE) to ethanol also increases negative affect during withdrawal, such as, increases in anxiety- and depressive-like behavior. Moreover, CIE exposure results in increased ethanol drinking and preference during withdrawal. Previous literature documents reductions in CIE-induced anxiety-, depressive-like behaviors and ethanol intake in response to kappa opioid receptor (KOR) blockade. KORs are located on presynaptic dopamine terminals in the nucleus accumbens (NAc) and inhibit release, an effect which has been linked to negative affective behaviors. Previous reports show an upregulation in KOR function following extended CIE exposure; however it is not clear whether there is a direct link between KOR upregulation and dopamine downregulation during withdrawal from CIE. This study aimed to examine the effects of KOR modulation on dopamine responses to ethanol of behaving mice exposed to air or ethanol vapor in a repeated intermittent pattern. First, we showed that KORs have a greater response to an agonist after moderate CIE compared to air exposed mice using ex vivo fast scan cyclic voltammetry. Second, using in vivo microdialysis, we showed that, in contrast to the expected increase in extracellular levels of dopamine following an acute ethanol challenge in air exposed mice, CIE exposed mice exhibited a robust decrease in dopamine levels. Third, we showed that blockade of KORs reversed the aberrant inhibitory dopamine response to ethanol in CIE exposed mice while not affecting the air exposed mice demonstrating that inhibition of KORs "rescued" dopamine responses in CIE exposed mice. Taken together, these findings indicate that augmentation of dynorphin/KOR system activity drives the reduction in stimulated (electrical and ethanol) dopamine release in the NAc. Thus, blockade of

  3. Salvinorin A inhibits colonic transit and neurogenic ion transport in mice by activating kappa-opioid and cannabinoid receptors.

    Science.gov (United States)

    Fichna, J; Schicho, R; Andrews, C N; Bashashati, M; Klompus, M; McKay, D M; Sharkey, K A; Zjawiony, J K; Janecka, A; Storr, M A

    2009-12-01

    The major active ingredient of the plant Salvia divinorum, salvinorin A (SA) has been used to treat gastrointestinal (GI) symptoms. As the action of SA on the regulation of colonic function is unknown, our aim was to examine the effects of SA on mouse colonic motility and secretion in vitro and in vivo. The effects of SA on GI motility were studied using isolated preparations of colon, which were compared with preparations from stomach and ileum. Colonic epithelial ion transport was evaluated using Ussing chambers. Additionally, we studied GI motility in vivo by measuring colonic propulsion, gastric emptying, and upper GI transit. Salvinorin A inhibited contractions of the mouse colon, stomach, and ileum in vitro, prolonged colonic propulsion and slowed upper GI transit in vivo. Salvinorin A had no effect on gastric emptying in vivo. Salvinorin A reduced veratridine-, but not forskolin-induced epithelial ion transport. The effects of SA on colonic motility in vitro were mediated by kappa-opioid receptors (KORs) and cannabinoid (CB) receptors, as they were inhibited by the antagonists nor-binaltorphimine (KOR), AM 251 (CB(1) receptor) and AM 630 (CB(2) receptor). However, in the colon in vivo, the effects were largely mediated by KORs. The effects of SA on veratridine-mediated epithelial ion transport were inhibited by nor-binaltorphimine and AM 630. Salvinorin A slows colonic motility in vitro and in vivo and influences neurogenic ion transport. Due to its specific regional action, SA or its derivatives may be useful drugs in the treatment of lower GI disorders associated with increased GI transit and diarrhoea.

  4. Kinetic modeling of 11C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans

    OpenAIRE

    Naganawa, Mika; Zheng, Ming-Qiang; Nabulsi, Nabeel; Tomasi, Giampaolo; Henry, Shannan; Lin, Shu-Fei; Ropchan, Jim; Labaree, David; Tauscher, Johannes; Neumeister, Alexander; Carson, Richard E.; Huang, Yiyun

    2014-01-01

    11C-LY2795050 is a novel kappa opioid receptor (KOR) antagonist tracer for positron emission tomography (PET) imaging. The purpose of this first-in-human study was to determine the optimal kinetic model for analysis of 11C-LY2795050 imaging data. Sixteen subjects underwent baseline scans and blocking scans after oral naltrexone. Compartmental modeling and multilinear analysis-1 (MA1) were applied using the arterial input functions. Two-tissue compartment model and MA1 were found to be the bes...

  5. A novel, potent, oral active and safe antinociceptive pyrazole targeting kappa opioid receptors.

    Science.gov (United States)

    Trevisan, Gabriela; Rossato, Mateus F; Walker, Cristiani I B; Oliveira, Sara M; Rosa, Fernanda; Tonello, Raquel; Silva, Cássia R; Machado, Pablo; Boligon, Aline A; Martins, Marcos A P; Zanatta, Nilo; Bonacorso, Hélio G; Athayde, Margareth L; Rubin, Maribel A; Calixto, João B; Ferreira, Juliano

    2013-10-01

    Pyrazole compounds are an intriguing class of compounds with potential analgesic activity; however, their mechanism of action remains unknown. Thus, the goal of this study was to explore the antinociceptive potential, safety and mechanism of action of novel 1-pyrazole methyl ester derivatives, which were designed by molecular simplification, using in vivo and in vitro methods in mice. First, tree 1-pyrazole methyl ester derivatives (DMPE, MPFE, and MPCIE) were tested in the capsaicin test and all presented antinociceptive effect; however the MPClE (methyl 5-trichloromethyl-3-methyl-1H-pyrazole-1-carboxylate) was the most effective. Thus, we selected this compound to assess the effects and mechanisms in subsequent pain models. MPCIE produced antinociception when administered by oral, intraperitoneal, intrathecal and intraplantar routes and was effective in the capsaicin and the acetic acid-induced nociception tests. Moreover, this compound reduced the hyperalgesia in diverse clinically-relevant pain models, including postoperative, inflammatory, and neuropathic nociception in mice. The antinociception produced by orally administered MPClE was mediated by κ-opioid receptors, since these effects were prevented by systemically pre-treatment with naloxone and the κ-opioid receptor antagonist nor-binaltorphimine. Moreover, MPCIE prevented binding of the κ-opioid ligand [(3)H]-CI-977 in vitro (IC₅₀ of 0.68 (0.32-1.4) μM), but not the TRPV1 ([(3)H]-resiniferatoxin) or the α₂-adrenoreceptor ([(3)H]-idazoxan) binding. Regarding the drug-induced side effects, oral administration of MPClE did not produce sedation, constipation or motor impairment at its active dose. In addition, MPCIE was readily absorbed after oral administration. Taken together, these results demonstrate that MPClE is a novel, potent, orally active and safe analgesic drug that targets κ-opioid receptors.

  6. Receptor-selective changes in mu-, delta- and kappa-opioid receptors after chronic naltrexone treatment in mice

    NARCIS (Netherlands)

    Lesscher, HMB; Bailey, Alexis; Burbach, JPH; van Ree, JM; Kitchen, [No Value; Gerrits, MAFM

    2003-01-01

    Chronic treatment with the opioid antagonist naltrexone induces functional supersensitivity to opioid agonists, which may be explained by receptor up-regulation induced by opioid receptor blockade. In the present study, the levels of opioid receptor subtypes through the brain of mice were determined

  7. Receptor-selective changes in mu-, delta- and kappa-opioid receptors after chronic naltrexone treatment in mice

    NARCIS (Netherlands)

    Lesscher, HMB; Bailey, Alexis; Burbach, JPH; van Ree, JM; Kitchen, [No Value; Gerrits, MAFM

    Chronic treatment with the opioid antagonist naltrexone induces functional supersensitivity to opioid agonists, which may be explained by receptor up-regulation induced by opioid receptor blockade. In the present study, the levels of opioid receptor subtypes through the brain of mice were determined

  8. Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans.

    Science.gov (United States)

    Butelman, Eduardo R; Mandau, Marek; Tidgewell, Kevin; Prisinzano, Thomas E; Yuferov, Vadim; Kreek, Mary Jeanne

    2007-01-01

    This study focused on the in vivo effects of the kappa-opioid hallucinogen salvinorin A, derived from the plant Salvia divinorum. The effects of salvinorin A (0.0032-0.056 mg/kg i.v.) were studied in a neuroendocrine biomarker assay of the anterior pituitary hormone prolactin in gonadally intact, adult male and female rhesus monkeys (n = 4 each). Salvinorin A produced dose- and time-dependent neuroendocrine effects, similar to the synthetic high-efficacy kappa-agonist U69,593 ((+)-(5alpha,7 alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiniyl)-1-oxaspiro[4.5]dec-8yl]-benzeneacetamide), but of shorter duration than the latter. Salvinorin A was approximately equipotent to U69,593 in this endpoint (salvinorin A ED50, 0.015 mg/kg; U69,593 ED(50), 0.0098 mg/kg). The effects of i.v. salvinorin A were not prevented by a small dose of the opioid antagonist nalmefene (0.01 mg/kg s.c.) but were prevented by a larger dose of nalmefene (0.1 mg/kg); the latter nalmefene dose is sufficient to produce kappa-antagonist effects in this species. In contrast, the 5HT2 receptor antagonist ketanserin (0.1 mg/kg i.m.) did not prevent the effects of salvinorin A. As expected, the neuroendocrine effects of salvinorin A (0.0032 mg/kg i.v.) were more robust in female than in male subjects. Related studies focused on full-length cloning of the coding region of the rhesus monkey kappa-opioid receptor (OPRK1) gene and revealed a high homology of the nonhuman primate OPRK1 gene compared with the human OPRK1 gene, including particular C-terminal residues thought to be involved in receptor desensitization and internalization. The present studies indicate that the hallucinogen salvinorin A acts as a high-efficacy kappa-agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay.

  9. Kinetic modeling of (11)C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans.

    Science.gov (United States)

    Naganawa, Mika; Zheng, Ming-Qiang; Nabulsi, Nabeel; Tomasi, Giampaolo; Henry, Shannan; Lin, Shu-Fei; Ropchan, Jim; Labaree, David; Tauscher, Johannes; Neumeister, Alexander; Carson, Richard E; Huang, Yiyun

    2014-11-01

    (11)C-LY2795050 is a novel kappa opioid receptor (KOR) antagonist tracer for positron emission tomography (PET) imaging. The purpose of this first-in-human study was to determine the optimal kinetic model for analysis of (11)C-LY2795050 imaging data. Sixteen subjects underwent baseline scans and blocking scans after oral naltrexone. Compartmental modeling and multilinear analysis-1 (MA1) were applied using the arterial input functions. Two-tissue compartment model and MA1 were found to be the best models to provide reliable measures of binding parameters. The rank order of (11)C-LY2795050 distribution volume (VT) matched the known regional KOR densities in the human brain. Blocking scans with naltrexone indicated no ideal reference region for (11)C-LY2795050. Three methods for calculation of the nondisplaceable distribution volume (VND) were assessed: (1) individual VND estimated from naltrexone occupancy plots, (2) mean VND across subjects, and (3) a fixed fraction of cerebellum VT. Approach (3) produced the lowest intersubject variability in the calculation of binding potentials (BPND, BPF, and BPP). Therefore, binding potentials of (11)C-LY2795050 can be determined if the specific binding fraction in the cerebellum is presumed to be unchanged by diseases and experimental conditions. In conclusion, results from the present study show the suitability of (11)C-LY2795050 to image and quantify KOR in humans.

  10. Kinetic modeling of 11C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans

    Science.gov (United States)

    Naganawa, Mika; Zheng, Ming-Qiang; Nabulsi, Nabeel; Tomasi, Giampaolo; Henry, Shannan; Lin, Shu-Fei; Ropchan, Jim; Labaree, David; Tauscher, Johannes; Neumeister, Alexander; Carson, Richard E; Huang, Yiyun

    2014-01-01

    11C-LY2795050 is a novel kappa opioid receptor (KOR) antagonist tracer for positron emission tomography (PET) imaging. The purpose of this first-in-human study was to determine the optimal kinetic model for analysis of 11C-LY2795050 imaging data. Sixteen subjects underwent baseline scans and blocking scans after oral naltrexone. Compartmental modeling and multilinear analysis-1 (MA1) were applied using the arterial input functions. Two-tissue compartment model and MA1 were found to be the best models to provide reliable measures of binding parameters. The rank order of 11C-LY2795050 distribution volume (VT) matched the known regional KOR densities in the human brain. Blocking scans with naltrexone indicated no ideal reference region for 11C-LY2795050. Three methods for calculation of the nondisplaceable distribution volume (VND) were assessed: (1) individual VND estimated from naltrexone occupancy plots, (2) mean VND across subjects, and (3) a fixed fraction of cerebellum VT. Approach (3) produced the lowest intersubject variability in the calculation of binding potentials (BPND, BPF, and BPP). Therefore, binding potentials of 11C-LY2795050 can be determined if the specific binding fraction in the cerebellum is presumed to be unchanged by diseases and experimental conditions. In conclusion, results from the present study show the suitability of 11C-LY2795050 to image and quantify KOR in humans. PMID:25182664

  11. Comparison of the diuretic effects of chemically diverse kappa opioid agonists in rats: nalfurafine, U50,488H, and salvinorin A.

    Science.gov (United States)

    Inan, S; Lee, D Y-W; Liu-Chen, L Y; Cowan, A

    2009-03-01

    Kappa opioid receptor agonists induce water diuresis in animals and humans. We investigated the effects of s.c. nalfurafine, U50,488H, salvinorin A, and its longer-acting analog, 2-methoxymethyl-salvinorin B (MOM-sal B), on urinary output and sodium excretion over 5 h in euvolemic rats. Nalfurafine (0.005-0.02 mg/kg), U50,488H (0.1-10 mg/kg), and MOM-sal B (0.625-5 mg/kg) induced diuresis dose-dependently. Systemically (0.1-10 mg/kg) or centrally (50 microg, i.c.v.) administered salvinorin A was ineffective. 5'-Guanidinonaltrindole, a kappa receptor antagonist, inhibited nalfurafine- and MOM-sal B-induced diuresis. Nalfurafine and MOM-sal B had no effect on arginine vasopressin levels, measured at 2 h. Tolerance did not develop to the diuresis accompanying subchronic administration of nalfurafine (0.02 mg/kg). On the basis of our work, we (a) promote nalfurafine as a candidate diuretic to relieve water retention and (b) highlight salvinorin A as a kappa agonist that does not cause diuresis, probably because of its short duration of action.

  12. Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors in vitro and their antipruritic and antinociceptive activities in vivo.

    Science.gov (United States)

    Wang, Yulin; Tang, Kang; Inan, Saadet; Siebert, Daniel; Holzgrabe, Ulrike; Lee, David Y W; Huang, Peng; Li, Jian-Guo; Cowan, Alan; Liu-Chen, Lee-Yuan

    2005-01-01

    Salvinorin A, TRK-820 (17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride), and 3FLB (diethyl 2,4-di-[3-fluorophenyl]-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane-9-one-1,5-dicarboxylate) are structurally distinctly different from U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate], the prototypic selective kappa agonist. Here, we investigated their in vitro pharmacological activities on receptors expressed in Chinese hamster ovary cells and in vivo antiscratch and antinociceptive activities in mice. All three compounds showed high selectivity for the kappa opioid receptor (KOR) over the mu opioid receptor (MOR) and delta opioid receptor (DOR) and nociceptin or orphanin FQ receptors. In the guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding assay, all three were full agonists on the KOR. The rank order of affinity and potency for the KOR was TRK-820 > U50,488H approximately salvinorin A > 3FLB. TRK-820 acted as a partial agonist on MOR and DOR, whereas salvinorin A and 3FLB showed no activities on these receptors. Salvinorin A, TRK-820, and 3FLB caused internalization of the human KOR in a dose-dependent manner. Interestingly, although salvinorin A and U50,488H had similar potencies in stimulating [(35)S]GTPgammaS binding, salvinorin A was about 40-fold less potent than U50,488H in promoting internalization. Following 4-h incubation, all three compounds induced down-regulation of the human KOR, with salvinorin A causing a lower extent of down-regulation. Although TRK-820 was potent and efficacious against compound 48/80-induced scratching, salvinorin A showed low and inconsistent effects, and 3FLB was inactive. In addition, salvinorin A and 3FLB were not active in the acetic acid abdominal constriction test. The discrepancy between in vitro and in vivo results may be due to in vivo metabolism of salvinorin A and 3FLB and

  13. Prenatal exposure to vanilla or alcohol induces crawling after these odors in the neonate rat: The role of mu and kappa opioid receptor systems.

    Science.gov (United States)

    Gaztañaga, Mirari; Aranda-Fernández, P Ezequiel; Chotro, M Gabriela

    2015-09-01

    Rat fetuses can perceive chemosensory stimuli derived from their mother's diet, and they may learn about those stimuli. In previous studies we have observed that prenatal exposure to alcohol during the last days of gestation increases the acceptance and liking of an alcohol flavor in infant and adolescent rats. While these results were not found after prenatal exposure to vanilla, cineole or anise, suggesting that the pharmacological properties of alcohol, mediated by the opioid system, underlie the effects observed with this drug. Considering that other studies report enhanced acceptance of non-alcohol flavors experienced prenatally when subjects were tested before infancy, we explore the possibility of observing similar results if testing 1-day old rats exposed prenatally to vanilla. Using an "odor-induced crawling" testing procedure, it was observed that neonates exposed prenatally to vanilla or alcohol crawl for a longer distance towards the experienced odor than to other odors or than control pups. Blocking mu, but not kappa opioid receptors, reduced the attraction of vanilla odor to neonates exposed to vanilla in utero, while the response to alcohol in pups exposed prenatally to this drug was affected by both antagonists. Results confirm that exposure to a non-alcohol odor enhances postnatal responses to it, observable soon after birth, while also suggesting that the mu opioid receptor system plays an important role in generating this effect. The results also imply that with alcohol exposure, the prenatal opioid system is wholly involved, which could explain the longer retention of the enhanced attraction to alcohol following prenatal experience with the drug.

  14. The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice.

    Science.gov (United States)

    Laman-Maharg, Abigail R; Copeland, Tiffany; Sanchez, Evelyn Ordoñes; Campi, Katharine L; Trainor, Brian C

    2017-08-14

    Psychosocial stress leads to the activation of kappa opioid receptors (KORs), which induce dysphoria and facilitate depression-like behaviors. However, less is known about the long-term effects of stress and KORs in females. We examined the long-term effects of social defeat stress on the aversive properties of KOR activation in male and female California mice (Peromyscus californicus) using a conditioned place aversion paradigm. Female California mice naïve to social defeat, formed a place aversion following treatment with 2.5mg/kg of the KOR agonist U50,488, but females exposed to defeat did not form a place aversion to this dose. This supports the finding by others that social defeat weakens the aversive properties of KOR agonists. In contrast, both control and stressed males formed an aversion to 10mg/kg of U50,488. We also examined EGR1 immunoreactivity, an indirect marker of neuronal activity, in the nucleus accumbens (NAc) and found that stress and treatment with 10mg/kg of U50,488 increased EGR1 immunoreactivity in the NAc core in females but reduced activation in males. The effects of stress and U50,488 on EGR1 were specific to the NAc, as we found no differences in the bed nucleus of the stria terminalis. In summary, our data indicate important sex differences in the long-term effects of stress and indicate the need for further study of the molecular mechanisms mediating the behavioral effects of KOR in both males and females. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress

    Science.gov (United States)

    Imbernon, Monica; Sanchez‐Rebordelo, Estrella; Romero‐Picó, Amparo; Kalló, Imre; Chee, Melissa J.; Porteiro, Begoña; Al‐Massadi, Omar; Contreras, Cristina; Fernø, Johan; Senra, Ana; Gallego, Rosalia; Folgueira, Cintia; Seoane, Luisa M.; van Gestel, Margriet; Adan, Roger A.; Liposits, Zsolt; Dieguez, Carlos; López, Miguel

    2016-01-01

    The opioid system is widely known to modulate the brain reward system and thus affect the behavior of humans and other animals, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and adenoviral vectors overexpressing or silencing κOR were stereotaxically delivered in the lateral hypothalamic area (LHA) of rats. Vagal denervation was performed to assess its effect on liver metabolism. Endoplasmic reticulum (ER) stress was inhibited by pharmacological (tauroursodeoxycholic acid) and genetic (overexpression of the chaperone glucose‐regulated protein 78 kDa) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and western blot. We show that in the LHA κOR directly controls hepatic lipid metabolism through the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor 1 (MCH‐R1) in the LHA, and genetic disruption of κOR reduced melanin concentrating hormone–induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of κOR in the LHA attenuated both methionine choline–deficient, diet‐induced and choline‐deficient, high‐fat diet–induced ER stress, inflammation, steatohepatitis, and fibrosis, whereas overexpression of κOR in this area promoted liver steatosis. Overexpression of glucose‐regulated protein 78 kDa in the liver abolished hypothalamic κOR‐induced steatosis by reducing hepatic ER stress. Conclusions: This study reveals a novel hypothalamic–parasympathetic circuit modulating hepatic function through inflammation and ER stress independent of changes in food intake or body weight; these findings might have implications for the clinical use of opioid receptor antagonists. (Hepatology 2016;64:1086‐1104) PMID:27387967

  16. Ablation of kappa-opioid receptors from brain dopamine neurons has anxiolytic-like effects and enhances cocaine-induced plasticity.

    Science.gov (United States)

    Van't Veer, Ashlee; Bechtholt, Anita J; Onvani, Sara; Potter, David; Wang, Yujun; Liu-Chen, Lee-Yuan; Schütz, Günther; Chartoff, Elena H; Rudolph, Uwe; Cohen, Bruce M; Carlezon, William A

    2013-07-01

    Brain kappa-opioid receptors (KORs) are implicated in states of motivation and emotion. Activation of KORs negatively regulates mesolimbic dopamine (DA) neurons, and KOR agonists produce depressive-like behavioral effects. To further evaluate how KOR function affects behavior, we developed mutant mice in which exon 3 of the KOR gene (Oprk1) was flanked with Cre-lox recombination (loxP) sites. By breeding these mice with lines that express Cre-recombinase (Cre) in early embryogenesis (EIIa-Cre) or only in DA neurons (dopamine transporter (DAT)-Cre), we developed constitutive KOR knockouts (KOR(-/-)) and conditional knockouts that lack KORs in DA-containing neurons (DAT-KOR(lox/lox)). Autoradiography demonstrated complete ablation of KOR binding in the KOR(-/-) mutants, and reduced binding in the DAT-KOR(lox/lox) mutants. Quantitative reverse transcription PCR (qPCR) studies confirmed that KOR mRNA is undetectable in the constitutive mutants and reduced in the midbrain DA systems of the conditional mutants. Behavioral characterization demonstrated that these mutant lines do not differ from controls in metrics, including hearing, vision, weight, and locomotor activity. Whereas KOR(-/-) mice appeared normal in the open field and light/dark box tests, DAT-KOR(lox/lox) mice showed reduced anxiety-like behavior, an effect that is broadly consistent with previously reported effects of KOR antagonists. Sensitization to the locomotor-stimulating effects of cocaine appeared normal in KOR(-/-) mutants, but was exaggerated in DAT-KOR(lox/lox) mutants. Increased sensitivity to cocaine in the DAT-KOR(lox/lox) mutants is consistent with a role for KORs in negative regulation of DA function, whereas the lack of differences in the KOR(-/-) mutants suggests compensatory adaptations after constitutive receptor ablation. These mouse lines may be useful in future studies of KOR function.

  17. Dose-related Behavioral, Subjective, Endocrine and Psychophysiological Effects Of the Kappa Opioid Agonist Salvinorin A in Humans

    Science.gov (United States)

    Ranganathan, Mohini; Schnakenberg, Ashley; Skosnik, Patrick D.; Cohen, Bruce; Pittman, Brian; Sewell, R. Andrew; D’Souza, Deepak Cyril

    2012-01-01

    Background Salvia divinorum (Salvia) is an increasingly popular recreational drug amongst adolescents and young adults. Its primary active ingredient, Salvinorin A (SA), a highly selective agonist at the kappa opiate receptor (KOR), is believed to be one of the most potent naturally occurring hallucinogens. However, there is little experimental data on the effects of SA in humans. Methods In a 3-day, double-blind, randomized, crossover, counterbalanced study, the behavioral, subjective, cognitive, psychophysiological and endocrine effects of 0 mg, 8 mg and 12 mg of inhaled SA were characterized in 10 healthy individuals who had previously used Salvia. Results SA produced psychotomimetic effects and perceptual alterations including dissociative and somaesthetic effects, increased plasma cortisol and prolactin and reduced resting EEG spectral power. SA administration was associated with a rapid increase of its levels in the blood. SA did not produce euphoria, cognitive deficits or changes in vital signs. The effects were transient and not dose-related. SA administration was very well tolerated without acute or delayed adverse effects. Conclusions SA produced a wide range of transient effects in healthy subjects. The perceptual altering effects and lack of euphoric effects would explain its intermittent use pattern. Such a profile would also suggest a low addictive potential similar to other hallucinogens and consistent with KOR agonism. Further work is warranted to carefully characterize a full spectrum of its effects in humans, to elucidate the underlying mechanisms involved and to explore the basis for individual variability in its effects. PMID:22817868

  18. Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism.

    Science.gov (United States)

    Kivell, Bronwyn; Uzelac, Zeljko; Sundaramurthy, Santhanalakshmi; Rajamanickam, Jeyaganesh; Ewald, Amy; Chefer, Vladimir; Jaligam, Vanaja; Bolan, Elizabeth; Simonson, Bridget; Annamalai, Balasubramaniam; Mannangatti, Padmanabhan; Prisinzano, Thomas E; Gomes, Ivone; Devi, Lakshmi A; Jayanthi, Lankupalle D; Sitte, Harald H; Ramamoorthy, Sammanda; Shippenberg, Toni S

    2014-11-01

    Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, produces dysphoria and pro-depressant like effects. These actions have been attributed to inhibition of striatal dopamine release. The dopamine transporter (DAT) regulates dopamine transmission via uptake of released neurotransmitter. KORs are apposed to DAT in dopamine nerve terminals suggesting an additional target by which SalA modulates dopamine transmission. SalA produced a concentration-dependent, nor-binaltorphimine (BNI)- and pertussis toxin-sensitive increase of ASP(+) accumulation in EM4 cells coexpressing myc-KOR and YFP-DAT, using live cell imaging and the fluorescent monoamine transporter substrate, trans 4-(4-(dimethylamino)-styryl)-N-methylpyridinium) (ASP(+)). Other KOR agonists also increased DAT activity that was abolished by BNI pretreatment. While SalA increased DAT activity, SalA treatment decreased serotonin transporter (SERT) activity and had no effect on norepinephrine transporter (NET) activity. In striatum, SalA increased the Vmax for DAT mediated DA transport and DAT surface expression. SalA up-regulation of DAT function is mediated by KOR activation and the KOR-linked extracellular signal regulated kinase-½ (ERK1/2) pathway. Co-immunoprecipitation and BRET studies revealed that DAT and KOR exist in a complex. In live cells, DAT and KOR exhibited robust FRET signals under basal conditions. SalA exposure caused a rapid and significant increase of the FRET signal. This suggests that the formation of KOR and DAT complexes is promoted in response to KOR activation. Together, these data suggest that enhanced DA transport and decreased DA release resulting in decreased dopamine signalling may contribute to the dysphoric and pro-depressant like effects of SalA and other KOR agonists. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Vagally mediated inhibition of acoustic stress-induced cortisol release by orally administered kappa-opioid substances in dogs.

    Science.gov (United States)

    Bueno, L; Gue, M; Fargeas, M J; Alvinerie, M; Junien, J L; Fioramonti, J

    1989-04-01

    The effects of oral vs. iv administration of kappa- and mu-opioid agonists on plasma cortisol release induced by acoustic stress (AS) were evaluated in fasted dogs with an implanted jugular catheter. AS was induced by 1 h of music (less than or equal to 86 decibels) played through earphones and was accompanied by a 382% maximal rise in plasma cortisol after 15-30 min. Administered orally 30 min before the AS session, both U-50488 (0.1 mg/kg) and PD 117-302 (0.05 mg/kg) significantly (P less than or equal to 0.01) decreased (by 71.2% and 80.9%, respectively) the maximal increase in plasma cortisol induced by AS, while bremazocine, morphine, as well as iv administration of U-50488 at similar doses were ineffective. The effects of U-50488 and PD 117-302 orally administered (0.1 mg/kg) on the hypercortisolemia induced by AS were abolished by pretreatment with iv naloxone (0.1 mg/kg) or MR 2266 (0.1 mg/kg). Naloxone given alone significantly (P less than 0.01) increased basal plasma cortisol, without affecting cortisol increase induced by AS. Vagotomy abolished the effects of orally administered U-50488 on the AS-induced increase in plasma cortisol. Neither U-50488 nor PD 117302 (0.1 mg/kg, orally) reduced the increase in plasma cortisol induced by intracerebroventricular administration of ovine CRF (100 ng/kg). It is concluded that kappa- but not mu-opioid agonists are able to inhibit the stimulation of the hypothalamo-pituitary-adrenocortical axis induced by AS by acting selectively on peripheral kappa-receptors located in the wall of the proximal gut. This action is neurally mediated through afferent vagal fibers affecting central nervous system release of CRF induced by a centrally acting stressor.

  20. Two short-acting kappa opioid receptor antagonists (zyklophin and LY2444296) exhibited different behavioral effects from the long-acting antagonist norbinaltorphimine in mouse anxiety tests.

    Science.gov (United States)

    Huang, Peng; Yakovleva, Tatyana; Aldrich, Jane V; Tunis, Julia; Parry, Christopher; Liu-Chen, Lee-Yuan

    2016-02-26

    Prototypical long-acting kappa opioid receptor (KOPR) antagonists [e.g., norbinaltorphimine (norBNI)] have been reported to exert anxiolytic-like effects in several commonly used anxiety tests in rodents including the novelty-induced hypophagia (NIH) and elevated plus maze (EPM) tests. It remains unknown if the short-acting KOPR antagonists (e.g., zyklophin and LY2444296) have similar effects. In this study effects of zyklophin and LY2444296 (s.c.) were investigated in the NIH and EPM tests in mice 1h post-injection and compared with norBNI (i.p.) 48h post-administration. In the NIH test, zyklophin at 3 and 1mg/kg, but not 0.3mg/kg, or LY2444296 at 30mg/kg decreased the latency of palatable food consumption in novel cages, but had no effect in training cages, similar to norBNI (10mg/kg). Zyklophin at 3 or 1mg/kg increased or had a trend of increasing the amount of palatable food consumption in novel cages, with no effects in training cages, further indicating its anxiolytic-like effect, but norBNI (10mg/kg) and LY2444296 (30mg/kg) did not. In the EPM test, norBNI (10mg/kg) increased open arm time and % open arm entries or time, but zyklophin at all three doses and LY2444296 (30mg/kg) had no effects. In addition, zyklophin at 3mg/kg increased numbers of close and total arm entries on EPM, suggesting increased activity; however, norBNI and LY2444296 had no effects on close and total arm entries. Thus, all three KOPR antagonists had anxiolytic-like effects in the NIH test. However, only the long-acting one (norBNI), but not the short-acting ones (zyklophin and LY2444296), demonstrated anti-anxiety like effects in the EPM test. It remains to be investigated if the differences are due to the differences in their durations of action and/or pharmacodynamic properties.

  1. A combined ligand-based and target-based drug design approach for G-protein coupled receptors: application to salvinorin A, a selective kappa opioid receptor agonist

    Science.gov (United States)

    Singh, Nidhi; Chevé, Gwénaël; Ferguson, David M.; McCurdy, Christopher R.

    2006-08-01

    Combined ligand-based and target-based drug design approaches provide a synergistic advantage over either method individually. Therefore, we set out to develop a powerful virtual screening model to identify novel molecular scaffolds as potential leads for the human KOP (hKOP) receptor employing a combined approach. Utilizing a set of recently reported derivatives of salvinorin A, a structurally unique KOP receptor agonist, a pharmacophore model was developed that consisted of two hydrogen bond acceptor and three hydrophobic features. The model was cross-validated by randomizing the data using the CatScramble technique. Further validation was carried out using a test set that performed well in classifying active and inactive molecules correctly. Simultaneously, a bovine rhodopsin based "agonist-bound" hKOP receptor model was also generated. The model provided more accurate information about the putative binding site of salvinorin A based ligands. Several protein structure-checking programs were used to validate the model. In addition, this model was in agreement with the mutation experiments carried out on KOP receptor. The predictive ability of the model was evaluated by docking a set of known KOP receptor agonists into the active site of this model. The docked scores correlated reasonably well with experimental p K i values. It is hypothesized that the integration of these two independently generated models would enable a swift and reliable identification of new lead compounds that could reduce time and cost of hit finding within the drug discovery and development process, particularly in the case of GPCRs.

  2. Behavioral stress may increase the rewarding valence of cocaine-associated cues through a dynorphin/kappa-opioid receptor-mediated mechanism without affecting associative learning or memory retrieval mechanisms.

    Science.gov (United States)

    Schindler, Abigail G; Li, Shuang; Chavkin, Charles

    2010-08-01

    Stress exposure increases the risk of addictive drug use in human and animal models of drug addiction by mechanisms that are not completely understood. Mice subjected to repeated forced swim stress (FSS) before cocaine develop significantly greater conditioned place preference (CPP) for the drug-paired chamber than unstressed mice. Analysis of the dose dependency showed that FSS increased both the maximal CPP response and sensitivity to cocaine. To determine whether FSS potentiated CPP by enhancing associative learning mechanisms, mice were conditioned with cocaine in the absence of stress, then challenged after association was complete with the kappa-opioid receptor (KOR) agonist U50,488 or repeated FSS, before preference testing. Mice challenged with U50,488 60 min before CPP preference testing expressed significantly greater cocaine-CPP than saline-challenged mice. Potentiation by U50,488 was dose and time dependent and blocked by the KOR antagonist norbinaltorphimine (norBNI). Similarly, mice subjected to repeated FSS before the final preference test expressed significantly greater cocaine-CPP than unstressed controls, and FSS-induced potentiation was blocked by norBNI. Novel object recognition (NOR) performance was not affected by U50,488 given 60 min before assay, but was impaired when given 15 min before NOR assay, suggesting that KOR activation did not potentiate CPP by facilitating memory retrieval or expression. The results from this study show that the potentiation of cocaine-CPP by KOR activation does not result from an enhancement of associative learning mechanisms and that stress may instead enhance the rewarding valence of cocaine-associated cues by a dynorphin-dependent mechanism.

  3. Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure

    Directory of Open Access Journals (Sweden)

    Jamie H. Rose

    2016-07-01

    Full Text Available The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc κ opioid receptors (KOR in chronic intermittent ethanol (CIE exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs.

  4. Michael Acceptor Approach to the Design of New Salvinorin A-based High Affinity Ligands for the Kappa-Opioid Receptor

    Science.gov (United States)

    Polepally, Prabhakar R.; Huben, Krzysztof; Vardy, Eyal; Setola, Vincent; Mosier, Philip D.; Roth, Bryan L.; Zjawiony, Jordan K.

    2014-01-01

    The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand–receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure–activity relationships, and previous salvinorin A–KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR. PMID:25193297

  5. Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor.

    Science.gov (United States)

    Polepally, Prabhakar R; Huben, Krzysztof; Vardy, Eyal; Setola, Vincent; Mosier, Philip D; Roth, Bryan L; Zjawiony, Jordan K

    2014-10-06

    The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand-receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure-activity relationships, and previous salvinorin A-KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR.

  6. Unconditioned behavioral effects of the powerful kappa-opioid hallucinogen salvinorin A in nonhuman primates: fast onset and entry into cerebrospinal fluid.

    Science.gov (United States)

    Butelman, Eduardo R; Prisinzano, Thomas E; Deng, Haiteng; Rus, Szymon; Kreek, Mary Jeanne

    2009-02-01

    Salvinorin A is the main active component of the widely available hallucinogenic plant, Salvia divinorum. Salvinorin A is a selective high-efficacy kappa-agonist in vitro, with some unique pharmacodynamic properties. Descriptive reports show that salvinorin A-containing products produce robust behavioral effects in humans. However, these effects have not been systematically characterized in human or nonhuman primates to date. Therefore, the present studies focused on the characterization of overt effects of salvinorin A, such as sedation (operationally defined as unresponsiveness to environmental stimuli) and postural relaxation, previously observed with centrally penetrating kappa-agonists in nonhuman primates. Salvinorin A was active in these endpoints (dose range, 0.01-0.1 mg/kg i.v.) in nonhuman primates (n = 3-5), similar to the synthetic kappa-agonist U69,593 [(+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]-dec-8-yl]-benzeneacetamide], used for comparison herein. Salvinorin A effects could be prevented by a clinically available opioid antagonist, nalmefene (0.1 mg/kg), at doses known to block kappa-receptor-mediated effects in nonhuman primates. When injected intravenously, salvinorin A (0.032 mg/kg) could enter the central nervous system (as reflected in cisternal cerebrospinal fluid) within 1 min and reach concentrations that are in the reported range of the affinity (K(i)) of this ligand for brain kappa-receptors. Consistent with this finding, specific translationally viable behavioral effects (e.g., facial relaxation and ptosis) could also be detected within 1 to 2 min of injection of salvinorin A. These are the first studies documenting rapid unconditioned effects of salvinorin A in a primate species, consistent with descriptive reports of rapid and robust effects of this powerful hallucinogen in humans.

  7. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: selective modification of the furan ring.

    Science.gov (United States)

    Harding, Wayne W; Schmidt, Matthew; Tidgewell, Kevin; Kannan, Pavitra; Holden, Kenneth G; Dersch, Christina M; Rothman, Richard B; Prisinzano, Thomas E

    2006-06-15

    A synthetic sequence has been developed to selectively functionalize the furan ring of the natural product salvinorin A (2a). The synthetic routes described convert the furan ring in 2a into an N-sulfonylpyrrole, oxazole or an oxadiazole. In addition, a procedure has been found to remove the furan skeleton completely. Biological results indicate that replacement of the furan ring with an N-sulfonylpyrrole leads to reduced affinity and efficacy at kappa opioid receptors.

  8. Antagonists of the kappa opioid receptor.

    Science.gov (United States)

    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward

    2014-05-01

    The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.

  9. A DFT and Semiempirical Model-Based Study of Opioid Receptor Affinity and Selectivity in a Group of Molecules with a Morphine Structural Core

    Directory of Open Access Journals (Sweden)

    Tamara Bruna-Larenas

    2012-01-01

    Full Text Available We report the results of a search for model-based relationships between mu, delta, and kappa opioid receptor binding affinity and molecular structure for a group of molecules having in common a morphine structural core. The wave functions and local reactivity indices were obtained at the ZINDO/1 and B3LYP/6-31 levels of theory for comparison. New developments in the expression for the drug-receptor interaction energy expression allowed several local atomic reactivity indices to be included, such as local electronic chemical potential, local hardness, and local electrophilicity. These indices, together with a new proposal for the ordering of the independent variables, were incorporated in the statistical study. We found and discussed several statistically significant relationships for mu, delta, and kappa opioid receptor binding affinity at both levels of theory. Some of the new local reactivity indices incorporated in the theory appear in several equations for the first time in the history of model-based equations. Interaction pharmacophores were generated for mu, delta, and kappa receptors. We discuss possible differences regulating binding and selectivity in opioid receptor subtypes. This study, contrarily to the statistically backed ones, is able to provide a microscopic insight of the mechanisms involved in the binding process.

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

    Science.gov (United States)

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

    2014-08-01

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

  11. Seabird nutrient subsidies benefit non-nitrogen fixing trees and alter species composition in South American coastal dry forests

    NARCIS (Netherlands)

    Havik, G.; Catenazzi, A.; Holmgren, M.

    2014-01-01

    Marine-derived nutrients can increase primary productivity and change species composition of terrestrial plant communities in coastal and riverine ecosystems. We hypothesized that sea nutrient subsidies have a positive effect on nitrogen assimilation and seedling survival of non-nitrogen fixing spec

  12. Seabird nutrient subsidies benefit non-nitrogen fixing trees and alter species composition in South American coastal dry forests.

    Directory of Open Access Journals (Sweden)

    Gilles Havik

    Full Text Available Marine-derived nutrients can increase primary productivity and change species composition of terrestrial plant communities in coastal and riverine ecosystems. We hypothesized that sea nutrient subsidies have a positive effect on nitrogen assimilation and seedling survival of non-nitrogen fixing species, increasing the relative abundance of non-nitrogen fixing species close to seashore. Moreover, we proposed that herbivores can alter the effects of nutrient supplementation by preferentially feeding on high nutrient plants. We studied the effects of nutrient fertilization by seabird guano on tree recruitment and how these effects can be modulated by herbivorous lizards in the coastal dry forests of northwestern Peru. We combined field studies, experiments and stable isotope analysis to study the response of the two most common tree species in these forests, the nitrogen-fixing Prosopis pallida and the non-nitrogen-fixing Capparis scabrida. We did not find differences in herbivore pressure along the sea-inland gradient. We found that the non-nitrogen fixing C. scabrida assimilates marine-derived nitrogen and is more abundant than P. pallida closer to guano-rich soil. We conclude that the input of marine-derived nitrogen through guano deposited by seabirds feeding in the Pacific Ocean affects the two dominant tree species of the coastal dry forests of northern Peru in contrasting ways. The non-nitrogen fixing species, C. scabrida may benefit from sea nutrient subsidies by incorporating guano-derived nitrogen into its foliar tissues, whereas P. pallida, capable of atmospheric fixation, does not.

  13. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine

    DEFF Research Database (Denmark)

    Kristensen, K; Christensen, C B; Christrup, Lona Louring

    1995-01-01

    The binding affinities of racemic methadone and its optical isomers R-methadone and S-methadone were evaluated for the opioid receptors mu1, mu2, delta and kappa, in comparison with that of morphine. The analgesic R-methadone had a 10-fold higher affinity for mu1 receptors than S-methadone (IC50 3.......0 nM and 26.4 nM, respectively). At the mu2 receptor, the IC50 value of R-methadone was 6.9 nM and 88 nM for S-methadone, respectively. As expected, R-methadone had twice the affinity for mu1 and mu2 receptors than the racemate. All of the compounds tested had low affinity for the delta and kappa...

  14. Evaluation of Neuroprotection and Behavioral Recovery by the Kappa- Opioid, PD 117302 Following Transient Forebrain Ischemia

    Science.gov (United States)

    1994-01-01

    recover at least 50% of baseline most rats, performance degradation was characterized by a com- values was caiculated. Quarter-life measures were...histological changes induced by transient global ce- 34:190-194; 1991. rebral ischemia in rats: Effects of cinnarizine and flunarizine. J. 17. Hall, E. D

  15. Determination of salvinorins and divinatorins in Salvia divinorum leaves by liquid chromatography/multistage mass spectrometry.

    Science.gov (United States)

    Medana, Claudio; Massolino, Cristina; Pazzi, Marco; Baiocchi, Claudio

    2006-01-01

    Salvinorin A is the most potent naturally occurring hallucinogen known and rivals synthetic LSD in potency. Structurally it belongs to the neoclerodane diterpenoids, and it is the only known non-nitrogenous kappa-opioid-selective agonist. Salvia divinorum (Diviner's sage) is a member of the mint family that was used in ancient Mexican traditional practices. Today it is widely cultivated in Europe as a recreational marijuana substitute; it is illegal to buy, sell or possess the plant or the active principle in some countries. Six different salvinorins and three divinatorins have been isolated from Salvia divinorum leaves. The ion fragmentation, separation and quantitation of these diterpenes by liquid chromatography/electrospray ionization multistage mass spectrometry (LC/ESI-MS(n)) are described. The importance of LC in herbal extract determination and the chemical diagnostic power of MS(n) in the analysis of classes of natural organic products are discussed.

  16. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A.

    Science.gov (United States)

    Harding, Wayne W; Schmidt, Matthew; Tidgewell, Kevin; Kannan, Pavitra; Holden, Kenneth G; Gilmour, Brian; Navarro, Hernan; Rothman, Richard B; Prisinzano, Thomas E

    2006-01-01

    Salvinorin A (1) is a hallucinogenic neoclerodane diterpene isolated from the widely available psychoactive plant Salvia divinorum and is the first example of a non-nitrogenous opioid receptor ligand. At present, there is little information available as to why this compound is selective for kappa opioid receptors. One approach to better understanding the mode of binding of 1 at kappa receptors is to systematically alter the structure of 1 and examine the effects on opioid receptor affinity and activity. Currently, there is a paucity of methods described for the preparation of analogues derived from 1. Here, we report the investigation of several chemical transformations of 1 isolated from S. divinorum. In particular, this work provides a semisynthesis of salvinicins A (2) and B (3) and has identified 10a as the first neoclerodane diterpene with delta opioid antagonist activity.

  17. Synthetic studies of neoclerodane diterpenoids from Salvia splendens and evaluation of Opioid Receptor affinity.

    Science.gov (United States)

    Fontana, Gianfranco; Savona, Giuseppe; Rodríguez, Benjamín; Dersch, Christina M; Rothman, Richard B; Prisinzano, Thomas E

    2008-12-20

    Salvinorin A (1), a neoclerodane diterpene from the hallucinogenic mint Salvia divinorum, is the only known non-nitrogenous and specific kappa-opioid agonist. Several structural congeners of 1 isolated from Salvia splendens (2 - 8) together with a series of semisynthetic derivatives (9 - 24), some of which possess a pyrazoline structural moiety (9, 19 - 22), have been tested for affinity at human mu, delta, and kappa opioid receptors. None of these compounds showed high affinity binding to these receptors. However, 10 showed modest affinity for kappa receptors suggesting other naturally neoclerodanes from different Salvia species may possess opioid affinity.

  18. Combined blockade of both mu- and kappa-opioid receptors prevents the acute orexigenic action of agouti-related protein

    NARCIS (Netherlands)

    Brugman, S; Clegg, DJ; Woods, SC; Seeley, RJ

    2002-01-01

    Agouti-related protein (AgRP) is an endogenous antagonist at the melanocortin 3 and 4 receptor in the hypothalamus. Central administration of AgRP produces a robust increase in food intake, and this effect can be blocked by administration of nonspecific opioid receptor antagonist. Such results impli

  19. Effects of ibogaine and noribogaine on the antinociceptive action of mu-, delta- and kappa-opioid receptor agonists in mice.

    Science.gov (United States)

    Bhargava, H N; Cao, Y J; Zhao, G M

    1997-03-28

    Ibogaine, an alkaloid isolated from the bark of the African shrub, Tabernanthe iboga, has been claimed to decrease the self-administration of drugs of abuse like morphine, cocaine and alcohol. To determine whether these effects are mediated via opioid receptor systems, the effects of ibogaine and its metabolite, noribogaine on the antinociceptive actions of morphine, U-50,488H and [D-Pen2,D-Pen5]enkephalin (DPDPE) which are mu- kappa- and delta-opioid receptor agonists, respectively, were determined in male Swiss-Webster mice. Administration of morphine (7 or 10 mg/kg, s.c.), U-50,488H (15 or 25 mg/kg, i.p.) or DPDPE (10 microg/mouse, i.c.v.) produced antinociception in mice as measured by the tail-flick test. Ibogaine (10, 20 or 40 mg/kg, i.p.) by itself did not alter the tail-flick latency. The same doses of ibogaine injected 10 min before the opioid drugs did not modify the antinociceptive actions of morphine, U-50,488H or DPDPE. Ibogaine administered 4 h or 24 h prior to morphine injection did not modify the antinociceptive action of the latter. A dose of 40 mg/kg (i.p.) of noribogaine enhanced the antinociceptive activity of morphine (10 mg/kg, s.c.). Similarly, the doses of 40 and 80 mg/kg of noribogaine enhanced the antinociception produced by a smaller dose of morphine (5 mg/kg, s.c.). However, antinociception induced by U-50,488H and DPDPE was not modified by noribogaine (10-40 mg/kg). It is concluded that ibogaine, which has been suggested to decrease the self-administration of cocaine and opiates like heroin in humans, does not produce such an action by interacting directly with multiple opioid receptors. However, the metabolite of ibogaine enhances the antinociception of morphine but not of U-50,488H or DPDPE. Thus, in vivo evidence has been provided for the possible interaction of ibogaine with mu-opioid receptor following its metabolism to noribogaine.

  20. Kappa-opioid receptor signaling in the striatum as a potential modulator of dopamine transmission in cocaine dependence

    Directory of Open Access Journals (Sweden)

    Pierre eTrifilieff

    2013-06-01

    Full Text Available Cocaine addiction is accompanied by a decrease in striatal dopamine signaling, measured as a decrease in dopamine D2 receptor binding as well as blunted dopamine release in the striatum. These alterations in dopamine transmission have clinical relevance, and have been shown to correlate with cocaine-seeking behavior and response to treatment for cocaine dependence. However, the mechanisms contributing to the hypodopaminergic state in cocaine addiction remain unknown. Here we review the Positron Emission Tomography (PET imaging studies showing alterations in D2 receptor binding potential and dopamine transmission in cocaine abusers and their significance in cocaine-seeking behavior. Based on animal and human studies, we propose that the kappa receptor/dynorphin system, because of its impact on dopamine transmission and upregulation following cocaine exposure, could contribute to the hypodopaminergic state reported in cocaine addiction, and could thus be a relevant target for treatment development.

  1. Synthesis and Characterization of 5-Hydroxy-2-(2-phenylethyl)chromone (5-HPEC) and Its Analogues as Non-nitrogenous 5-HT2B Ligands.

    Science.gov (United States)

    Williams, Dwight A; Zaidi, Saheem A; Zhang, Yan

    2015-08-28

    The involvement of the neurotransmitter serotonin (5-HT) in numerous physiological functions is often attributed to the diversity of receptors with which it interacts. Ligands targeting serotonin receptor 2B (5-HT2B) have received renewed interest for their potential to help understand the role of 5-HT2B in migraines, drug abuse, neurodegenerative diseases, and irritable bowel syndrome. To date, most of the ligands targeting 5-HT2B have been nitrogen-containing compounds. The natural product 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 5) has been shown previously to act as a non-nitrogenous antagonist for the 5-HT2B receptor (pKi = 5.6). This report describes further progress on the study of the structure-activity relationship of both naturally occurring and synthetic compounds bearing the 2-(2-phenylethyl)chromone scaffold at the 5-HT2B receptor. The inhibitory activity of the newly synthesized compounds (at 10 μM) was tested against each of the 5-HT2 receptors. Following this assay, the binding affinity and antagonism of the most promising compounds were then evaluated at 5-HT2B. Among all the analogues, 5-hydroxy-2-(2-phenylpropyl)chromone (5-HPPC, 22h) emerged as a new lead compound, showing a 10-fold improvement in affinity (pKi = 6.6) over 5-HPEC with reasonable antagonist properties at 5-HT2B. Additionally, ligand docking studies have identified a putative binding pocket for 5-HPPC and have helped understand its improved affinity.

  2. Type and location of fluorescent probes incorporated into the potent mu-opioid peptide [Dmt]DALDA affect potency, receptor selectivity and intrinsic efficacy.

    Science.gov (United States)

    Schiller, P W; Berezowska, I; Weltrowska, G; Chen, H; Lemieux, C; Chung, N N

    2005-06-01

    The dermorphin-derived tetrapeptide H-Dmt-d-Arg-Phe-Lys-NH(2) (Dmt = 2',6'-dimethyltyrosine) ([Dmt(1)]DALDA) is a highly potent and selective mu-opioid agonist capable of crossing the blood-brain barrier and producing a potent, centrally mediated analgesic effect when given systemically. For the purpose of biodistribution studies by fluorescence techniques, [Dmt(1)]DALDA analogues containing various fluorescent labels [dansyl, anthraniloyl (atn), fluorescein, or 6-dimethylamino-2'-naphthoyl] in several different locations of the peptide were synthesized and characterized in vitro in the guinea-pig ileum and mouse vas deferens assays, and in mu-, delta- and kappa-opioid receptor-binding assays. The analogues showed various degrees of mu receptor-binding selectivity, but all of them were less mu-selective than the [Dmt(1)]DALDA parent peptide. Most analogues retained potent, full mu-agonist activity, except for one with fluorescein attached at the C-terminus (3a) (partial mu-agonist) and one containing beta-(6'-dimethylamino-2'-naphthoyl)alanine (aladan) in place of Phe(3) (4) (mu- and kappa-antagonist). The obtained data indicate that the receptor-binding affinity, receptor selectivity and intrinsic efficacy of the prepared analogues vary very significantly, depending on the type of fluorescent label used and on its location in the peptide. The results suggest that the biological activity profile of fluorescence-labeled peptide analogues should always be carefully determined prior to their use in biodistribution studies or other studies. One of the analogues containing the atn group (2a) proved highly useful in a study of cellular uptake and intracellular distribution by confocal laser scanning microscopy.

  3. [{sup 11}C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl] -1-piperazinecarboxylate ([{sup 11}C]GR89696): synthesis and in vivo binding to kappa opiate receptors

    Energy Technology Data Exchange (ETDEWEB)

    Ravert, Hayden T.; Mathews, William B.; Musachio, John L.; Scheffel, Ursula; Finley, Paige; Dannals, Robert F

    1999-10-01

    GR89696, racemic methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl] -1-piperazinecarboxylate, a kappa opioid receptor ligand, was labeled with [{sup 11}C]methyl chloroformate. The radiochemical yield was 20% with an observed specific radioactivity of 75.5 GBq/{mu}mol at end of synthesis (2,040 mCi/{mu}mol). Five minutes after intravenous administration, 5.4% of the injected dose accumulated in mouse whole brain. Brain region to cerebellar ratios increased over time with ratios at 90 min of 7.8, 5.6, and 4.5 for the hypothalamus, olfactory tubercle, and striatum, respectively. The uptake of [{sup 11}C]GR89696 correlated with known kappa opioid receptor densities and was inhibited by kappa opioid selective drugs.

  4. Salvia divinorum and salvinorin A: an update on pharmacology and analytical methodology.

    Science.gov (United States)

    Grundmann, Oliver; Phipps, Stephen M; Zadezensky, Immo; Butterweck, Veronika

    2007-08-01

    Salvia divinorum L. (Lamiaceae) has been used for centuries by the Mazatecan culture and has gained popularity as a recreational drug in recent years. Its potent hallucinogenic effects seen in case reports has triggered research and led to the discovery of the first highly selective non-nitrogenous kappa opioid receptor agonist salvinorin A. This review critically evaluates the reported pharmacological and toxicological properties of S. divinorum and one of its major compounds salvinorin A, its pharmacokinetic profile, and the analytical methods developed so far for its detection and quantification. Recent research puts a strong emphasis on salvinorin A , which has been shown to be a selective opioid antagonist and is believed to have further beneficial properties , rather than the leaf extract of S. divinorum. Currently animal studies show a rapid onset of action and short distribution and elimination half-lives as well as a lack of evidence of short- or long-term toxicity. Salvinorin A seems to be the most promising approach to new treatment options for a variety of CNS illnesses. However, many further investigations are necessary to fully understand and elucidate the various medicinal properties of the plant itself and to provide the legislative authorities with enough information to cast judgement on S. divinorum.

  5. Salvinorin A fails to substitute for the discriminative stimulus effects of LSD or ketamine in Sprague-Dawley rats.

    Science.gov (United States)

    Killinger, Bryan A; Peet, Mary M; Baker, Lisa E

    2010-09-01

    Salvia divinorum is a small perennial shrub that has gained recent popularity among the drug-using subculture as a legal alternative to hallucinogens. Salvinorin A, the main active compound found in the S.divinorum plant, is an atypical hallucinogen with pharmacological selectivity at kappa opioid (KOP) receptor sites and is a unique non-nitrogenous neoclerodane diterpene which is structurally distinct from other opioid compounds. The novel structure of salvinorin A and its specific binding affinity to KOP receptors provide a unique opportunity to investigate neurochemical mechanisms of hallucination and hallucinogenic compounds. The current investigation assessed the substitution of salvinorin A in 16 male Sprague-Dawley rats trained to discriminate either the prototypical serotonergic hallucinogen, LSD (0.08mg/kg, S.C., n=8) or the dissociative anesthetic and glutamatergic hallucinogen, ketamine (8.0mg/kg, I.P., n=8) from vehicle under a FR 20 schedule of food-reinforced responding. Results indicated that neither LSD nor ketamine discrimination generalized to salvinorin A. These findings are consistent with the growing body of evidence that salvinorin A is pharmacologically distinct from other traditional hallucinogenic compounds.

  6. Anti-nociceptive role of neuropeptide Y in the nucleus accumbens in rats with inflammation, an effect modulated by mu- and kappa-opioid receptors

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Recent study in our laboratory showed that neuropeptide Y (NPY) plays an antinociceptive role in the nucleus accumbens (NAc) in intact rats. The present study was performed to further investigate the effect of NPY in nociceptive modulation in the NAc of rats with inflammation, and the possible interaction between NPY and the opioid systems. Experimental inflammation was induced by subcutaneous injection of carrageenan into the left hindpaw of rats. Intra-NAc administration of NPY induced a dose-dependent increase of hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulations in rats with inflammation. The anti-nociceptive effect of NPY was significantly blocked by subsequent intra-NAc injection of the Y1 receptor antagonist NPY28-36, suggesting an involvement of Y1 receptor in the NPY-induced anti-nociception. Furthermore, intra-NAc administration of the opioid antagonist naloxone significantly antagonized the increased HWLs induced by preceding intra-NAc injection of NPY, suggesting an involvement of the endogenous opioid system in the NPY-induced anti-nociception in the NAc during inflammation. Moreover, the NPY-induced anti-nociception was attenuated by following intra-NAc injection of the μ-opioid antagonist β-funaltrexamine (β-FNA), and κ-opioid antagonist nor-binaltorphimine (norBNI), but not by δ-opioid antagonist naltrindole, indicating that μ- and κ-opioid receptors, not δ-opioid receptor, are involved in the NPY-induced anti-nociception in the NAc in rats with inflammation.

  7. Novel neoclerodane diterpene derivatives from the smoke of salvinorin A

    Science.gov (United States)

    Ma, Zhongze; Deng, Gang; Lee, David Y. W.

    2010-01-01

    Salvinorin A is a naturally-occurring potent and selective kappa opioid receptor agonist, and smoking salvinorin A produces the most intense hallucinogenic effects in human. Eight neoclerodane diterpene derivatives were isolated from the smoke of salvinorin A, and their structures were identified by spectroscopic methods. The major structural changes include epimerizations, eliminations, and rearrangements. PMID:20936100

  8. A facile synthesis of [{sup 14}C]enadoline [(5R)-(5{alpha},7{alpha},8{beta})]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-4-benzofuranacetamide

    Energy Technology Data Exchange (ETDEWEB)

    Pu, Y.-M.; Scripko, J.; Huang, C.C. [Parke, Davis and Co., Ann Arbor, MI (United States)

    1995-12-01

    4-Chloromethylbenzofuran (10) was synthesized from 2,3-dimethylanisole in 7 steps. The corresponding Grignard reagent prepared from magnesium-anthracene complex reacts with {sup 14}CO{sub 2}, SOCl{sub 2}, and PD130812 successively to give [{sup 14}C]enadoline (2), a non-peptide, selective kappa opioid receptor agonist. This method could be readily modified for the rapid, one-pot synthesis of [{sup 11}C]enadoline. (author).

  9. [Natural selection].

    Science.gov (United States)

    Mayr, E

    1985-05-01

    Much of the resistance against Darwin's theory of natural selection has been due to misunderstandings. It is shown that natural selection is not a tautology and that it is a two-step process. The first step, the production of variation, is under the control of chance; the second step, selection proper, is an anti-chance process, but subject to many constraints. The target of selection is the individual as a whole, and many neutral mutations can be retained as hitchhikers of successful genotypes. Sexual selection results from selection for pure reproductive success.

  10. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: role of the furan in affinity for opioid receptors.

    Science.gov (United States)

    Simpson, Denise S; Lovell, Kimberly M; Lozama, Anthony; Han, Nina; Day, Victor W; Dersch, Christina M; Rothman, Richard B; Prisinzano, Thomas E

    2009-09-21

    Further synthetic modification of the furan ring of salvinorin A (1), the major active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. A computational study has predicted 1 to be a reproductive toxicant in mammals and is suggestive that use of 1 may be associated with adverse effects. We report in this study that piperidine 21 and thiomorpholine 23 have been identified as selective partial agonists at kappa opioid receptors. This indicates that additional structural modifications of 1 may provide ligands with good selectivity for opioid receptors but with reduced potential for toxicity.

  11. Benchmark selection

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Tvede, Mich

    2002-01-01

    Within a production theoretic framework, this paper considers an axiomatic approach to benchmark selection. It is shown that two simple and weak axioms; efficiency and comprehensive monotonicity characterize a natural family of benchmarks which typically becomes unique. Further axioms are added...

  12. Evaluation of the transport, in vitro metabolism and pharmacokinetics of Salvinorin A, a potent hallucinogen.

    Science.gov (United States)

    Teksin, Zeynep S; Lee, Insong J; Nemieboka, Noble N; Othman, Ahmed A; Upreti, Vijay V; Hassan, Hazem E; Syed, Shariq S; Prisinzano, Thomas E; Eddington, Natalie D

    2009-06-01

    Salvinorin A is an unregulated potent hallucinogen isolated from the leaves of Salvia divinorum. It is the only known non-nitrogenous kappa-opioid selective agonist, and rivals synthetic lysergic acid diethylamide (LSD) in potency. The objective of this study was to characterize the in vitro transport, in vitro metabolism, and pharmacokinetic properties of Salvinorin A. The transport characteristics of Salvinorin A were assessed using MDCK-MDR1 cell monolayers. The P-glycoprotein (P-gp) affinity status was assessed by the P-gp ATPase assay. In vitro metabolism studies were performed with various specific human CYP450 isoforms and UGT2B7 to assess the metabolic characteristics of Salvinorin A. Cohorts (n = 3) of male Sprague Dawley rats were used to evaluate the pharmacokinetics and brain distribution of Salvinorin A (10 mg/kg, intraperitoneal (i.p.) over a 240-min period. A validated UV-HPLC and LC/MS/MS method was used to quantify the hallucinogen concentrations obtained from the in vitro and in vivo studies, respectively. Salvinorin A displayed a high secretory transport in the MDCK-MDR1 cells (4.07 +/- 1.34 x 10(-)5 cm/s). Salvinorin A also stimulated the P-gp ATPase activity in a concentration (5 and 10 microM)-dependent manner, suggesting that it may be a substrate of (P-gp). A significant decrease in Salvinorin A concentration ranging from 14.7 +/- 0.80% to 31.1 +/- 1.20% was observed after incubation with CYP2D6, CYP1A1, CYP2C18, and CYP2E1, respectively. A significant decrease was also observed after incubation with UGT2B7. These results suggest that Salvinorin A maybe a substrate of UGT2B7, CYP2D6, CYP1A1, CYP2E1, and CYP2C18. The in vivo pharmacokinetic study showed a relatively fast elimination with a half-life (t1/2) of 75 min and a clearance (Cl/F) of 26 L/h/kg. The distribution was extensive (Vd of 47.1 L/kg); however, the brain to plasma ratio was 0.050. Accordingly, the brain half-life was relatively short, 36 min. Salvinorin A is rapidly eliminated

  13. Selected papers

    CERN Document Server

    Tamm, I E; Frenkel, V Ya

    1991-01-01

    I.E. Tamm is one of the great figures of 20th-century physics and the mentor of the late A.D. Sakharov. Together with I.M. Frank, he received the Nobel Prize in 1958 for the explanation of the Cherenkov effect. This book contains an annotated selection of his most important contributions to physics literature and essays on his contemporaries - Mandelstam, Einstein, Landau and Bohr as well as his contributions to the Pugwash conferences. About a third of the selections originally appeared in Russian and are now available to Western readers. This volume includes a preface by Sir Rudolf Peierls, a biography compiled by Tamm's former students, V.Ya. Frenkel and B.M. Bolotovskii, and a complete bibliography. This monograph on quantum theory, science history, particles and fields and the Cherenkov effect is intended for students, researchers, mathematicians and natural scientists in general.

  14. Selective Reproduction

    DEFF Research Database (Denmark)

    Svendsen, Mette N.

    2015-01-01

    This article employs a multi-species perspective in investigating how life's worth is negotiated in the field of neonatology in Denmark. It does so by comparing decision-making processes about human infants in the Danish neonatal intensive care unit with those associated with piglets who serve as...... as expectations within linear or predictive time frames are key markers in both sites. Exploring selective reproductive processes across human infants and research piglets can help us uncover aspects of the cultural production of viability that we would not otherwise see or acknowledge....

  15. EDITORIAL: Nanotechnological selection Nanotechnological selection

    Science.gov (United States)

    Demming, Anna

    2013-01-01

    At the nanoscale measures can move from a mass-scale analogue calibration to counters of discrete units. The shift redefines the possible levels of control that can be achieved in a system if adequate selectivity can be imposed. As an example as ionic substances pass through nanoscale pores, the quantity of ions is low enough that the pore can contain either negative or positive ions. Yet precise control over this selectivity still raises difficulties. In this issue researchers address the challenge of how to regulate the ionic selectivity of negative and positive charges with the use of an external charge. The approach may be useful for controlling the behaviour, properties and chemical composition of liquids and has possible technical applications for nanofluidic field effect transistors [1]. Selectivity is a critical advantage in the administration of drugs. Nanoparticles functionalized with targeting moieties can allow delivery of anti-cancer drugs to tumour cells, whilst avoiding healthy cells and hence reducing some of the debilitating side effects of cancer treatments [2]. Researchers in Belarus and the US developed a new theranostic approach—combining therapy and diagnosis—to support the evident benefits of cellular selectivity that can be achieved when nanoparticles are applied in medicine [3]. Their process uses nanobubbles of photothermal vapour, referred to as plasmonic nanobubbles, generated by plasmonic excitations in gold nanoparticles conjugated to diagnosis-specific antibodies. The intracellular plasmonic nanobubbles are controlled by laser fluence so that the response can be tuned in individual living cells. Lower fluence allows non-invasive high-sensitive imaging for diagnosis and higher fluence can disrupt the cellular membrane for treatments. The selective response of carbon nanotubes to different gases has leant them to be used within various different types of sensors, as summarized in a review by researchers at the University of

  16. Salvinorin A: A Mini Review of Physical and Chemical Properties Affecting Its Translation from Research to Clinical Applications in Humans.

    Science.gov (United States)

    Orton, Edward; Liu, Renyu

    2014-01-01

    Salvinorin A is a potent and selective agonist of kappa opioid receptors in the brain. Recent studies in several animal models have revealed that Salvinorin A has anti-addiction, anti-depression properties and exhibits pronounced neuroprotective effects against hypoxia/ischemia induced brain damage, and have raised interest in potential clinical applications in several acute pathologies involving oxygen deficiency in the brain. This review focuses on the chemical and physical properties of Salvinorin A and their impact on development of a rational formulation to enable its translation from a research compound to a novel therapeutic agent.

  17. Selected writings

    CERN Document Server

    Galilei, Galileo

    2012-01-01

    'Philosophy is written in this great book which is continually open before our eyes - I mean the universe...' Galileo's astronomical discoveries changed the way we look at the world, and our place in the universe. Threatened by the Inquisition for daring to contradict the literal truth of the Bible, Galileo ignited a scientific revolution when he asserted that the Earth moves. This generous selection from his writings contains all the essential texts for a reader to appreciate his lasting significance. Mark Davie's new translation renders Galileo's vigorous Italian prose into clear modern English, while William R. Shea's version of the Latin Sidereal Message makes accessible the book that created a sensation in 1610 with its account of Galileo's observations using the newly invented telescope. All Galileo's contributions to the debate on science and religion are included, as well as key documents from his trial before the Inquisition in 1633. A lively introduction and clear notes give an overview of Galileo's...

  18. Naltrexone but Not Ketanserin Antagonizes the Subjective, Cardiovascular, and Neuroendocrine Effects of Salvinorin-A in Humans

    Science.gov (United States)

    Maqueda, Ana Elda; Valle, Marta; Addy, Peter H.; Antonijoan, Rosa Maria; Puntes, Montserrat; Coimbra, Jimena; Ballester, Maria Rosa; Garrido, Maite; González, Mireia; Claramunt, Judit; Barker, Steven; Lomnicka, Izabela; Waguespack, Marian; Johnson, Matthew W.; Griffiths, Roland R.

    2016-01-01

    Background: Salvinorin-A is a terpene found in the leaves of the plant Salvia divinorum. When administered to humans, salvinorin-A induces an intense but short-lasting modified state of awareness, sharing features with those induced by the classical serotonin-2A receptor agonist psychedelics. However, unlike substances such as psilocybin or mescaline, salvinorin-A shows agonist activity at the kappa-opioid receptor rather than at the serotonin-2A receptor. Here, we assessed the involvement of kappa-opioid receptor and serotonin-2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans. Methods: We conducted a placebo-controlled, randomized, double-blind study with 2 groups of 12 healthy volunteers with experience with psychedelic drugs. There were 4 experimental sessions. In group 1, participants received the following treatment combinations: placebo+placebo, placebo+salvinorin-A, naltrexone+placebo, and naltrexone+salvinorin-A. Naltrexone, a nonspecific opioid receptor antagonist, was administered at a dose of 50mg orally. In group 2, participants received the treatment combinations: placebo+placebo, placebo+salvinorin-A, ketanserin+placebo, and ketanserin+salvinorin-A. Ketanserin, a selective serotonin-2A antagonist, was administered at a dose of 40mg orally. Results: Inhalation of 1mg of vaporized salvinorin-A led to maximum plasma concentrations at 1 and 2 minutes after dosing. When administered alone, salvinorin-A severely reduced external sensory perception and induced intense visual and auditory modifications, increased systolic blood pressure, and cortisol and prolactin release. These effects were effectively blocked by naltrexone, but not by ketanserin. Conclusions: Results support kappa opioid receptor agonism as the mechanism of action underlying the subjective and physiological effects of salvinorin-A in humans and rule out the involvement of a serotonin-2A-mediated mechanism. PMID:26874330

  19. Selected papers

    CERN Document Server

    Elgot, Calvin C

    1982-01-01

    Cal Elgot was a very serious and thoughtful researcher, who with great determi­ nation attempted to find basic explanations for certain mathematical phenomena­ as the selection of papers in this volume well illustrate. His approach was, for the most part, rather finitist and constructivist, and he was inevitably drawn to studies of the process of computation. It seems to me that his early work on decision problems relating automata and logic, starting with his thesis under Roger Lyndon and continuing with joint work with Biichi, Wright, Copi, Rutledge, Mezei, and then later with Rabin, set the stage for his attack on the theory of computation through the abstract treatment of the notion of a machine. This is also apparent in his joint work with A. Robinson reproduced here and in his joint papers with John Shepherdson. Of course in the light of subsequent work on decision problems by Biichi, Rabin, Shelah, and many, many others, the subject has been placed on a completely different plane from what it was whe...

  20. DREAM ablation selectively alters THC place aversion and analgesia but leaves intact the motivational and analgesic effects of morphine.

    Science.gov (United States)

    Cheng, Hai-Ying M; Laviolette, Steven R; van der Kooy, Derek; Penninger, Josef M

    2004-06-01

    DREAM (downstream regulatory element antagonistic modulator) is a novel transcriptional repressor for the prodynorphin gene, and genetic deletion of DREAM in mice results in a phenotype of ongoing analgesia by virtue of its effect on opioid gene expression. In the present study, we evaluated the motivational effects of opioids (morphine), cannabinoids [Delta(9)-tetrahydrocannabinol (THC)] and cocaine in mice lacking the dream gene (dream(-/-)). The aversive effects of THC were potentiated in dream(-/-) mice in a kappa-opioid receptor-dependent fashion, whereas morphine reward and the aversive effects of morphine withdrawal remained intact. The rewarding and aversive effects of cocaine were likewise unperturbed in dream(-/-) mice. Moreover, the aversive properties of lithium chloride and naloxone were unaffected by the absence of DREAM, indicating that the effect of DREAM on THC-induced dysphoria is not due to a general involvement in the behavioral response to aversive stimuli. Additionally, physical dependence to morphine and the locomotor-sensitizing effects of cocaine were unaltered in these animals. Finally, whereas the absence of DREAM reduced the analgesic efficacy of THC, morphine analgesia was unaffected in dream(-/-) mice.

  1. Molecular modelling of the ORL1 receptor and its complex with nociceptin.

    Science.gov (United States)

    Topham, C M; Moulédous, L; Poda, G; Maigret, B; Meunier, J C

    1998-12-01

    The opioid receptor like (ORL1) receptor is a G-protein coupled receptor superfamily, and regulates a plethora of neurophysiological functions. The structural requirements for receptor activation by its endogenous agonist, nociceptin (FGGFTGARKSARKLANQ), differ markedly from those of the kappa-opioid receptor and its putative peptide agonist, dynorphin A (YGGFLRRIRPKLKWDNQ). In order to probe the functional architecture of the ORL1 receptor, a molecular model of the receptor has been built, including the TM domain and the extra- and intracellular loops. An extended binding site able to accommodate nociceptin-(1-13), the shortest fully active analogue of nociceptin, has been characterized. The N-terminal FGGF tetrapeptide is proposed to bind in a highly conserved region, comprising two distinct hydrophobic pockets in a cavity formed by TM helices 3, 5, 6 and 7, capped by the acidic second extracellular (EL2) loop controlling access to the TM elements of the peptide binding site. The nociceptin conformation provides for the selective preference of the ORL1 receptor for nociceptin over dynorphin A, conferred by residue positions 5 and 6 (TG versus LR), and the favourable interaction of its highly positively charged core (residues 8-13) with the EL2 loop, thought to mediate receptor activation. The functional roles of the EL2 loop and the conserved N-terminal tetrapeptide opioid 'message' binding site are discussed in the context of the different structural requirements of the ORL1 and kappa-opioid receptors for activation.

  2. Study on alleviating forebrain ischemia-induced brain edema of rats by kappa-opioid receptor agonist salvinorin A via regulation of vascular endothelial growth factor%Kappa阿片受体激动剂salvinorin A调节血管内皮生长因子减轻大鼠前脑缺血后脑水肿的研究

    Institute of Scientific and Technical Information of China (English)

    张磊; 董海平; 何振洲; 王震虹

    2015-01-01

    目的 探讨kappa阿片受体(KOR)激动剂salvinorin A(SA)对前脑缺血再灌注(I/R)损伤大鼠脑水肿和神经功能的改善作用及机制.方法 成年雄性SD大鼠经夹闭颈动脉联合低血压建立前脑I/R损伤模型,并根据不同处理方式分为I/R组、I/R+ DMSO组、I/R+ SA组和I/R+ SA+ norBIN(KOR拮抗剂),另设立假手术组.采用Western blotting和免疫组织化学方法检测各组大鼠脑组织血管内皮生长因子(VEGF)蛋白表达;评估脑水肿情况;I/R后1、2、5d对各组大鼠神经功能进行评定.结果 前脑I/R损伤后,I/R组和I/R+DMSO组脑水含量显著高于假手术组(P<0.05),I/R+ SA组脑水含量显著低于I/R组(P<0.05),I/R+ SA+ nor-BIN组脑水量显著高于I/R+ SA组(P<0.05).脑组织VEGF蛋白表达检测结果显示:I/R+ SA组显著高于I/R组(P<0.01),I/R+ SA+ nor-BIN组显著低于I/R+ SA组(P<0.05).I/R+ SA组I/R损伤后1、2、5d神经运动功能评分均显著高于I/R组、I/R+ DMSO组和I/R+SA+norBIN(P<0.05).结论 SA可以减轻I/R损伤造成的脑组织水肿并改善神经功能,其机制可能与通过KOR上调VEGF蛋白表达有关.

  3. 电针对佐剂性关节炎大鼠炎症局部κ阿片受体mRNA表达的影响%Effects of Electro-acupuncture on Kappa Opioid Receptor in Inflammatory Location of Adjuvant Arthritis Rats

    Institute of Scientific and Technical Information of China (English)

    盛佑祥; 赵仓焕

    2008-01-01

    目的:从阿片受体角度观察电针(EA)对佐剂性关节炎(AA)大鼠产生镇痛的外周机制.方法:以Freund's完全佐荆造成AA大鼠模型,在EA治疗后观测大鼠痛阈、炎症局部κ阿片受体(KOR)mRNA的表达.结果:EA治疗后,大鼠的痛阈提高,炎症局部KOR mRNA的表达增强.结论:EA对从大鼠有明显镇痛效应,且镇痛效应的产生与大鼠炎症局部的KOR mRNA表达增强有关.

  4. Pilot Candidate Selection

    Science.gov (United States)

    1989-05-01

    pilot selection system and to best support up-front track selection for SUPT? Assumptions The USAF Trainer Masterplan does not include a plan to...replace the T-41 with a new flight screening aircraft. In addition, the Masterplan states that candidates will be track selected prior to entry into primary...training. (3:10) While the Masterplan is not a static document and aircraft procurement plans and/or the timing of track selection are subject to

  5. IT Project Selection

    DEFF Research Database (Denmark)

    Pedersen, Keld

    2016-01-01

    Selecting the right IT projects is increasingly important for many organizations. Project portfolio managers play a key role during project selection, but even though they have a great impact on the selection process, we have little knowledge about how they decide which projects to recommend for ...

  6. Selection of Anesthesiology Residents.

    Science.gov (United States)

    Baker, J. David, III; And Others

    1993-01-01

    Selection data for all Medical University of South Carolina anesthesiology residency applicants (about 200 per year) and the 8 selected per year were compared for 4 years. Results showed standardized test scores, grades, and class ranks of those selected were not higher than of others, but interview and recommendation scores were higher.…

  7. Strategic Sample Selection

    DEFF Research Database (Denmark)

    Di Tillio, Alfredo; Ottaviani, Marco; Sørensen, Peter Norman

    2017-01-01

    is double logconvex, as with normal noise. The results are applied to the analysis of strategic sample selection by a biased researcher and extended to the case of uncertain and unanticipated selection. Our theoretical analysis offers applied research a new angle on the problem of selection in empirical...

  8. Economic Selection Theory

    DEFF Research Database (Denmark)

    Knudsen, Thorbjørn

    2003-01-01

    The present article provides a minimal description of the causal structure of economic selection theory and outlines how the internal selection dynamics of business organisations can be reconciled with selection in competitive markets. In addition to generic similarity in terms of the Darwinian...... principles of variation, continuity and selection, it is argued that economic selection theory should mimic the causal structure of neo-Darwinian theory. Two of the most influential explanations of economic evolution, Alchian's and Nelson and Winter's, are used to illustrate how this could be achieved....

  9. Economic Selection Theory

    DEFF Research Database (Denmark)

    Knudsen, Thorbjørn

    2003-01-01

    The present article provides a minimal description of the causal structure of economic selection theory and outlines how the internal selection dynamics of business organisations can be reconciled with selection in competitive markets. In addition to generic similarity in terms of the Darwinian...... principles of variation, continuity and selection, it is argued that economic selection theory should mimic the causal structure of neo-Darwinian theory. Two of the most influential explanations of economic evolution, Alchian's and Nelson and Winter's, are used to illustrate how this could be achieved....

  10. Competition and facilitation between unicellular nitrogen-fixing cyanobacteria and non-nitrogen-fixing phytoplankton species

    NARCIS (Netherlands)

    Agawin, N.S.; Rabouille, S.; Veldhuis, M.; Servatius, L.; Hol, S.; van Overzee, H.M.J.; Huisman, J.

    2007-01-01

    Abstract: Recent discoveries show that small unicellular nitrogen-fixing cyanobacteria are more widespread than previously thought and can make major contributions to the nitrogen budget of the oceans. We combined theory and experiments to investigate competition for nitrogen and light between these

  11. Preperation and characterization of a phosphorous free and non-nitrogen antiscalant in industrial cooling systems

    Energy Technology Data Exchange (ETDEWEB)

    Fu, C. [Southeast Univ., School of Chemistry and Chemical Engineering, Nanjing (China); Nanjing College of Chemical Technology, Nanjing (China); Zhou, Y.; Huang, J.; Xie, H.; Liu, G. [Southeast Univ., School of Chemistry and Chemical Engineering, Nanjing (China); Wu, W.; Sun, W. [Jiangsu Jianhai Chemcial Co., Ltd., Changzhou (China)

    2011-01-15

    A novel nonpolluting type of calcium phosphate and iron(III) antiscalant MCn was synthesized. The observation shows that MCn causes a disordered calcium phosphate. Furthermore, both calcium phosphate and iron(III) inhibition increase with increasing degree of polymerization of MCn from 5 to 13, and the dosage of MCn plays an important role on calcium phosphate and iron(III) inhibition. Inhibition mechanism is proposed the interactions between calcium or iron ions and polyethylene glycol (PEG) are the fundamental impetus to restrain the formation of the scale in cooling water systems. (orig.)

  12. Synthesis, inhibition and binding of simple non-nitrogen inhibitors of monoamine transporters.

    Science.gov (United States)

    Petersen, Mikkel Due; Boye, Søren Valdgård; Nielsen, Erik Holm; Willumsen, Jeanette; Sinning, Steffen; Wiborg, Ove; Bols, Mikael

    2007-06-15

    A series of simple truncated analogues of phenyl tropanes, 2-arylcycloalk-1-enyl carboxylic acid methylesters, were prepared and investigated for their activity towards the dopamine, serotonin and norepinephrine transporters. The compounds were prepared from cyclic ketoesters, which were converted to enolic triflates and reacted with arylboronates using the Suzuki coupling. For comparison the corresponding piperidines were also made and investigated. The new compounds inhibit monoamine-transporters with Ki values ranging from 0.1 to 1000 microM.

  13. Compressors selection and sizing

    CERN Document Server

    Brown, Royce N

    2005-01-01

    This practical reference provides in-depth information required to understand and properly estimate compressor capabilities and to select the proper designs. Engineers and students will gain a thorough understanding of compression principles, equipment, applications, selection, sizing, installation, and maintenance. The many examples clearly illustrate key aspects to help readers understand the ""real world"" of compressor technology.Compressors: Selection and Sizing, third edition is completely updated with new API standards. Additions requested by readers include a new section on di

  14. Recruiter Selection Model

    Science.gov (United States)

    2006-05-01

    interests include feature selection, statistical learning, multivariate statistics, market research, and classification. He may be contacted at...current youth market , and reducing barriers to Army enlistment. Part of the Army Recruiting Initiatives was the creation of a recruiter selection...Selection Model DevelPed by the Openuier Reseach Crate of E...lneSstm Erapseeeng Depce-teo, WViitd Ntt. siliec Academy, NW..t Point, 271 Weau/’itt 21M

  15. IT Project Selection

    DEFF Research Database (Denmark)

    Pedersen, Keld

    2016-01-01

    Selecting the right IT projects is increasingly important for many organizations. Project portfolio managers play a key role during project selection, but even though they have a great impact on the selection process, we have little knowledge about how they decide which projects to recommend...... the development of methods that better fit current practice. The study is based on naturalistic decision-making theory and interviews with experienced project portfolio managers who, when selecting projects, primarily rely on political skills, experience and personal networks rather than on formal IT project...

  16. Frequency selective infrared sensors

    Science.gov (United States)

    Davids, Paul; Peters, David W

    2013-05-28

    A frequency selective infrared (IR) photodetector having a predetermined frequency band. The exemplary frequency selective photodetector includes: a dielectric IR absorber having a first surface and a second surface substantially parallel to the first surface; an electrode electrically coupled to the first surface of the dielectric IR absorber; and a frequency selective surface plasmonic (FSSP) structure formed on the second surface of the dielectric IR absorber. The FSSP structure is designed to selectively transmit radiation in the predetermined frequency band that is incident on the FSSP structure substantially independent of the angle of incidence of the incident radiation on the FSSP structure.

  17. Entrepreneurs and Economic Selection

    DEFF Research Database (Denmark)

    Holm, Jacob Rubæk

    of Schumpeter's models is also mapped and it is shown that the traditional interpretation of selection as a source of allocative efficiency is at most applicable to input markets in manufacturing sectors. In output markets and in service sectors in general selection is a more dynamic phenomenon where resources...

  18. HYBASE : HYperspectral BAnd SElection

    NARCIS (Netherlands)

    Schwering, P.B.W.; Bekman, H.H.P.T.; Seijen, H.H. van

    2009-01-01

    Band selection is essential in the design of multispectral sensor systems. This paper describes the TNO hyperspectral band selection tool HYBASE. It calculates the optimum band positions given the number of bands and the width of the spectral bands. HYBASE is used to assess the minimum number of spe

  19. Sexual selection in Fungi

    NARCIS (Netherlands)

    Nieuwenhuis, B.P.S.

    2012-01-01

    Sexual selection is an important factor that drives evolution, in which fitness is increased, not by increasing survival or viability, but by acquiring more or better mates. Sexual selection favours traits that increase the ability of an individual to obtain more matings than other individuals that

  20. Selected areas in cryptography

    CERN Document Server

    Oorschot, Paul

    1997-01-01

    Selected Areas in Cryptography brings together in one place important contributions and up-to-date research results in this fast moving area. Selected Areas in Cryptography serves as an excellent reference, providing insight into some of the most challenging research issues in the field.

  1. Sexual selection in Fungi

    NARCIS (Netherlands)

    Nieuwenhuis, B.P.S.

    2012-01-01

    Sexual selection is an important factor that drives evolution, in which fitness is increased, not by increasing survival or viability, but by acquiring more or better mates. Sexual selection favours traits that increase the ability of an individual to obtain more matings than other individuals that

  2. Selection of Electronic Resources.

    Science.gov (United States)

    Weathers, Barbara

    1998-01-01

    Discusses the impact of electronic resources on collection development; selection of CD-ROMs, (platform, speed, video and sound, networking capability, installation and maintenance); selection of laser disks; and Internet evaluation (accuracy of content, authority, objectivity, currency, technical characteristics). Lists Web sites for evaluating…

  3. Selective Reproductive Technologies

    DEFF Research Database (Denmark)

    Gammeltoft, Tine; Wahlberg, Ayo

    2014-01-01

    selective reproduction has been placed under the aegis of science and expertise in novel ways. New laboratory and clinical techniques allow for the selective fertilization of gametes, implantation of embryos, or abortion of fetuses. Although they will often overlap with assisted reproductive technologies...

  4. Potentiometric anion selective sensors

    NARCIS (Netherlands)

    Antonisse, Martijn M.G.; Reinhoudt, David N.

    1999-01-01

    In comparison with selective receptors (and sensors) for cationic species, work on the selective complexation and detection of anions is of more recent date. There are three important components for a sensor, a transducer element, a membrane material that separates the transducer element and the aqu

  5. Range Selection and Median

    DEFF Research Database (Denmark)

    Jørgensen, Allan Grønlund; Larsen, Kasper Green

    2011-01-01

    Range selection is the problem of preprocessing an input array A of n unique integers, such that given a query (i; j; k), one can report the k'th smallest integer in the subarray A[i];A[i+1]; : : : ;A[j]. In this paper we consider static data structures in the word-RAM for range selection and sev...

  6. Autonomous component carrier selection

    DEFF Research Database (Denmark)

    Garcia, Luis Guilherme Uzeda; Pedersen, Klaus; Mogensen, Preben

    2009-01-01

    in local areas, basing our study case on LTE-Advanced. We present extensive network simulation results to demonstrate that a simple and robust interference management scheme, called autonomous component carrier selection allows each cell to select the most attractive frequency configuration; improving...

  7. Green Supplier Selection Criteria

    DEFF Research Database (Denmark)

    Nielsen, Izabela Ewa; Banaeian, Narges; Mobli, Hossein

    2014-01-01

    Green supplier selection (GSS) criteria arise from an organization inclination to respond to any existing trends in environmental issues related to business management and processes, so GSS is integrating environmental thinking into conventional supplier selection. This research is designed...... to determine prevalent general and environmental supplier selection criteria and develop a framework which can help decision makers to determine and prioritize suitable green supplier selection criteria (general and environmental). In this research we considered several parameters (evaluation objectives......) to establish suitable criteria for GSS such as their production type, requirements, policy and objectives instead of applying common criteria. At first a comprehensive and deep review on prevalent and green supplier selection literatures performed. Then several evaluation objectives defined to assess the green...

  8. Range Selection and Median

    DEFF Research Database (Denmark)

    Jørgensen, Allan Grønlund; Larsen, Kasper Green

    2011-01-01

    and several natural special cases thereof. The rst special case is known as range median, which arises when k is xed to b(j 􀀀 i + 1)=2c. The second case, denoted prex selection, arises when i is xed to 0. Finally, we also consider the bounded rank prex selection problem and the xed rank range......Range selection is the problem of preprocessing an input array A of n unique integers, such that given a query (i; j; k), one can report the k'th smallest integer in the subarray A[i];A[i+1]; : : : ;A[j]. In this paper we consider static data structures in the word-RAM for range selection...... selection problem. In the former, data structures must support prex selection queries under the assumption that k for some value n given at construction time, while in the latter, data structures must support range selection queries where k is xed beforehand for all queries. We prove cell probe lower bounds...

  9. Selecting Schizosaccharomyces pombe diploids

    DEFF Research Database (Denmark)

    Ekwall, Karl; Thon, Genevieve

    2017-01-01

    .g., for genetic complementation tests), and in these cases mating an h− strain with an h90 mat2-Pi-102 strain can be used to prevent sporulation. When ade6-M210/ade6-M216 mutations impact on, or show synthetic interactions with, the gene of interest, two different auxotrophic markers can be used to select......Here we describe procedures for the selection of diploid Schizosaccharomyces pombe. ade6-M210/ade6-M216 heteroallelic complementation is widely used to select for Ade+ diploids. Such diploids will readily sporulate when starved of nitrogen. For some investigations, stable diploids are preferable (e...

  10. Selective Reproductive Technologies

    DEFF Research Database (Denmark)

    Gammeltoft, Tine; Wahlberg, Ayo

    2014-01-01

    selective reproduction has been placed under the aegis of science and expertise in novel ways. New laboratory and clinical techniques allow for the selective fertilization of gametes, implantation of embryos, or abortion of fetuses. Although they will often overlap with assisted reproductive technologies...... (ARTs), what we term selective reproductive technologies (SRTs) are of a more specific nature: Rather than aiming to overcome infertility, they are used to prevent or allow the birth of certain kinds of children. This review highlights anthropological research into SRTs in different parts of the world...

  11. The Administrator Selection Process

    Science.gov (United States)

    Griffin, Michael F.

    1974-01-01

    Proposes that education establish for administrators systematic, rigorous, albeit subjective, selection procedures that recognize the principle of organizational democracy and the public nature of the educational enterprise. (Author/DN)

  12. Mode selection laser

    DEFF Research Database (Denmark)

    2014-01-01

    The invention relates to a semiconductor mode selection laser, particularly to a VCSEL laser (200) having mode selection properties. The mode selection capability of the laser is achieved by configuring one of the reflectors (15,51) in the resonance cavity so that a reflectivity of the reflector...... (15) varies spatially in one dimension or two dimensions. Accordingly, the reflector (15) with spatially varying reflectivity is part both of the resonance cavity and the mode selection functionality of the laser. A plurality of the lasers configured with different mode selectors, i.e. different...... spatial reflector variations, may be combined to generate a laser beam containing a plurality of orthogonal modes. The laser beam may be injected into a few- mode optical fiber, e.g. for the purpose of optical communication. The VCSEL may have intra-cavity contacts (31,37) and a Tunnel junction (33...

  13. Kin Selection - Mutation Balance

    DEFF Research Database (Denmark)

    Dyken, J. David Van; Linksvayer, Timothy Arnold; Wade, Michael J.

    2011-01-01

    Abstract Social conflict, in the form of intraspecific selfish "cheating" has been observed in a number of natural systems. However, a formal, evolutionary genetic theory of social cheating that provides an explanatory, predictive framework for these observations is lacking. Here we derive the kin...... selection-mutation balance, which provides an evolutionary null hypothesis for the statics and dynamics of cheating. When social interactions have linear fitness effects and Hamilton´s rule is satisfied, selection is never strong enough to eliminate recurrent cheater mutants from a population, but cheater...... lineages are transient and do not invade. Instead, cheating lineages are eliminated by kin selection but are constantly reintroduced by mutation, maintaining a stable equilibrium frequency of cheaters. The presence of cheaters at equilibrium creates a "cheater load" that selects for mechanisms of cheater...

  14. Selection of Celebrity Endorsers

    DEFF Research Database (Denmark)

    Hollensen, Svend; Schimmelpfennig, Christian

    2013-01-01

    Purpose - This research aims at shedding some light on the various avenues marketers can undertake until finally an endorsement contract is signed. The focus of the study lies on verifying the generally held assumption that endorser selection is usually taken care of by creative agencies, vetting...... several candidates by means of subtle evaluation procedures. Design/methodology/approach – A case study research has been carried out among companies experienced in celebrity endorsements to learn more about the endorser selection process in practise. Based on these cases theory is inductively developed....... Findings – Our research suggests that generally held assumption that endorsers being selected and thoroughly vetted by a creative agency may not be universally valid. A normative model to illustrate the continuum of the selection process in practise is suggested and the two polar case studies (Swiss brand...

  15. HARMONIC DRIVE SELECTION

    Directory of Open Access Journals (Sweden)

    Piotr FOLĘGA

    2014-03-01

    Full Text Available The variety of types and sizes currently in production harmonic drive is a problem in their rational choice. Properly selected harmonic drive must meet certain requirements during operation, and achieve the anticipated service life. The paper discusses the problems associated with the selection of the harmonic drive. It also presents the algorithm correct choice of harmonic drive. The main objective of this study was to develop a computer program that allows the correct choice of harmonic drive by developed algorithm.

  16. Selection in artistic gymnastics

    Directory of Open Access Journals (Sweden)

    Maria Olaru

    2009-06-01

    Full Text Available This study envisages the analysis of the specific aspects of the selection process in artistic gymnastics, focusing particularly onthe selection of Romania’s recent years. In our opinion, the shift to a cone of darkness of the artistic gymnastics, an extremelypopular sport in our country 20 years ago, is also based on and the orientation of children to other fields – unfortunately manyof them outside sports and physical activities in general. In the present study, we shall present the stages of the artisticgymnastics, as its importance in the subsequent performances has been proven a long time ago. The plethora of qualities andskills which are necessary to select a child for gymnastics and those that this sport develops when performed as a spare timeactivity. The case studied in this endeavour is the one of the main centers for gymnast recruitment in Romania; the attentionpaid by the trainers to the selection for this sport makes the data regarding the number of children involved to increase oncemore. This is a satisfactory fact as it is a well-known fact that a wide range primary selection sets a serious basis for thesecondary selection, and the third, respectively, envisaging the future performance and concurrently ensures the involvementof more children in a physical activity that will prepare them, both physically and mentally for a healthy life.

  17. Spectrally selective glazings

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-08-01

    Spectrally selective glazing is window glass that permits some portions of the solar spectrum to enter a building while blocking others. This high-performance glazing admits as much daylight as possible while preventing transmission of as much solar heat as possible. By controlling solar heat gains in summer, preventing loss of interior heat in winter, and allowing occupants to reduce electric lighting use by making maximum use of daylight, spectrally selective glazing significantly reduces building energy consumption and peak demand. Because new spectrally selective glazings can have a virtually clear appearance, they admit more daylight and permit much brighter, more open views to the outside while still providing the solar control of the dark, reflective energy-efficient glass of the past. This Federal Technology Alert provides detailed information and procedures for Federal energy managers to consider spectrally selective glazings. The principle of spectrally selective glazings is explained. Benefits related to energy efficiency and other architectural criteria are delineated. Guidelines are provided for appropriate application of spectrally selective glazing, and step-by-step instructions are given for estimating energy savings. Case studies are also presented to illustrate actual costs and energy savings. Current manufacturers, technology users, and references for further reading are included for users who have questions not fully addressed here.

  18. Behavioral meaningful opioidergic stimulation activates kappa receptor gene expression

    Directory of Open Access Journals (Sweden)

    E. Teodorov

    2012-10-01

    Full Text Available The periaqueductal gray (PAG has been reported to be a location for opioid regulation of pain and a potential site for behavioral selection in females. Opioid-mediated behavioral and physiological responses differ according to the activity of opioid receptor subtypes. The present study investigated the effects of the peripheral injection of the kappa-opioid receptor agonist U69593 into the dorsal subcutaneous region of animals on maternal behavior and on Oprk1 gene activity in the PAG of female rats. Female Wistar rats weighing 200-250 g at the beginning of the study were randomly divided into 2 groups for maternal behavior and gene expression experiments. On day 5, pups were removed at 7:00 am and placed in another home cage that was distant from their mother. Thirty minutes after removing the pups, the dams were treated with U69593 (0.15 mg/kg, sc or 0.9% saline (up to 1 mL/kg and after 30 min were evaluated in the maternal behavior test. Latencies in seconds for pup retrieval, grouping, crouching, and full maternal behavior were scored. The results showed that U69593 administration inhibited maternal behavior (P < 0.05 because a lower percentage of kappa group dams showed retrieval of first pup, retrieving all pups, grouping, crouching and displaying full maternal behavior compared to the saline group. Opioid gene expression was evaluated using real-time reverse-transcription polymerase chain reaction (RT-PCR. A single injection of U69593 increased Oprk1 PAG expression in both virgin (P < 0.05 and lactating female rats (P < 0.01, with no significant effect on Oprm1 or Oprd1 gene activity. Thus, the expression of kappa-opioid receptors in the PAG may be modulated by single opioid receptor stimulation and behavioral meaningful opioidergic transmission in the adult female might occur simultaneously to specific changes in gene expression of kappa-opioid receptor subtype. This is yet another alert for the complex role of the opioid system in

  19. Behavioral meaningful opioidergic stimulation activates kappa receptor gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Teodorov, E. [Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, São Paulo, SP (Brazil); Ferrari, M.F.R. [Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP (Brazil); Fior-Chadi, D.R. [Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP (Brazil); Camarini, R. [Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP (Brazil); Felício, L.F. [Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil)

    2012-06-01

    The periaqueductal gray (PAG) has been reported to be a location for opioid regulation of pain and a potential site for behavioral selection in females. Opioid-mediated behavioral and physiological responses differ according to the activity of opioid receptor subtypes. The present study investigated the effects of the peripheral injection of the kappa-opioid receptor agonist U69593 into the dorsal subcutaneous region of animals on maternal behavior and on Oprk1 gene activity in the PAG of female rats. Female Wistar rats weighing 200-250 g at the beginning of the study were randomly divided into 2 groups for maternal behavior and gene expression experiments. On day 5, pups were removed at 7:00 am and placed in another home cage that was distant from their mother. Thirty minutes after removing the pups, the dams were treated with U69593 (0.15 mg/kg, sc) or 0.9% saline (up to 1 mL/kg) and after 30 min were evaluated in the maternal behavior test. Latencies in seconds for pup retrieval, grouping, crouching, and full maternal behavior were scored. The results showed that U69593 administration inhibited maternal behavior (P < 0.05) because a lower percentage of U69593 group dams showed retrieval of first pup, retrieving all pups, grouping, crouching and displaying full maternal behavior compared to the saline group. Opioid gene expression was evaluated using real-time reverse-transcription polymerase chain reaction (RT-PCR). A single injection of U69593 increased Oprk1 PAG expression in both virgin (P < 0.05) and lactating female rats (P < 0.01), with no significant effect on Oprm1 or Oprd1 gene activity. Thus, the expression of kappa-opioid receptors in the PAG may be modulated by single opioid receptor stimulation and behavioral meaningful opioidergic transmission in the adult female might occur simultaneously to specific changes in gene expression of kappa-opioid receptor subtype. This is yet another alert for the complex role of the opioid system in female

  20. Selecting and evoking innovators

    DEFF Research Database (Denmark)

    Kanstrup, Anne Marie; Christiansen, Ellen

    2006-01-01

    The practical undertaking of selecting users to work as innovators and of evoking their creative potential is crucial, but underexposed in the literature on user involvement in design. This paper reports findings from a recent case of user-driven innovation, the FEEDBACK-project, where the authors...... prepared for and conducted selection of and collaboration with innovators. The outcome was successful in the sense that the innovators produced excellent foundation for conceptual interaction design by creating mock-ups and explanations incarnating their preferences, attitudes and habits. By referring...... to theories of learning we try to explain how our way of working with selection and evoking of innovators has contributed to this positive result and how our approach to user-driven innovation can be regarded as a way to combine democracy and creativity in design....

  1. Online Distributed Sensor Selection

    CERN Document Server

    Golovin, Daniel; Krause, Andreas

    2010-01-01

    A key problem in sensor networks is to decide which sensors to query when, in order to obtain the most useful information (e.g., for performing accurate prediction), subject to constraints (e.g., on power and bandwidth). In many applications the utility function is not known a priori, must be learned from data, and can even change over time. Furthermore for large sensor networks solving a centralized optimization problem to select sensors is not feasible, and thus we seek a fully distributed solution. In this paper, we present Distributed Online Greedy (DOG), an efficient, distributed algorithm for repeatedly selecting sensors online, only receiving feedback about the utility of the selected sensors. We prove very strong theoretical no-regret guarantees that apply whenever the (unknown) utility function satisfies a natural diminishing returns property called submodularity. Our algorithm has extremely low communication requirements, and scales well to large sensor deployments. We extend DOG to allow observatio...

  2. Progressive Band Selection

    Science.gov (United States)

    Fisher, Kevin; Chang, Chein-I

    2009-01-01

    Progressive band selection (PBS) reduces spectral redundancy without significant loss of information, thereby reducing hyperspectral image data volume and processing time. Used onboard a spacecraft, it can also reduce image downlink time. PBS prioritizes an image's spectral bands according to priority scores that measure their significance to a specific application. Then it uses one of three methods to select an appropriate number of the most useful bands. Key challenges for PBS include selecting an appropriate criterion to generate band priority scores, and determining how many bands should be retained in the reduced image. The image's Virtual Dimensionality (VD), once computed, is a reasonable estimate of the latter. We describe the major design details of PBS and test PBS in a land classification experiment.

  3. Antecedent Selection for Sluicing

    DEFF Research Database (Denmark)

    Anand, Pranav; Hardt, Daniel

    2016-01-01

    Sluicing is an elliptical process where the majority of a question can go unpronounced as long as there is a salient antecedent in previous discourse. This paper considers the task of antecedent selection: finding the correct antecedent for a given case of sluicing. We argue that both syntactic...... and discourse relationships are important in antecedent selection, and we construct linguistically sophisticated features that describe the relevant relationships. We also define features that describe the relation of the content of the antecedent and the sluice type. We develop a linear model which achieves...... accuracy of 72.4%, a substantial improvement over a strong manually constructed baseline. Feature analysis confirms that both syntactic and discourse features are important in antecedent selection....

  4. High Selectivity Oxygen Delignification

    Energy Technology Data Exchange (ETDEWEB)

    Lucian A. Lucia

    2005-11-15

    Project Objective: The objectives of this project are as follows: (1) Examine the physical and chemical characteristics of a partner mill pre- and post-oxygen delignified pulp and compare them to lab generated oxygen delignified pulps; (2) Apply the chemical selectivity enhancement system to the partner pre-oxygen delignified pulps under mill conditions (with and without any predetermined amounts of carryover) to determine how efficiently viscosity is preserved, how well selectivity is enhanced, if strength is improved, measure any yield differences and/or bleachability differences; and (3) Initiate a mill scale oxygen delignification run using the selectivity enhancement agent, collect the mill data, analyze it, and propose any future plans for implementation.

  5. A Selective CPS Transformation

    DEFF Research Database (Denmark)

    Nielsen, Lasse Riechstein

    2001-01-01

    The CPS transformation makes all functions continuation-passing, uniformly. Not all functions, however, need continuations: they only do if their evaluation includes computational effects. In this paper we focus on control operations, in particular "call with current continuation" and "throw". We...... characterize this involvement as a control effect and we present a selective CPS transformation that makes functions and expressions continuation-passing if they have a control effect, and that leaves the rest of the program in direct style. We formalize this selective CPS transformation with an operational...

  6. Variable selection through CART

    CERN Document Server

    Sauvé, Marie

    2011-01-01

    This paper deals with variable selection in the regression and binary classification frameworks. It proposes an automatic and exhaustive procedure which relies on the use of the CART algorithm and on model selection via penalization. This work, of theoretical nature, aims at determining adequate penalties, i.e. penalties which allow to get oracle type inequalities justifying the performance of the proposed procedure. Since the exhaustive procedure can not be executed when the number of variables is too big, a more practical procedure is also proposed and still theoretically validated. A simulation study completes the theoretical results.

  7. Ion-selective electrodes

    CERN Document Server

    Mikhelson, Konstantin N

    2013-01-01

    Ion-selective electrodes (ISEs) have a wide range of applications in clinical, environmental, food and pharmaceutical analysis as well as further uses in chemistry and life sciences. Based on his profound experience as a researcher in ISEs and a course instructor, the author summarizes current knowledge for advanced teaching and training purposes with a particular focus on ionophore-based ISEs. Coverage includes the basics of measuring with ISEs, essential membrane potential theory and a comprehensive overview of the various classes of ion-selective electrodes. The principles of constructing I

  8. A Selective CPS Transformation

    DEFF Research Database (Denmark)

    Nielsen, Lasse Riechstein

    2001-01-01

    The CPS transformation makes all functions continuation-passing, uniformly. Not all functions, however, need continuations: they only do if their evaluation includes computational effects. In this paper we focus on control operations, in particular "call with current continuation" and "throw". We...... characterize this involvement as a control effect and we present a selective CPS transformation that makes functions and expressions continuation-passing if they have a control effect, and that leaves the rest of the program in direct style. We formalize this selective CPS transformation with an operational...

  9. Selective Coronary Arteriography

    Science.gov (United States)

    Parker, John O.; Challis, Thomas W.; West, Roxroy O.

    1966-01-01

    The technique of selective coronary arteriography, as described originally by Sones, was employed in 255 patients. Successful catheterization of both coronary arteries was carried out in 88% of these patients, and in the last 100 examinations both coronary arteries were entered in 95 patients. Selective coronary arteriography is a useful diagnostic tool but is a potentially hazardous form of examination as we encountered four episodes of ventricular fibrillation in the present series. ImagesFig. 1Fig. 2Figs. 3A-DFig. 3EFig. 3FFig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9 PMID:5902704

  10. Selecting Sums in Arrays

    DEFF Research Database (Denmark)

    Brodal, Gerth Stølting; Jørgensen, Allan Grønlund

    2008-01-01

    In an array of n numbers each of the \\binomn2+nUnknown control sequence '\\binom' contiguous subarrays define a sum. In this paper we focus on algorithms for selecting and reporting maximal sums from an array of numbers. First, we consider the problem of reporting k subarrays inducing the k larges...... an algorithm with this running time and by proving a matching lower bound. Finally, we combine the ideas and obtain an O(n· max {1,log(k/n)}) time algorithm that selects a subarray storing the k’th largest sum among all subarrays of length at least l and at most u....

  11. A Note on Semantic Selection.

    Science.gov (United States)

    Endo, Yoshio

    1989-01-01

    The notions of categorical selection (c-selection) and semantic selection (s-selection) as outlined in recent research on generative grammar are discussed. The first section addresses the type of selectional constraint imposed on English small clauses (e.g., "John considers [Mary smart]"). In the second section, it is suggested that the constraint…

  12. Ecology, sexual selection and speciation

    NARCIS (Netherlands)

    Maan, Martine E.; Seehausen, Ole

    2011-01-01

    P>The spectacular diversity in sexually selected traits among animal taxa has inspired the hypothesis that divergent sexual selection can drive speciation. Unfortunately, speciation biologists often consider sexual selection in isolation from natural selection, even though sexually selected traits e

  13. Selecting a Reference Object

    Science.gov (United States)

    Miller, Jared E.; Carlson, Laura A.; Hill, Patrick L.

    2011-01-01

    One way to describe the location of an object is to relate it to another object. Often there are many nearby objects, each of which could serve as a candidate to be the reference object. A common theoretical assumption is that features that make a given object salient relative to the candidate set are instrumental in determining which is selected.…

  14. Antenna (Selected Articles),

    Science.gov (United States)

    1981-10-16

    optimum selection of the parameters of parabola and the subsequent gradient descent. The corresponding positions of elements/cells are given in F~g...are known from literatura (5], and were also in Ietail invastigated both thecritically and experimental £ 5-7]. DOC = 81082604 PAGE Page 59. By tha

  15. Selected Resources and Bibliography

    Science.gov (United States)

    New Directions for Higher Education, 2011

    2011-01-01

    This chapter provides an annotated bibliography of resources pertaining to international branch campuses (IBCs). This collection of references has been selected to represent the breadth of emerging scholarship on cross-border higher education and is intended to provide further resources on a range of concerns surrounding cross-border higher…

  16. Multiband frequency selective surface

    Science.gov (United States)

    Wu, Te-Kao

    1998-10-01

    This paper addresses the similarity of microwave/millimeter wave frequency selective surfaces (FSS) to optical filters. Specifically, the design approaches of the 4-band FSSs developed for NASA's CASSINI high gain antenna are described in detail. Representative RF test results are given to demonstrate the validity of these designs. These design approaches are very general and can be applied to multiband optical filters.

  17. Selecting Your First Telescope.

    Science.gov (United States)

    Harrington, Sherwood

    1982-01-01

    Designed for first-time telescope purchasers, provides information on how a telescope works; major telescope types (refractors, reflectors, compound telescopes); tripod, pier, altazimuth, and equatorial mounts; selecting a telescope; visiting an astronomy club; applications/limitations of telescope use; and tips on buying a telescope. Includes a…

  18. Selection and Serial Entrepreneurs

    DEFF Research Database (Denmark)

    Chen, Jing

    2011-01-01

    Although it has been broadly evidenced that entrepreneurial experience plays a substantial role in the emergence of serial entrepreneurship, the debate is still going on about whether this relationship should be attributed to learning by doing or instead be explained by selection on ability. This...

  19. Entrepreneurs and Economic Selection

    DEFF Research Database (Denmark)

    Holm, Jacob Rubæk

    This paper suggests how George Price's general mathematical theory of selection may be applied to economic data; and it is discussed how Price's equation may be expanded and interpreted so that it describes the mechanisms of Schumpeterian competition and thus the industrial dynamics underlying th...

  20. Selection and Serial Entrepreneurs

    DEFF Research Database (Denmark)

    Chen, Jing

    2013-01-01

    There is substantial evidence that serial entrepreneurs outperform de novo entrepreneurs. But is this positive association between prior experience and performance the result of learning by doing or of selection on ability? This paper proposes a strategy that combines the fixed-effects model and IV...... when the analysis focuses on founding new startups in sectors closely related to entrepreneurs' previous ventures....

  1. Selecting a Sample

    Science.gov (United States)

    Ritter, Lois A., Ed.; Sue, Valerie M., Ed.

    2007-01-01

    This chapter provides an overview of sampling methods that are appropriate for conducting online surveys. The authors review some of the basic concepts relevant to online survey sampling, present some probability and nonprobability techniques for selecting a sample, and briefly discuss sample size determination and nonresponse bias. Although some…

  2. Enlisted Selection Strategies

    Science.gov (United States)

    1974-09-01

    substantial 1 grades related (modera ance. School failure ra , but selection tests we restimated their school ement to paygrade E-4 we...supervisor; only in a minor sense does it evaluate job proficiency and supervisory skills. There were no differences in Class A School failure rates for

  3. Sustainable agriculture - selected papers

    OpenAIRE

    Krasowicz, Stanisław; Wrzaszcz, Wioletta; Zegar, Jozef St.

    2007-01-01

    The concept of research on socially sustainable agriculture. Features of sustainable agriculture. Sustainability of private farms in the light of selected criteria. Subsistence agricultural holdings and the sustainable development of agriculture. Sustainable farms in the light of the FADN data. Description of organic holdings in Poland.

  4. Heilongjiang Pictorial (Selected Articles),

    Science.gov (United States)

    2014-09-26

    65 UNCLASSIFIED FIG S/9 Nt "’.7 1U*4 -6 FTD-ID(RS )T-0293-8s 0V FOREIGN TECHNOLOGY DIVISION HEILONGJIANG PICTORIAL (Selected Articles ) DITIC LJ. EECT... Articles ) English pages: 12 Source: Heilongjianghuavao, Nr. 4, 1984, pp. 1-4 Country of origin: China Acceqs , - Translated by: FLS, INC.NTSG

  5. Selecting the Right Software.

    Science.gov (United States)

    Shearn, Joseph

    1987-01-01

    Selection of administrative software requires analyzing present needs and, to meet future needs, choosing software that will function with a more powerful computer system. Other important factors to include are a professional system demonstration, maintenance and training, and financial considerations that allow leasing or renting alternatives.…

  6. [{sup 11}C]-GR89696, a potent kappa opiate receptor radioligand; in vivo binding of the R and S enantiomers

    Energy Technology Data Exchange (ETDEWEB)

    Ravert, Hayden T. E-mail: htr@jhu.edu; Scheffel, Ursula; Mathews, William B.; Musachio, John L.; Dannals, Robert F

    2002-01-01

    The R and S enantiomers of [{sup 11}C]GR89696, [{sup 11}C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl] -1-piperazinecarboxylate, were synthesized from their appropriate chiral precursors and [{sup 11}C]methyl chloroformate. The [{sup 11}C]-labeled R enantiomer of GR89696, also known as GR103545, demonstrated high affinity in mouse brain with region to cerebellar ratios at 90 minutes of 11.4 and 8.7 for the hypothalamus and olfactory tubercle, respectively. The [{sup 11}C]-labeled S enantiomer showed low affinity and region to cerebellar ratios of 1 for all brain regions. The [{sup 11}C]-labeled GR103545 exhibited a selective and saturable binding for the kappa opioid receptor.

  7. Drug models of schizophrenia

    Science.gov (United States)

    Steeds, Hannah; Carhart-Harris, Robin L.

    2015-01-01

    Schizophrenia is a complex mental health disorder with positive, negative and cognitive symptom domains. Approximately one third of patients are resistant to currently available medication. New therapeutic targets and a better understanding of the basic biological processes that drive pathogenesis are needed in order to develop therapies that will improve quality of life for these patients. Several drugs that act on neurotransmitter systems in the brain have been suggested to model aspects of schizophrenia in animals and in man. In this paper, we selectively review findings from dopaminergic, glutamatergic, serotonergic, cannabinoid, GABA, cholinergic and kappa opioid pharmacological drug models to evaluate their similarity to schizophrenia. Understanding the interactions between these different neurotransmitter systems and their relationship with symptoms will be an important step towards building a coherent hypothesis for the pathogenesis of schizophrenia. PMID:25653831

  8. Opioid receptors and legal highs: Salvia divinorum and Kratom.

    Science.gov (United States)

    Babu, Kavita M; McCurdy, Christopher R; Boyer, Edward W

    2008-02-01

    Salvia divinorum and Mitragyna speciosa ("Kratom"), two unscheduled dietary supplements whose active agents are opioid receptor agonists, have discrete psychoactive effects that have contributed to their increasing popularity. Salvia divinorum contains the highly selective kappa- opioid receptor agonist salvinorin A; this compound produces visual hallucinations and synesthesia. Mitragynine, the major alkaloid identified from Kratom, has been reported as a partial opioid agonist producing similar effects to morphine. An interesting minor alkaloid of Kratom, 7-hydroxymitragynine, has been reported to be more potent than morphine. Both Kratom alkaloids are reported to activate supraspinal mu- and delta- opioid receptors, explaining their use by chronic narcotics users to ameliorate opioid withdrawal symptoms. Despite their widespread Internet availability, use of Salvia divinorum and Kratom represents an emerging trend that escapes traditional methods of toxicologic monitoring. The purpose of this article is to familiarize toxicologists and poison control specialists with these emerging psychoactive dietary supplements.

  9. Selective vulnerability in brain hypoxia

    DEFF Research Database (Denmark)

    Cervos-Navarro, J.; Diemer, Nils Henrik

    1991-01-01

    Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis......Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis...

  10. Natural Selection and Morality

    Directory of Open Access Journals (Sweden)

    Alejandro Rosas

    2006-12-01

    Full Text Available Resumen:En este ensayo abordo los intentos, relativamente recientes, de dar una explicación de la moralidad como adaptación por selección natural. Mi exposición tiene una introducción y cuatro partes: en la primera explico en qué consiste la paradoja del altruismo biológico. En la segunda expongo la solución que apela a la selección de grupos, recientemente resurgida; la solución que presuntamente aplicó Charles Darwin cuando formuló sus reflexiones biológicas sobre la moralidad humana. En la tercera expongo la solución sociobiológica, que opta por negar que la selección natural pueda explicar directamente la moralidad humana. La moralidad se presenta más bien como opuesta a la naturaleza diseñada por selección natural. En la cuarta parte desarrollo brevemente una explicación de la moralidad como adaptación que beneficia a los individuos. No opone la moralidad a la naturaleza, ni apela a la selección de grupos. Se sirve de un mecanismo de selección que opera a través de preferencias en la interacción social.Abstract:In this essay, I address recent attempts to account for morality as an adaptation due to natural selection. After a brief introduction, my exposition has four sections. I first explain the paradox of biological altruism. Second, I explain the solution to the paradox in terms of group selection. This solution was presumably applied by Darwin himself as he discussed human morality, and it has experienced a recent revival, though it remains suspicious to most biologists. In the third section I offer a socio-biological solution that opts for denying that morality can be explained by any form of natural selection. Morality is opposed to human nature as designed by natural selection. In the fourth, I argue for an explanation in terms of individual selection. It does not oppose morality to nature, and does not need the workings of group selection; rather, it operates through the agents’ psychological preferences

  11. A Selective Review of Group Selection in High Dimensional Models

    CERN Document Server

    Huang, Jian; Ma, Shuangge

    2012-01-01

    Grouping structures arise naturally in many statistical modeling problems. Several methods have been proposed for variable selection that respect grouping structure in variables. Examples include the group LASSO and several concave group selection methods. In this article, we give a selective review of group selection concerning methodological developments, theoretical properties, and computational algorithms. We pay particular attention to group selection methods involving concave penalties. We address both group selection and bi-level selection methods. We describe several applications of these methods in nonparametric additive models, semiparametric regression, seemingly unrelated regressions, genomic data analysis and genome wide association studies. We also highlight some issues that require further study.

  12. Humor and sexual selection.

    Science.gov (United States)

    Storey, Robert

    2003-12-01

    Recently Geoffrey Miller has suggested that humor evolved through sexual selection as a signal of "creativity," which in turn implies youthfulness, intelligence, and adaptive unpredictability. Drawing upon available empirical studies, I argue that the evidence for a link between humor and creativity is weak and ambiguous. I also find only tenuous support for Miller's assumption that the attractiveness of the "sense of humor" is to be found in the wittiness of its possessor, since those who use the phrase often seem to associate it with the affects of relatively mirthless "bonding" laughter. Humor, I conclude, may have evolved as an instrument for achieving broad social adhesiveness and for facilitating the individual's maneuverability within the group, but that it evolved through sexual selection has yet to be convincingly demonstrated.

  13. On consensus biomarker selection

    Directory of Open Access Journals (Sweden)

    Gambin Anna

    2007-05-01

    Full Text Available Abstract Background Recent development of mass spectrometry technology enabled the analysis of complex peptide mixtures. A lot of effort is currently devoted to the identification of biomarkers in human body fluids like serum or plasma, based on which new diagnostic tests for different diseases could be constructed. Various biomarker selection procedures have been exploited in recent studies. It has been noted that they often lead to different biomarker lists and as a consequence, the patient classification may also vary. Results Here we propose a new approach to the biomarker selection problem: to apply several competing feature ranking procedures and compute a consensus list of features based on their outcomes. We validate our methods on two proteomic datasets for the diagnosis of ovarian and prostate cancer. Conclusion The proposed methodology can improve the classification results and at the same time provide a unified biomarker list for further biological examinations and interpretation.

  14. Subset selection in regression

    CERN Document Server

    Miller, Alan

    2002-01-01

    Originally published in 1990, the first edition of Subset Selection in Regression filled a significant gap in the literature, and its critical and popular success has continued for more than a decade. Thoroughly revised to reflect progress in theory, methods, and computing power, the second edition promises to continue that tradition. The author has thoroughly updated each chapter, incorporated new material on recent developments, and included more examples and references. New in the Second Edition:A separate chapter on Bayesian methodsComplete revision of the chapter on estimationA major example from the field of near infrared spectroscopyMore emphasis on cross-validationGreater focus on bootstrappingStochastic algorithms for finding good subsets from large numbers of predictors when an exhaustive search is not feasible Software available on the Internet for implementing many of the algorithms presentedMore examplesSubset Selection in Regression, Second Edition remains dedicated to the techniques for fitting...

  15. Selection of Celebrity Endorsers

    DEFF Research Database (Denmark)

    Hollensen, Svend; Schimmelpfennig, Christian

    2013-01-01

    Purpose - This research aims at shedding some light on the various avenues marketers can undertake until finally an endorsement contract is signed. The focus of the study lies on verifying the generally held assumption that endorser selection is usually taken care of by creative agencies, vetting....... Practical implications – Conducted case studies indicate that there are various avenues how brands come to their endorser. We could not find evidence of a best practice strategy....... several candidates by means of subtle evaluation procedures. Design/methodology/approach – A case study research has been carried out among companies experienced in celebrity endorsements to learn more about the endorser selection process in practise. Based on these cases theory is inductively developed...

  16. Very strict selectional restrictions

    CERN Document Server

    Laporte, Eric; Dias, Maria Carmelita P

    2007-01-01

    We discuss the characteristics and behaviour of two parallel classes of verbs in two Romance languages, French and Portuguese. Examples of these verbs are Port. abater [gado] and Fr. abattre [b\\'etail], both meaning "slaughter [cattle]". In both languages, the definition of the class of verbs includes several features: - They have only one essential complement, which is a direct object. - The nominal distribution of the complement is very limited, i.e., few nouns can be selected as head nouns of the complement. However, this selection is not restricted to a single noun, as would be the case for verbal idioms such as Fr. monter la garde "mount guard". - We excluded from the class constructions which are reductions of more complex constructions, e.g. Port. afinar [instrumento] com "tune [instrument] with".

  17. Entrepreneurs and Economic Selection

    DEFF Research Database (Denmark)

    Holm, Jacob Rubæk

    This paper suggests how George Price's general mathematical theory of selection may be applied to economic data; and it is discussed how Price's equation may be expanded and interpreted so that it describes the mechanisms of Schumpeterian competition and thus the industrial dynamics underlying...... the evolution of economic data. The model is applied to the evolution of Danish labour productivity and systematic differences are identiffied between manufacturing industries and service industries. It is argued that similar results for the US and Sweden may be extracted from productivity studies following...... a certain methodology. The paper concludes that George Price's general mathematical theory of selection can provide important building blocks for an empirical economic model inspired by Schumpeter. There are, however, a number of hurdles for future research; most notably arriving at a clear denition...

  18. Symmetrization Selection Rules, 1

    CERN Document Server

    Page, P R

    1996-01-01

    We introduce a category of strong and electromagnetic interaction selection rules for the two-body connected decay and production of exotic J^{PC} = 0^{+-}, 1^{-+}, 2^{+-}, 3^{-+}, ... hybrid and four-quark mesons. The rules arise from symmetrization in states in addition to Bose symmetry and CP invariance. Examples include various decays to \\eta'\\eta, \\eta\\pi, \\eta'\\pi and four-quark interpretations of a 1^{-+} signal.

  19. Symmetrization Selection Rules, 2

    CERN Document Server

    Page, P R

    1996-01-01

    We introduce strong interaction selection rules for the two-body decay and production of hybrid and conventional mesons coupling to two S-wave hybrid or conventional mesons. The rules arise from symmetrization in states in the limit of non-relativistically moving quarks. The conditions under which hybrid coupling to S-wave states is suppressed are determined by the rules, and the nature of their breaking is indicated.

  20. Myanmar; Selected Issues

    OpenAIRE

    International Monetary Fund

    2015-01-01

    This Selected Issues paper analyzes how Myanmar can manage its natural resources for people’s development. Myanmar’s natural resource endowments provide much needed national wealth to finance the country’s development. Given Myanmar’s low tax revenue, mobilizing resource revenues is particularly important in the current macroeconomic environment of widening fiscal and current account deficits, inflationary pressures and exchange rate depreciation. The government should consider revisi...

  1. Swedish Officer Selection

    Science.gov (United States)

    2000-08-01

    1940’ s . The psychological examinations at that time were heavily influenced by German methods developed in the 1930’ s with an emphasis on personality...crystallization (Gc) in tasks that demand ogics (Bloom, 1956), and moral standards ( Kohlberg , 1971). Selection instruments for the acquired knowledge...unsuit- Jung’s (1971) theory of psychological types as a ability for the officer profession, mainly for ethical source of inspiration, and moral reasons

  2. Ukraine; Selected Issues

    OpenAIRE

    2008-01-01

    This Selected Issues paper investigates the economic importance of institutions in Ukraine, and attempts to quantify the potential benefits of market-friendly structural reforms. The paper reviews some of the key findings of the development-accounting literature, which has tried to explain the significant differences in income that persist across countries. It introduces the stochastic-frontier approach, outlining its key assumptions and strengths, and results obtained with the stochastic-fro...

  3. Velocity selective optical pumping

    OpenAIRE

    Aminoff, C. G.; Pinard, M.

    1982-01-01

    We consider optical pumping with a quasi monochromatic tunable light beam, in the low intensity limit where a rate equation regime is obtained The velocity selective optical pumping (V.S.O.P.) introduces a correlation between atomic velocity and internal variables in the ground (or metastable) state. The aim of this article is to evaluate these atomic observables (orientation, alignment, population) as a function of velocity, using a phenomenological description of the relaxation effect of co...

  4. Optimal Internet Media Selection

    OpenAIRE

    Peter J. Danaher; Janghyuk Lee; Laoucine Kerbache

    2010-01-01

    In this study we develop a method that optimally selects online media vehicles and determines the number of advertising impressions that should be purchased and then served from each chosen website. As a starting point, we apply Danaher's [Danaher, P. J. 2007. Modeling page views across multiple websites with an application to Internet reach and frequency prediction. (3) 422–437] multivariate negative binomial distribution (MNBD) for predicting online media exposure distributions. The MNBD is...

  5. Selected response test items.

    Science.gov (United States)

    Tomey, A M

    1999-01-01

    Classroom assessment is complex and challenging. Teachers need to consider the cognitive, affective, and psychomotor levels for achievement of their educational objectives. This series of six articles discusses how to develop testing blue-prints; selected-response tests, including multiple-choice, true-false, matching, or other objective tests; completion or essay testing; problem solving/critical thinking activities; performance assessment; and computer-based testing.

  6. Unsupervised Feature Subset Selection

    DEFF Research Database (Denmark)

    Søndberg-Madsen, Nicolaj; Thomsen, C.; Pena, Jose

    2003-01-01

    This paper studies filter and hybrid filter-wrapper feature subset selection for unsupervised learning (data clustering). We constrain the search for the best feature subset by scoring the dependence of every feature on the rest of the features, conjecturing that these scores discriminate some...... irrelevant features. We report experimental results on artificial and real data for unsupervised learning of naive Bayes models. Both the filter and hybrid approaches perform satisfactorily....

  7. Miniature spectrally selective dosimeter

    Energy Technology Data Exchange (ETDEWEB)

    Adams, R.R.; Macconochie, I.O.; Poole, B.D.

    1983-02-08

    The present invention discloses a miniature spectrally selective dosimeter capable of measuring selected bandwidths of radiation exposure on small mobile areas. This is achieved by the combination of photovoltaic detectors, electrochemical integrators (e-cells) and filters in a small compact case which can be easily attached in close proximity to and substantially parallel to the surface being measured. In one embodiment two photovoltaic detectors, two e-cells and three filters are packaged in a small case with attaching means consisting of a safety pin. In another embodiment, two detectors, one e-cell and three filters are packaged in a small case with attaching means consisting of a clip to clip over a side piece of an eye glass frame in a further embodiment, the electro-optic elements a packaged in a wristwatch case with attaching means being a watchband. The filters in all embodiments allow only selected wavelengths of radiation to be detected by the photovoltaic detectors and then integrated by the e-cells.

  8. Selective leptin resistance revisited

    Science.gov (United States)

    2013-01-01

    In addition to effects on appetite and metabolism, leptin influences many neuroendocrine and physiological systems, including the sympathetic nervous system. Building on my Carl Ludwig Lecture of the American Physiological Society, I review the sympathetic and cardiovascular actions of leptin. The review focuses on a critical analysis of the concept of selective leptin resistance (SLR) and the role of leptin in the pathogenesis of obesity-induced hypertension in both experimental animals and humans. We introduced the concept of SLR in 2002 to explain how leptin might increase blood pressure (BP) in obese states, such as diet-induced obesity (DIO), that are accompanied by partial leptin resistance. This concept, analogous to selective insulin resistance in the metabolic syndrome, holds that in several genetic and acquired models of obesity, there is preservation of the renal sympathetic and pressor actions of leptin despite attenuation of the appetite and weight-reducing actions. Two potential overlapping mechanisms of SLR are reviewed: 1) differential leptin molecular signaling pathways that mediate selective as opposed to universal leptin action and 2) brain site-specific leptin action and resistance. Although the phenomenon of SLR in DIO has so far focused on preservation of sympathetic and BP actions of leptin, consideration should be given to the possibility that this concept may extend to preservation of other actions of leptin. Finally, I review perplexing data on the effects of leptin on sympathetic activity and BP in humans and its role in human obesity-induced hypertension. PMID:23883674

  9. Selective enforcement of regulation

    Institute of Scientific and Technical Information of China (English)

    Donghua; Chen; Dequan; Jiang; Shangkun; Liang; Fangping; Wang

    2011-01-01

    Regulatory agencies may,whether outside of set rules or within their discretion,depart from the original goals or principles set for enforcing the rules,which we term selective enforcement.Taking China,a country in transition,as an example,and using cases and large-sample tests,we present empirical evidence of selective enforcement.The results show that the China Securities Regulatory Commission(CSRC) takes into account whether companies violating the rules have a state-owned background and the strength of that background when investigating and punishing non-compliance.After controlling for the degree of violation,state-owned-enterprises(SOEs) are punished less severely than private companies;and the higher the hierarchy of the SOE in question,the less severe the punishment.It also takes longer for SOEs to be punished.We also find that companies that violate the rules less seriously have a greater tendency to apply for refinancing than those that violate the rules more seriously.This may be because the severity of the violation can affect listed companies’ expectations of obtaining refinancing.The analysis and conclusions of this study prove useful in understanding the causes and consequences of selective enforcement in transition economies.

  10. Selective File Dumper

    Science.gov (United States)

    Bassetti, Nanni; Frati, Denis

    During a computer forensics investigation we faced a problem how to get all the interesting files we need fast. We work, mainly, using the Open Source software products and Linux OS, and we consider the Sleuthkit and the Foremost two very useful tools, but for reaching our target they were too complicated and time consuming to use. For this reason we developed the Selective File Dumper, a Linux Bash script which makes it possible to extract all the referenced, deleted and unallocated files and finally to perform a keyword search, in a simple way.

  11. Pilot selection and training

    Science.gov (United States)

    Helmreich, Robert L.

    1982-01-01

    Personality and situational factors relevant to individual and group performance in highly demanding environments, such as those faced by astronauts or by jet transport crew, are discussed. It is emphasized that although technical competence and proficiency in pilot selection are prerequisites for safety, operating a modern jet transport is a group endeavor that requires the effective coordination of the entire crew. A self-report test battery for measuring positive and negative personality traits of pilot candidates, termed the Personal Characteristics Inventory, is described.

  12. Selected DOE headquarters publications

    Energy Technology Data Exchange (ETDEWEB)

    None

    1979-07-01

    Selected DOE Headquarters Publications provides cumulative listings, from October 1, 1977 onward, of two groups of publications issued by headquarters organizations of the Department of Energy, and an index to their title keywords. The two groups consist of publications assigned a DOE/XXX-type report number code and headquarters contractor publications, prepared by contractors (and published by DOE) to describe research and development work they have performed for the Department. Publications such as pamphlets, fact sheets, bulletins, newsletters, and telephone directories, are omitted, as are publications issued under the DOE-tr, CONF, DOE/JPL, and DOE/NASA codes. (RWR)

  13. Selfish spermatogonial selection

    DEFF Research Database (Denmark)

    Lim, Jasmine; Maher, Geoffrey J; Turner, Gareth D H

    2012-01-01

    The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia-caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively-represent classical examples of paternal age-effect mutation, a class that arises at particularly high...... frequencies in the sperm of older men. Previous analyses of DNA from randomly selected cadaveric testes showed that the levels of the corresponding FGFR2, FGFR3 and RET mutations exhibit very uneven spatial distributions, with localised hotspots surrounded by large mutation-negative areas. These studies imply...

  14. Hydrogen-selective membrane

    Science.gov (United States)

    Collins, J.P.; Way, J.D.

    1995-09-19

    A hydrogen-selective membrane comprises a tubular porous ceramic support having a palladium metal layer deposited on an inside surface of the ceramic support. The thickness of the palladium layer is greater than about 10 {micro}m but typically less than about 20 {micro}m. The hydrogen permeation rate of the membrane is greater than about 1.0 moles/m{sup 2}s at a temperature of greater than about 500 C and a transmembrane pressure difference of about 1,500 kPa. Moreover, the hydrogen-to-nitrogen selectivity is greater than about 600 at a temperature of greater than about 500 C and a transmembrane pressure of about 700 kPa. Hydrogen can be separated from a mixture of gases using the membrane. The method may include the step of heating the mixture of gases to a temperature of greater than about 400 C and less than about 1000 C before the step of flowing the mixture of gases past the membrane. The mixture of gases may include ammonia. The ammonia typically is decomposed to provide nitrogen and hydrogen using a catalyst such as nickel. The catalyst may be placed inside the tubular ceramic support. The mixture of gases may be supplied by an industrial process such as the mixture of exhaust gases from the IGCC process. 9 figs.

  15. [{sup 11}C]GR103545: novel one-pot radiosynthesis with high specific activity

    Energy Technology Data Exchange (ETDEWEB)

    Nabulsi, Nabeel B., E-mail: nabeel.nabulsi@yale.ed [Department of Diagnostic Radiology, PET Center, Yale School of Medicine, PO Box 208048, New Haven, CT 06520-8048 (United States); Zheng Mingqiang; Ropchan, Jim; Labaree, David; Ding Yushin [Department of Diagnostic Radiology, PET Center, Yale School of Medicine, PO Box 208048, New Haven, CT 06520-8048 (United States); Blumberg, Laura [Pfizer Global R and D, Groton, CT 06340 (United States); Huang Yiyun [Department of Diagnostic Radiology, PET Center, Yale School of Medicine, PO Box 208048, New Haven, CT 06520-8048 (United States)

    2011-02-15

    Introduction: GR103545 is a potent and selective kappa-opioid receptor agonist. Previous studies in non-human primates demonstrated favorable properties of [{sup 11}C]GR103545 as a positron emission tomography tracer for in vivo imaging of cerebral kappa-opioid receptor. Nonetheless, advancement of [{sup 11}C]GR103545 to imaging studies in humans was hampered by difficulties of its multiple-step radiosynthesis, which produces a final product with low specific activity (SA), which in turn could induce undesirable physiological side effects resulting from the mass associated with an injected amount of radioactivity. We report herein an alternative radiosynthesis of [{sup 11}C]GR103545 with higher SA and radiochemical yields. Methods: The TRACERLab FXC automated synthesis module was used to carry out the two-step, one-pot procedure. In the first step, the desmethoxycarbonyl precursor was converted to the carbamic acid intermediate desmethyl-GR103545 via transcarboxylation with the zwitterionic carbamic complex, 1,8-diazabicyclo[5.4.0]undec-7-ene-carbon dioxide, in the presence and/or absence of cesium carbonate and tetrabutylammonium triflate. In the second step, the intermediate was radiolabeled at the carboxyl oxygen with [{sup 11}C]methyl trifluoromethanesulfonate to give [{sup 11}C]GR103545. Results: This novel synthesis produced [{sup 11}C]GR103545 with {>=}90% chemical and radiochemical purities and an SA of 290.45{+-}99.9 MBq/nmol at the end of synthesis (n=26). Injectable radioactivity was 1961{+-}814 GBq/{mu}mol with 43 min of average synthesis time from the end of beam. Conclusion: We have developed a practical one-pot method for the routine production of [{sup 11}C]GR103545 with reliably high SA and radiochemical yield, thus allowing the advancement of this radiotracer to imaging applications in humans.

  16. Ecology, sexual selection and speciation.

    Science.gov (United States)

    Maan, Martine E; Seehausen, Ole

    2011-06-01

    The spectacular diversity in sexually selected traits among animal taxa has inspired the hypothesis that divergent sexual selection can drive speciation. Unfortunately, speciation biologists often consider sexual selection in isolation from natural selection, even though sexually selected traits evolve in an ecological context: both preferences and traits are often subject to natural selection. Conversely, while behavioural ecologists may address ecological effects on sexual communication, they rarely measure the consequences for population divergence. Herein, we review the empirical literature addressing the mechanisms by which natural selection and sexual selection can interact during speciation. We find that convincing evidence for any of these scenarios is thin. However, the available data strongly support various diversifying effects that emerge from interactions between sexual selection and environmental heterogeneity. We suggest that evaluating the evolutionary consequences of these effects requires a better integration of behavioural, ecological and evolutionary research. © 2011 Blackwell Publishing Ltd/CNRS.

  17. Ion-selective electrode reviews

    CERN Document Server

    Thomas, J D R

    1983-01-01

    Ion-Selective Electrode Reviews, Volume 5 is a collection of articles that covers ion-speciation. The book aims to present the advancements of the range and capabilities of selective ion-sensors. The topics covered in the selection are neutral carrier based ion-selective electrodes; reference electrodes and liquid junction effects in ion-selective electrode potentiometry; ion transfer across water/organic phase boundaries and analytical; and carbon substrate ion-selective electrodes. The text will be of great use to chemists and chemical engineers.

  18. Selective Impairment of Auditory Selective Attention under Concurrent Cognitive Load

    Science.gov (United States)

    Dittrich, Kerstin; Stahl, Christoph

    2012-01-01

    Load theory predicts that concurrent cognitive load impairs selective attention. For visual stimuli, it has been shown that this impairment can be selective: Distraction was specifically increased when the stimulus material used in the cognitive load task matches that of the selective attention task. Here, we report four experiments that…

  19. Selective inorganic thin films

    Energy Technology Data Exchange (ETDEWEB)

    Phillips, M.L.F.; Weisenbach, L.A.; Anderson, M.T. [Sandia National Laboratories, Albuquerque, NM (United States)] [and others

    1995-05-01

    This project is developing inorganic thin films as membranes for gas separation applications, and as discriminating coatings for liquid-phase chemical sensors. Our goal is to synthesize these coatings with tailored porosity and surface chemistry on porous substrates and on acoustic and optical sensors. Molecular sieve films offer the possibility of performing separations involving hydrogen, air, and natural gas constituents at elevated temperatures with very high separation factors. We are focusing on improving permeability and molecular sieve properties of crystalline zeolitic membranes made by hydrothermally reacting layered multicomponent sol-gel films deposited on mesoporous substrates. We also used acoustic plate mode (APM) oscillator and surface plasmon resonance (SPR) sensor elements as substrates for sol-gel films, and have both used these modified sensors to determine physical properties of the films and have determined the sensitivity and selectivity of these sensors to aqueous chemical species.

  20. Darwinian Adverse Selection

    CERN Document Server

    Kuhle, Wolfgang

    2015-01-01

    We develop a model to study the role of rationality in economics and biology. The model's agents differ continuously in their ability to make rational choices. The agents' objective is to ensure their individual survival over time or, equivalently, to maximize profits. In equilibrium, however, rational agents who maximize their objective survival probability are, individually and collectively, eliminated by the forces of competition. Instead of rationality, there emerges a unique distribution of irrational players who are individually not fit for the struggle of survival. The selection of irrational players over rational ones relies on the fact that all rational players coordinate on the same optimal action, which leaves them collectively undiversified and thus vulnerable to aggregate risks.

  1. [Selective immunoglobulin A deficiency].

    Science.gov (United States)

    Binek, Alicja; Jarosz-Chobot, Przemysława

    2012-01-01

    Immunoglobulin class A is the main protein of the mucosal immune system. Selective immunoglobulin A deficiency (sIgAD) is the most common primary immunodeficiency in Caucasians. sIGAD is strongly associated with the certain major histocompatibility complex region. Most individuals with sIgAD are asymptomatic and identified coincidentally. However, some patients may present with recurrent infections, allergic disorders and autoimmune manifestations. Several autoimmune diseases, such as systemic lupus erythematosus, diabetes mellitus type 1, Graves disease and celiac disease, are associated with an increased prevalence of sIgAD. Screening for sIgAD in coeliac disease is essential. Patients need treatment of associated diseases. It is also known that IgA deficiency may progress into a common variable immunodeficiency (CVID). Pathogenesis and molecular mechanism involved in sIgAD should be elucidated in the future.

  2. Entrepreneurs and Economic Selection

    DEFF Research Database (Denmark)

    Holm, Jacob Rubæk

    The paper discusses Schumpeter's models of competition and then attempts to identify the Mark I model empirically. The results are that entrepreneurial activity is important in young sectors, as expected, but also often in high-tech sectors and in many service sectors. The relevance of the Mark I...... model for competition in service sectors is seen as particularly interesting, as the Mark I model thus provides a framework for future analysis of competition in sectors that are very poorly described by the focus on production, goods and quantities of most traditional theory. The selection aspect...... are allocated not towards the most productive firms but to the firms with the greatest growth of productivity....

  3. Toothbrush selection : A dilemma?

    Directory of Open Access Journals (Sweden)

    Sasan Dhiraj

    2006-01-01

    Full Text Available The toothbrush is a fundamental tool used for accomplishing plaque control. Various types of toothbrushes available in the market keep the buyer in a state of dilemma as to which one to choose, due to lack of information about the "quality" of it. This study has been designed to understand whether all the products available in the market adhere to the specifications laid down by the ADA, which is universally accepted in standardization of a tooth brush. 95% of the brushes surveyed contain less number of bristles per tuft than specified and a large percentage deviate from the standard prescribed value for their bristle diameter and other dimensions. Few brushes labeled as "Soft" were "Medium" and labeled "Medium" were "Hard". The study will bring to light the quality of toothbrushes available in India for a rationalised selection of appropriate toothbrush by the community at large.

  4. Feature selection in bioinformatics

    Science.gov (United States)

    Wang, Lipo

    2012-06-01

    In bioinformatics, there are often a large number of input features. For example, there are millions of single nucleotide polymorphisms (SNPs) that are genetic variations which determine the dierence between any two unrelated individuals. In microarrays, thousands of genes can be proled in each test. It is important to nd out which input features (e.g., SNPs or genes) are useful in classication of a certain group of people or diagnosis of a given disease. In this paper, we investigate some powerful feature selection techniques and apply them to problems in bioinformatics. We are able to identify a very small number of input features sucient for tasks at hand and we demonstrate this with some real-world data.

  5. COTS software selection process.

    Energy Technology Data Exchange (ETDEWEB)

    Watkins, William M. (Strike Wire Technologies, Louisville, CO); Lin, Han Wei; McClelland, Kelly (U.S. Security Associates, Livermore, CA); Ullrich, Rebecca Ann; Khanjenoori, Soheil; Dalton, Karen; Lai, Anh Tri; Kuca, Michal; Pacheco, Sandra; Shaffer-Gant, Jessica

    2006-05-01

    Today's need for rapid software development has generated a great interest in employing Commercial-Off-The-Shelf (COTS) software products as a way of managing cost, developing time, and effort. With an abundance of COTS software packages to choose from, the problem now is how to systematically evaluate, rank, and select a COTS product that best meets the software project requirements and at the same time can leverage off the current corporate information technology architectural environment. This paper describes a systematic process for decision support in evaluating and ranking COTS software. Performed right after the requirements analysis, this process provides the evaluators with more concise, structural, and step-by-step activities for determining the best COTS software product with manageable risk. In addition, the process is presented in phases that are flexible to allow for customization or tailoring to meet various projects' requirements.

  6. Fluctuating Selection in the Moran

    Science.gov (United States)

    Dean, Antony M.; Lehman, Clarence; Yi, Xiao

    2017-01-01

    Contrary to classical population genetics theory, experiments demonstrate that fluctuating selection can protect a haploid polymorphism in the absence of frequency dependent effects on fitness. Using forward simulations with the Moran model, we confirm our analytical results showing that a fluctuating selection regime, with a mean selection coefficient of zero, promotes polymorphism. We find that increases in heterozygosity over neutral expectations are especially pronounced when fluctuations are rapid, mutation is weak, the population size is large, and the variance in selection is big. Lowering the frequency of fluctuations makes selection more directional, and so heterozygosity declines. We also show that fluctuating selection raises dn/ds ratios for polymorphism, not only by sweeping selected alleles into the population, but also by purging the neutral variants of selected alleles as they undergo repeated bottlenecks. Our analysis shows that randomly fluctuating selection increases the rate of evolution by increasing the probability of fixation. The impact is especially noticeable when the selection is strong and mutation is weak. Simulations show the increase in the rate of evolution declines as the rate of new mutations entering the population increases, an effect attributable to clonal interference. Intriguingly, fluctuating selection increases the dn/ds ratios for divergence more than for polymorphism, a pattern commonly seen in comparative genomics. Our model, which extends the classical neutral model of molecular evolution by incorporating random fluctuations in selection, accommodates a wide variety of observations, both neutral and selected, with economy. PMID:28108586

  7. Selectivity in capillary electrokinetic separations

    NARCIS (Netherlands)

    de Zeeuw, R.A; de Jong, G.J.; Ensing, K

    1999-01-01

    This review gives a survey of selectivity modes in capillary electrophoresis separations in pharmaceutical analysis and bioanalysis. Despite the high efficiencies of these separation techniques, good selectivity is required to allow quantitation or identification of a Chemistry and Toxicology, parti

  8. Selection signature in domesticated animals.

    Science.gov (United States)

    Zhangyuan, Pan; Xiaoyun, He; Xiangyu, Wang; Xiaofei, Guo; Xiaohan, Cao; Wenping, Hu; Ran, Di; Qiuyue, Liu; Mingxing, Chu

    2016-12-20

    Domesticated animals play an important role in the life of humanity. All these domesticated animals undergo same process, first domesticated from wild animals, then after long time natural and artificial selection, formed various breeds that adapted to the local environment and human needs. In this process, domestication, natural and artificial selection will leave the selection signal in the genome. The research on these selection signals can find functional genes directly, is one of the most important strategies in screening functional genes. The current studies of selection signal have been performed in pigs, chickens, cattle, sheep, goats, dogs and other domestic animals, and found a great deal of functional genes. This paper provided an overview of the types and the detected methods of selection signal, and outlined researches of selection signal in domestic animals, and discussed the key issues in selection signal analysis and its prospects.

  9. Flight selection at United Airlines

    Science.gov (United States)

    Traub, W.

    1980-01-01

    Airline pilot selection proceedures are discussed including psychogical and personality tests, psychomotor performance requirements, and flight skills evaluation. Necessary attitude and personality traits are described and an outline of computer selection, testing, and training techniques is given.

  10. Ion-selective electrode reviews

    CERN Document Server

    Thomas, J D R

    1985-01-01

    Ion-Selective Electrode Reviews, Volume 7 is a collection of papers that covers the applications of electrochemical sensors, along with the versatility of ion-selective electrodes. The coverage of the text includes solid contact in membrane ion-selective electrodes; immobilized enzyme probes for determining inhibitors; potentiometric titrations based on ion-pair formation; and application of ion-selective electrodes in soil science, kinetics, and kinetic analysis. The text will be of great use to chemists and chemical engineers.

  11. Variable selection with error control: Another look at Stability Selection

    CERN Document Server

    Shah, Rajen

    2011-01-01

    Stability Selection was recently introduced by Meinshausen and Buhlmann (2010) as a very general technique designed to improve the performance of a variable selection algorithm. It is based on aggregating the results of applying a selection procedure to subsamples of the data. We introduce a variant, called Complementary Pairs Stability Selection (CPSS), and derive bounds both on the expected number of variables included by CPSS that have low selection probability under the original procedure, and on the expected number of high selection probability variables that are excluded. These results require no (e.g. exchangeability) assumptions on the underlying model or on the quality of the original selection procedure. Under reasonable shape restrictions, the bounds can be further tightened, yielding improved error control, and therefore increasing the applicability of the methodology.

  12. Ion-selective electrodes, 3

    Energy Technology Data Exchange (ETDEWEB)

    Pungor, E. (ed.)

    1981-01-01

    Thirty-two papers which were presented at the Third Symposium on Ion-Selective Electrodes are presented in this Proceedings. These papers dealt with standardization, fabrication, chemical properties of ion-selective electrodes and their application. Selected papers have been abstracted and indexed separately for the data base. (ATT)

  13. Beef Cattle: Selection and Evaluation.

    Science.gov (United States)

    Clemson Univ., SC. Vocational Education Media Center.

    Designed for secondary vocational agriculture students, this text provides an overview of selecting and evaluating beef cattle in Future Farmers of America livestock judging events. The first of four major sections addresses topics such as the ideal beef animal, selecting steers, selecting breeding animals, studying the animal systematically, and…

  14. Beef Cattle: Selection and Evaluation.

    Science.gov (United States)

    Clemson Univ., SC. Vocational Education Media Center.

    Designed for secondary vocational agriculture students, this text provides an overview of selecting and evaluating beef cattle in Future Farmers of America livestock judging events. The first of four major sections addresses topics such as the ideal beef animal, selecting steers, selecting breeding animals, studying the animal systematically, and…

  15. Adaptive Robust Variable Selection

    CERN Document Server

    Fan, Jianqing; Barut, Emre

    2012-01-01

    Heavy-tailed high-dimensional data are commonly encountered in various scientific fields and pose great challenges to modern statistical analysis. A natural procedure to address this problem is to use penalized least absolute deviation (LAD) method with weighted $L_1$-penalty, called weighted robust Lasso (WR-Lasso), in which weights are introduced to ameliorate the bias problem induced by the $L_1$-penalty. In the ultra-high dimensional setting, where the dimensionality can grow exponentially with the sample size, we investigate the model selection oracle property and establish the asymptotic normality of the WR-Lasso. We show that only mild conditions on the model error distribution are needed. Our theoretical results also reveal that adaptive choice of the weight vector is essential for the WR-Lasso to enjoy these nice asymptotic properties. To make the WR-Lasso practically feasible, we propose a two-step procedure, called adaptive robust Lasso (AR-Lasso), in which the weight vector in the second step is c...

  16. Selective inorganic thin films

    Energy Technology Data Exchange (ETDEWEB)

    Phillips, M.L.F.; Pohl, P.I.; Brinker, C.J. [Sandia National Labs., Albuquerque, NM (United States)

    1997-04-01

    Separating light gases using membranes is a technology area for which there exists opportunities for significant energy savings. Examples of industrial needs for gas separation include hydrogen recovery, natural gas purification, and dehydration. A membrane capable of separating H{sub 2} from other gases at high temperatures could recover hydrogen from refinery waste streams, and facilitate catalytic dehydrogenation and the water gas shift (CO + H{sub 2}O {yields} H{sub 2} + CO{sub 2}) reaction. Natural gas purification requires separating CH{sub 4} from mixtures with CO{sub 2}, H{sub 2}S, H{sub 2}O, and higher alkanes. A dehydrating membrane would remove water vapor from gas streams in which water is a byproduct or a contaminant, such as refrigeration systems. Molecular sieve films offer the possibility of performing separations involving hydrogen, natural gas constituents, and water vapor at elevated temperatures with very high separation factors. It is in applications such as these that the authors expect inorganic molecular sieve membranes to compete most effectively with current gas separation technologies. Cryogenic separations are very energy intensive. Polymer membranes do not have the thermal stability appropriate for high temperature hydrogen recovery, and tend to swell in the presence of hydrocarbon natural gas constituents. The authors goal is to develop a family of microporous oxide films that offer permeability and selectivity exceeding those of polymer membranes, allowing gas membranes to compete with cryogenic and adsorption technologies for large-scale gas separation applications.

  17. Selective sorting of waste

    CERN Multimedia

    2007-01-01

    Not much effort needed, just willpower In order to keep the cost of disposing of waste materials as low as possible, CERN provides two types of recipient at the entrance to each building: a green plastic one for paper/cardboard and a metal one for general refuse. For some time now we have noticed, to our great regret, a growing negligence as far as selective sorting is concerned, with, for example, the green recipients being filled with a mixture of cardboard boxes full of polystyrene or protective wrappers, plastic bottles, empty yogurts pots, etc. …We have been able to ascertain, after careful checking, that this haphazard mixing of waste cannot be attributed to the cleaning staff but rather to members of the personnel who unscrupulously throw away their rubbish in a completely random manner. Non-sorted waste entails heavy costs for CERN. For information, once a non-compliant item is found in a green recipient, the entire contents are sent off for incineration rather than recycling… We are all concerned...

  18. Selecting nonprescription analgesics.

    Science.gov (United States)

    Peterson, Gregory M

    2005-01-01

    Worldwide, there has been an emerging patient demand for access to efficient drugs without consulting a doctor and obtaining a prescription. As a result, there has been an expanding movement of prescription-only drugs to over-the-counter (OTC) status. An increasing number of drugs are becoming available OTC, empowering patients to treat themselves. Where the principle of empowering individuals to treat themselves can fail is when consumers lack the knowledge to do so safely. This potentially applies to the self-selection of analgesic drugs by consumers. When used inappropriately, these drugs pose significant risks. The nonsteroidal antiinflammatory drugs (NSAIDs) are associated with many adverse reactions, interactions, and contraindications in a number of patient groups, even at OTC doses. In particular, in the elderly, the high incidence of cardiovascular and gastrointestinal disease, coupled with age-related decline in renal function and multiple medication use, all warrant extra caution with the use of NSAIDs and make paracetamol the simple analgesic drug of first choice. Despite the possibility of hepatotoxicity in overdose, paracetamol represents a better all-round option for most patients requiring OTC analgesic therapy.

  19. Sexual selection is a form of social selection.

    Science.gov (United States)

    Lyon, Bruce E; Montgomerie, Robert

    2012-08-19

    Social selection influences the evolution of weapons, ornaments and behaviour in both males and females. Thus, social interactions in both sexual and non-sexual contexts can have a powerful influence on the evolution of traits that would otherwise appear to be detrimental to survival. Although clearly outlined by West-Eberhard in the early 1980s, the idea that social selection is a comprehensive framework for the study of ornaments and weapons has largely been ignored. In West-Eberhard's view, sexual selection is a form of social selection-a concept supported by several lines of evidence. Darwin's distinction between natural and sexual selection has been useful, but recent confusion about the limits of sexual selection suggests that some traits are not easily categorized as naturally or sexually selected. Because social selection theory has much to offer the current debates about both sexual selection and reproductive competition in females, it is sometimes viewed, narrowly, to be most useful when considering female roles. However, social selection theory encompasses much more than female reproductive competition. Our goal here was to provide that broader perspective.

  20. Opportunity structures for selective exposure

    DEFF Research Database (Denmark)

    Skovsgaard, Morten; Shehata, Adam; Strömbäck, Jesper

    2016-01-01

    Abstract The transition from low-choice to high-choice media environments has raised new concerns about selective exposure. In this context, two types of selective media exposure are relevant. One is selectivity based on political ideological preferences, the other selectivity based on political...... interest. Evidence for both has been found primarily in an American context, while there is less research on European countries. This is problematic, as the opportunity structures for different forms of selectivity vary across media environments. Against this background, the purpose of this study...... that selective exposure based on political interest is substantially more important than selective exposure based on ideological preferences in explaining exposure to party-leader interviews. To substantiate this finding, the results are replicated with partisan learning as the dependent variable....

  1. Sexual selection: Another Darwinian process.

    Science.gov (United States)

    Gayon, Jean

    2010-02-01

    Why was sexual selection so important to Darwin? And why was it de-emphasized by almost all of Darwin's followers until the second half of the 20th century? These two questions shed light on the complexity of the scientific tradition named "Darwinism". Darwin's interest in sexual selection was almost as old as his discovery of the principle of natural selection. From the beginning, sexual selection was just another "natural means of selection", although different from standard "natural selection" in its mechanism. But it took Darwin 30 years to fully develop his theory, from the early notebooks to the 1871 book The Descent of Man, and Selection in Relation to Sex. Although there is a remarkable continuity in his basic ideas about sexual selection, he emphasized increasingly the idea that sexual selection could oppose the action of natural selection and be non adaptive. In time, he also gave more weight to mate choice (especially female choice), giving explicit arguments in favor of psychological notions such as "choice" and "aesthetic sense". But he also argued that there was no strict demarcation line between natural and sexual selection, a major difficulty of the theory from the beginning. Female choice was the main reason why Alfred Russel Wallace, the co-discoverer of the principle of natural selection, engaged in a major controversy with Darwin about sexual selection. Wallace was suspicious about sexual selection in general, trying to minimize it by all sorts of arguments. And he denied entirely the existence of female choice, because he thought that it was both unnecessary and an anthropomorphic notion. This had something to do with his spiritualist convictions, but also with his conception of natural selection as a sufficient principle for the evolutionary explanation of all biological phenomena (except for the origin of mind). This is why Wallace proposed to redefine Darwinism in a way that excluded Darwin's principle of sexual selection. The main result of

  2. The in vitro selection world.

    Science.gov (United States)

    Jijakli, Kenan; Khraiwesh, Basel; Fu, Weiqi; Luo, Liming; Alzahmi, Amnah; Koussa, Joseph; Chaiboonchoe, Amphun; Kirmizialtin, Serdal; Yen, Laising; Salehi-Ashtiani, Kourosh

    2016-08-15

    Through iterative cycles of selection, amplification, and mutagenesis, in vitro selection provides the ability to isolate molecules of desired properties and function from large pools (libraries) of random molecules with as many as 10(16) distinct species. This review, in recognition of a quarter of century of scientific discoveries made through in vitro selection, starts with a brief overview of the method and its history. It further covers recent developments in in vitro selection with a focus on tools that enhance the capabilities of in vitro selection and its expansion from being purely a nucleic acids selection to that of polypeptides and proteins. In addition, we cover how next generation sequencing and modern biological computational tools are being used to complement in vitro selection experiments. On the very least, sequencing and computational tools can translate the large volume of information associated with in vitro selection experiments to manageable, analyzable, and exploitable information. Finally, in vivo selection is briefly compared and contrasted to in vitro selection to highlight the unique capabilities of each method.

  3. Darwin, artificial selection, and poverty.

    Science.gov (United States)

    Sanchez, Luis

    2010-03-01

    This paper argues that the processes of evolutionary selection are becoming increasingly artificial, a trend that goes against the belief in a purely natural selection process claimed by Darwin's natural selection theory. Artificial selection is mentioned by Darwin, but it was ignored by Social Darwinists, and it is all but absent in neo-Darwinian thinking. This omission results in an underestimation of probable impacts of artificial selection upon assumed evolutionary processes, and has implications for the ideological uses of Darwin's language, particularly in relation to poverty and other social inequalities. The influence of artificial selection on genotypic and phenotypic adaptations arguably represents a substantial shift in the presumed path of evolution, a shift laden with both biological and political implications.

  4. Universal statistics of selected values

    Science.gov (United States)

    Smerlak, Matteo; Youssef, Ahmed

    2017-03-01

    Selection, the tendency of some traits to become more frequent than others under the influence of some (natural or artificial) agency, is a key component of Darwinian evolution and countless other natural and social phenomena. Yet a general theory of selection, analogous to the Fisher-Tippett-Gnedenko theory of extreme events, is lacking. Here we introduce a probabilistic definition of selection and show that selected values are attracted to a universal family of limiting distributions which generalize the log-normal distribution. The universality classes and scaling exponents are determined by the tail thickness of the random variable under selection. Our results provide a possible explanation for skewed distributions observed in diverse contexts where selection plays a key role, from molecular biology to agriculture and sport.

  5. Opportunity Structures for Selective Exposure

    DEFF Research Database (Denmark)

    Skovsgaard, Morten; Shehata, Adam; Strömbäck, Jesper

    2016-01-01

    is to investigate the two types of selective exposure in a country—Sweden—where the opportunity structures for selective exposure differ from the American context. This study investigates both types of selective exposure in relation to televised party-leader interviews. Based on panel survey data, the findings show...... interest. Evidence for both has been found primarily in an American context, while there is less research on European countries. This is problematic, as the opportunity structures for different forms of selectivity vary across media environments. Against this background, the purpose of this study...... that selective exposure based on political interest is substantially more important than selective exposure based on ideological preferences in explaining exposure to party-leader interviews. To substantiate this finding, the results are replicated with partisan learning as the dependent variable....

  6. Model Selection for Geostatistical Models

    Energy Technology Data Exchange (ETDEWEB)

    Hoeting, Jennifer A.; Davis, Richard A.; Merton, Andrew A.; Thompson, Sandra E.

    2006-02-01

    We consider the problem of model selection for geospatial data. Spatial correlation is typically ignored in the selection of explanatory variables and this can influence model selection results. For example, the inclusion or exclusion of particular explanatory variables may not be apparent when spatial correlation is ignored. To address this problem, we consider the Akaike Information Criterion (AIC) as applied to a geostatistical model. We offer a heuristic derivation of the AIC in this context and provide simulation results that show that using AIC for a geostatistical model is superior to the often used approach of ignoring spatial correlation in the selection of explanatory variables. These ideas are further demonstrated via a model for lizard abundance. We also employ the principle of minimum description length (MDL) to variable selection for the geostatistical model. The effect of sampling design on the selection of explanatory covariates is also explored.

  7. Detecting selection needs comparative data

    DEFF Research Database (Denmark)

    Nielsen, Rasmus; Hubisz, Melissa J.

    2005-01-01

    Positive selection at the molecular level is usually indicated by an increase in the ratio of non-synonymous to synonymous substitutions (dN/dS) in comparative data. However, Plotkin et al. 1 describe a new method for detecting positive selection based on a single nucleotide sequence. We show here...... that this method is particularly sensitive to assumptions regarding the underlying mutational processes and does not provide a reliable way to identify positive selection....

  8. Ion-selective electrode reviews

    CERN Document Server

    Thomas, J D R

    1982-01-01

    Ion-Selective Electrode Reviews, Volume 3, provides a review of articles on ion-selective electrodes (ISEs). The volume begins with an article on methods based on titration procedures for surfactant analysis, which have been developed for discrete batch operation and for continuous AutoAnalyser use. Separate chapters deal with detection limits of ion-selective electrodes; the possibility of using inorganic ion-exchange materials as ion-sensors; and the effect of solvent on potentials of cells with ion-selective electrodes. Also included is a chapter on advances in calibration procedures, the d

  9. Selection Method for COTS Systems

    DEFF Research Database (Denmark)

    Hedman, Jonas; Andersson, Bo

    2014-01-01

    requires new skills and methods supporting the process of evaluating and selecting information systems. This paper presents a method for selecting COTS systems. The method includes the following phases: problem framing, requirements and appraisal, and selection of systems. The idea and distinguishing...... of approaching the selection of COTS systems as viewing them as a ‘means’ to reach organizational ‘ends’ is different from the mainstream views of information systems development, namely the view that sees information systems development as a problem-solving process, and the underlying ontological view in other...

  10. Reasons for being selective when choosing personnel selection procedures

    NARCIS (Netherlands)

    König, C.J.; Klehe, U.-C.; Berchtold, M.; Kleinmann, M.

    2010-01-01

    The scientist-practitioner gap in personnel selection is large. Thus, it is important to gain a better understanding of the reasons that make organizations use or not use certain selection procedures. Based on institutional theory, we predicted that six variables should determine the use of selectio

  11. Reasons for being selective when choosing personnel selection procedures

    NARCIS (Netherlands)

    König, C.J.; Klehe, U.-C.; Berchtold, M.; Kleinmann, M.

    2010-01-01

    The scientist-practitioner gap in personnel selection is large. Thus, it is important to gain a better understanding of the reasons that make organizations use or not use certain selection procedures. Based on institutional theory, we predicted that six variables should determine the use of

  12. Binding Mechanisms in Selective Laser Sintering and Selective Laser Melting

    NARCIS (Netherlands)

    Kruth, J.-P.; Mercelis, P.; Van Vaerenbergh, J.; Froyen, L.; Rombouts, M.

    2005-01-01

    Purpose – This paper provides an overview of the different binding mechanisms in selective laser sintering (SLS) and selective laser melting (SLM), thus improving the understanding of these processes. Design/methodology/approach – A classification of SLS/SLM processes was developed, based on the bin

  13. -selection, -selection, effectiveness, and tolerance in competition: density-dependent selection revisited

    Indian Academy of Sciences (India)

    Amitabh Joshi; N. G. Prasad; Mallikarjun Shakarad

    2001-08-01

    In the Drosophila literature, selection for faster development and selection for adapting to high density are often confounded, leading, for example, to the expectation that selection for faster development should also lead to higher competitive ability. At the same time, results from experimental studies on evolution at high density do not agree with many of the predictions from classical density-dependent selection theory. We put together a number of theoretical and empirical results from the literature, and some new experimental results on Drosophila populations successfully subjected to selection for faster development, to argue for a broader interpretation of density-dependent selection. We show that incorporating notions of -selection, and the division of competitive ability into effectiveness and tolerance components, into the concept of density-dependent selection yields a formulation that allows for a better understanding of the empirical results. We also use this broader formulation to predict that selection for faster development in Drosophila should, in fact, lead to the correlated evolution of decreased competitive ability, even though it does lead to the evolution of greater efficiency and higher population growth rates at high density when in monotypic culture.

  14. HYBASE - HYperspectral BAnd SElection tool

    NARCIS (Netherlands)

    Schwering, P.B.W.; Bekman, H.H.P.T.; Seijen, H.H. van

    2008-01-01

    Band selection is essential in the design of multispectral sensor systems. This paper describes the TNO hyperspectral band selection tool HYBASE. It calculates the optimum band positions given the number of bands and the width of the spectral bands. HYBASE is used to calculate the minimum number of

  15. Complexity regularized hydrological model selection

    NARCIS (Netherlands)

    Pande, S.; Arkesteijn, L.; Bastidas, L.A.

    2014-01-01

    This paper uses a recently proposed measure of hydrological model complexity in a model selection exercise. It demonstrates that a robust hydrological model is selected by penalizing model complexity while maximizing a model performance measure. This especially holds when limited data is available.

  16. Selection of Air Terminal Device

    DEFF Research Database (Denmark)

    Nielsen, Peter V.

    This paper discusses the selection of the air terminal device for the experiments and numerical prediction in the International Energy Agency Annex 20 work: Air Flow Pattern within Buildings,......This paper discusses the selection of the air terminal device for the experiments and numerical prediction in the International Energy Agency Annex 20 work: Air Flow Pattern within Buildings,...

  17. Selective Exposure to Televised Violence.

    Science.gov (United States)

    Atkin, Charles; And Others

    1979-01-01

    Present the results of a study conducted to determine the correlation between children's selection of television programs and aggression. The regression analysis suggests that the relationship between viewing and aggression may be attributable to selective exposure rather than the reverse viewing-causes-aggression sequence. (Author/JVP)

  18. Complexity regularized hydrological model selection

    NARCIS (Netherlands)

    Pande, S.; Arkesteijn, L.; Bastidas, L.A.

    2014-01-01

    This paper uses a recently proposed measure of hydrological model complexity in a model selection exercise. It demonstrates that a robust hydrological model is selected by penalizing model complexity while maximizing a model performance measure. This especially holds when limited data is available.

  19. Partner selection and Hollywood Films

    DEFF Research Database (Denmark)

    Grodal, Torben Kragh; Kramer, Mette

    2012-01-01

    Based on cognitive, neurological and evolutionary based film theory the article describes the representation of partner selection in Hollywood films. It analyses paradigm scenarios of partner selection and love, It further describes some of those mechanisms that regulate the relation between auto...

  20. Individual Influence on Model Selection

    Science.gov (United States)

    Sterba, Sonya K.; Pek, Jolynn

    2012-01-01

    Researchers in psychology are increasingly using model selection strategies to decide among competing models, rather than evaluating the fit of a given model in isolation. However, such interest in model selection outpaces an awareness that one or a few cases can have disproportionate impact on the model ranking. Though case influence on the fit…

  1. Selecting Landscape Plants: Flowering Trees

    OpenAIRE

    Relf, Diane; Appleton, Bonnie Lee, 1948-2012

    2009-01-01

    This publication helps the reader to select wisely among the many species and varieties of flowering trees available. The following are considerations that should be taken into account when choosing flowering trees for the home landscape: selections factors, environmental responses, availability and adaptability, and flowering tree descriptions.

  2. Selections, Extensions and Collectionwise Normality

    CERN Document Server

    Gutev, Valentin

    2008-01-01

    We demonstrate that the classical Michael's selection theorem for l.s.c. mappings with a collectionwise normal domain can be reduced only to compact-valued mappings modulo the Dowker's extension theorem for such spaces. The technique developed to achieve this result is applied to construct selections for set-valued mappings whose point images are in completely metrizable absolute retracts.

  3. Advertising media selection and planning

    NARCIS (Netherlands)

    Moorman, M.; Neijens, P.C.; Smit, E.G.; Belch, M.A.; Belch, G.E.

    2010-01-01

    Reach, frequency, and timing are key concepts in selecting TV, radio, newspapers, magazines, out-of-home, direct mail, Internet, and other media for advertising campaigns. We discuss these concepts and their role in media selection and media planning processes. We also describe media and audience fa

  4. Comparing Patterns of Natural Selection Across Species Using Selective Signatures

    Energy Technology Data Exchange (ETDEWEB)

    Alm, Eric J.; Shapiro, B. Jesse; Alm, Eric J.

    2007-12-18

    Comparing gene expression profiles over many different conditions has led to insights that were not obvious from single experiments. In the same way, comparing patterns of natural selection across a set of ecologically distinct species may extend what can be learned from individual genome-wide surveys. Toward this end, we show how variation in protein evolutionary rates, after correcting for genome-wide effects such as mutation rate and demographic factors, can be used to estimate the level and types of natural selection acting on genes across different species. We identify unusually rapidly and slowly evolving genes, relative to empirically derived genome-wide and gene family-specific background rates for 744 core protein families in 30 gamma-proteobacterial species. We describe the pattern of fast or slow evolution across species as the 'selective signature' of a gene. Selective signatures represent a profile of selection across species that is predictive of gene function: pairs of genes with correlated selective signatures are more likely to share the same cellular function, and genes in the same pathway can evolve in concert. For example, glycolysis and phenylalanine metabolism genes evolve rapidly in Idiomarina loihiensis, mirroring an ecological shift in carbon source from sugars to amino acids. In a broader context, our results suggest that the genomic landscape is organized into functional modules even at the level of natural selection, and thus it may be easier than expected to understand the complex evolutionary pressures on a cell.

  5. Comparing Patterns of Natural Selection across Species Using Selective Signatures

    Energy Technology Data Exchange (ETDEWEB)

    Shapiro, Jesse; Alm, Eric J.

    2007-12-01

    Comparing gene expression profiles over many different conditions has led to insights that were not obvious from single experiments. In the same way, comparing patterns of natural selection across a set of ecologically distinct species may extend what can be learned from individual genome-wide surveys. Toward this end, we show how variation in protein evolutionary rates, after correcting for genome-wide effects such as mutation rate and demographic factors, can be used to estimate the level and types of natural selection acting on genes across different species. We identify unusually rapidly and slowly evolving genes, relative to empirically derived genome-wide and gene family-specific background rates for 744 core protein families in 30 c-proteobacterial species. We describe the pattern of fast or slow evolution across species as the"selective signature" of a gene. Selective signatures represent aprofile of selection across species that is predictive of gene function: pairs of genes with correlated selective signatures are more likely to share the same cellular function, and genes in the same pathway can evolve in concert. For example,glycolysis and phenylalanine metabolism genes evolve rapidly in Idiomarina loihiensis, mirroring an ecological shift in carbon source from sugars to amino acids. In a broader context, our results suggest that the genomic landscape is organized into functional modules even at the level of natural selection, and thus it may be easier than expected to understand the complex evolutionary pressures on a cell.

  6. Feature selection for portfolio optimization

    DEFF Research Database (Denmark)

    Bjerring, Thomas Trier; Ross, Omri; Weissensteiner, Alex

    2016-01-01

    Most portfolio selection rules based on the sample mean and covariance matrix perform poorly out-of-sample. Moreover, there is a growing body of evidence that such optimization rules are not able to beat simple rules of thumb, such as 1/N. Parameter uncertainty has been identified as one major...... reason for these findings. A strand of literature addresses this problem by improving the parameter estimation and/or by relying on more robust portfolio selection methods. Independent of the chosen portfolio selection rule, we propose using feature selection first in order to reduce the asset menu....... While most of the diversification benefits are preserved, the parameter estimation problem is alleviated. We conduct out-of-sample back-tests to show that in most cases different well-established portfolio selection rules applied on the reduced asset universe are able to improve alpha relative...

  7. Feature selection for portfolio optimization

    DEFF Research Database (Denmark)

    Bjerring, Thomas Trier; Ross, Omri; Weissensteiner, Alex

    2016-01-01

    Most portfolio selection rules based on the sample mean and covariance matrix perform poorly out-of-sample. Moreover, there is a growing body of evidence that such optimization rules are not able to beat simple rules of thumb, such as 1/N. Parameter uncertainty has been identified as one major...... reason for these findings. A strand of literature addresses this problem by improving the parameter estimation and/or by relying on more robust portfolio selection methods. Independent of the chosen portfolio selection rule, we propose using feature selection first in order to reduce the asset menu....... While most of the diversification benefits are preserved, the parameter estimation problem is alleviated. We conduct out-of-sample back-tests to show that in most cases different well-established portfolio selection rules applied on the reduced asset universe are able to improve alpha relative...

  8. Verb Semantics and Lexical Selection

    CERN Document Server

    Wu, Z; Wu, Zhibiao; Palmer, Martha

    1994-01-01

    This paper will focus on the semantic representation of verbs in computer systems and its impact on lexical selection problems in machine translation (MT). Two groups of English and Chinese verbs are examined to show that lexical selection must be based on interpretation of the sentence as well as selection restrictions placed on the verb arguments. A novel representation scheme is suggested, and is compared to representations with selection restrictions used in transfer-based MT. We see our approach as closely aligned with knowledge-based MT approaches (KBMT), and as a separate component that could be incorporated into existing systems. Examples and experimental results will show that, using this scheme, inexact matches can achieve correct lexical selection.

  9. Benchmarking Variable Selection in QSAR.

    Science.gov (United States)

    Eklund, Martin; Norinder, Ulf; Boyer, Scott; Carlsson, Lars

    2012-02-01

    Variable selection is important in QSAR modeling since it can improve model performance and transparency, as well as reduce the computational cost of model fitting and predictions. Which variable selection methods that perform well in QSAR settings is largely unknown. To address this question we, in a total of 1728 benchmarking experiments, rigorously investigated how eight variable selection methods affect the predictive performance and transparency of random forest models fitted to seven QSAR datasets covering different endpoints, descriptors sets, types of response variables, and number of chemical compounds. The results show that univariate variable selection methods are suboptimal and that the number of variables in the benchmarked datasets can be reduced with about 60 % without significant loss in model performance when using multivariate adaptive regression splines MARS and forward selection.

  10. Sports selection system in triathlon

    Directory of Open Access Journals (Sweden)

    Volodymyr Vodlozerov

    2016-06-01

    Full Text Available Purpose: to analyze the contents of the main stages of sports selection of triathletes. Material & Methods: study and generalization of special literature on the issue of sports selection in continuous triathlon, analysis of triathletes selection based on normative documents. Results: there were reviewed the particularities of sports selection of triathletes on each of its main stages and the role of heredity as a necessary condition for practicing sports for endurance, and also there was shown the procedure of calculation of rating points. Conclusions: sports selection plays a key role in the admission of pupils to the departments of triathlon in sports schools as well as in the formation of picked teams of all levels for participation in competitions on continuous triathlon.

  11. Selective Serotonin Reuptake Inhibitors for Treatment of Selective Mutism

    Directory of Open Access Journals (Sweden)

    Mazlum Çöpür

    2012-03-01

    Full Text Available Some authors suggest that selective mutism should be considered as a variant of social phobia or a disorder in the obsessive-compulsive spectrum. Recent studies indicate that pharmacological treatments may be effective in the treatment of selective mutism. In this article, four cases who were treated with citalopram and escitalopram are presented. The results indicate that the drugs were well tolerated, and the level of social and verbal interactions improved significantly. These findings have shown that citalopram and escitalopram can be considered in medication of selective mutism; nevertheless, it is essential that research be done with more cases than previous ones, in order to prove their accuracy

  12. Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse.

    Science.gov (United States)

    Kivell, Bronwyn M; Ewald, Amy W M; Prisinzano, Thomas E

    2014-01-01

    Acute activation of kappa-opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use. Salvinorin A (Sal A), a novel kappa-opioid receptor agonist extracted from the plant Salvia divinorum, has been identified as a potential therapy for drug abuse and addiction. Here, we review the preclinical effects of Sal A in comparison with traditional kappa-opioid agonists and several new analogs. Sal A retains the anti-addictive properties of traditional kappa-opioid receptor agonists with several improvements including reduced side effects. However, the rapid metabolism of Sal A makes it undesirable for clinical development. In an effort to improve the pharmacokinetics and tolerability of this compound, kappa-opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addictive therapeutics.

  13. Stimulator Selection in SSVEP-Based Spatial Selective Attention Study.

    Science.gov (United States)

    Xie, Songyun; Liu, Chang; Obermayer, Klaus; Zhu, Fangshi; Wang, Linan; Xie, Xinzhou; Wang, Wei

    2016-01-01

    Steady-State Visual Evoked Potentials (SSVEPs) are widely used in spatial selective attention. In this process the two kinds of visual simulators, Light Emitting Diode (LED) and Liquid Crystal Display (LCD), are commonly used to evoke SSVEP. In this paper, the differences of SSVEP caused by these two stimulators in the study of spatial selective attention were investigated. Results indicated that LED could stimulate strong SSVEP component on occipital lobe, and the frequency of evoked SSVEP had high precision and wide range as compared to LCD. Moreover a significant difference between noticed and unnoticed frequencies in spectrum was observed whereas in LCD mode this difference was limited and selectable frequencies were also limited. Our experimental finding suggested that average classification accuracies among all the test subjects in our experiments were 0.938 and 0.853 in LED and LCD mode, respectively. These results indicate that LED simulator is appropriate for evoking the SSVEP for the study of spatial selective attention.

  14. Measurement invariance versus selection invariance : Is fair selection possible?

    NARCIS (Netherlands)

    Borsboom, Denny; Romeijn, Jan-Willem; Wicherts, Jelte M.

    2008-01-01

    This article shows that measurement invariance (defined in terms of an invariant measurement model in different groups) is generally inconsistent with selection invariance (defined in terms of equal sensitivity and specificity across groups). In particular, when a unidimensional measurement instrume

  15. Measurement invariance versus selection invariance : Is fair selection possible?

    NARCIS (Netherlands)

    Borsboom, Denny; Romeijn, Jan-Willem; Wicherts, Jelte M.

    2008-01-01

    This article shows that measurement invariance (defined in terms of an invariant measurement model in different groups) is generally inconsistent with selection invariance (defined in terms of equal sensitivity and specificity across groups). In particular, when a unidimensional measurement instrume

  16. Measurement invariance versus selection invariance: Is fair selection possible?

    NARCIS (Netherlands)

    Borsboom, D.; Romeijn, J.W.; Wicherts, J.M.

    2008-01-01

    This article shows that measurement invariance (defined in terms of an invariant measurement model in different groups) is generally inconsistent with selection invariance (defined in terms of equal sensitivity and specificity across groups). In particular, when a unidimensional measurement instrume

  17. Measurement invariance versus selection invariance: Is fair selection possible?

    NARCIS (Netherlands)

    Borsboom, D.; Romeijn, J.W.; Wicherts, J.M.

    2008-01-01

    This article shows that measurement invariance (defined in terms of an invariant measurement model in different groups) is generally inconsistent with selection invariance (defined in terms of equal sensitivity and specificity across groups). In particular, when a unidimensional measurement

  18. Measurement invariance versus selection invariance : Is fair selection possible?

    NARCIS (Netherlands)

    Borsboom, Denny; Romeijn, Jan-Willem; Wicherts, Jelte M.

    This article shows that measurement invariance (defined in terms of an invariant measurement model in different groups) is generally inconsistent with selection invariance (defined in terms of equal sensitivity and specificity across groups). In particular, when a unidimensional measurement

  19. Contemporary views on selective mutism

    Directory of Open Access Journals (Sweden)

    Dimoski Sanja

    2016-01-01

    Full Text Available The aim of this paper is to review contemporary literature on selective mutism (SM, available in our language. The paper includes a contemporary definition of the disorder, previous studies of selective mutism, theories about its origin, and treatment. SM is a disorder that occurs in childhood, when a child's speech is selectively lacking in certain social situations. School is the context in which the disorder is typically manifested, which is why SM is often diagnosed only after children start school. The paper gives a historical account of changes in views on this disorder. Modern conceptions emphasize selective inability of children to spontaneously and successfully express themselves verbally. In researching SM, case studies on children who have selective mutism are most commonly published. Etiological factors are not precisely defined, and different conceptions give their interpretations depending on various theoretical frameworks. Some studies consistently indicate a relation between SM and social anxiety, and some with opposing behavior and delays in language development. Based on theoretical explanations of SM, psychological interventions (behavioral and cognitive-behavioral, psychodynamic and projective techniques, counseling and family therapy are created. Modern treatment of selective mutism includes an eclectic approach and emphasizes the role of teachers and school in general. Future studies should deepen the knowledge about selective mutism, specify the methodological procedure and stimulate the individualized treatment of children with SM.

  20. X-ray selected BALQSOs

    CERN Document Server

    Page, M J; Ceballos, M; Corral, A; Ebrero, J; Esquej, P; Krumpe, M; Mateos, S; Rosen, S; Schwope, A; Streblyanska, A; Symeonidis, M; Tedds, J A; Watson, M G

    2016-01-01

    We study a sample of six X-ray selected broad absorption line (BAL) quasi-stellar objects (QSOs) from the XMM-Newton Wide Angle Survey. All six objects are classified as BALQSOs using the classic balnicity index, and together they form the largest sample of X-ray selected BALQSOs. We find evidence for absorption in the X-ray spectra of all six objects. An ionized absorption model applied to an X-ray spectral shape that would be typical for non-BAL QSOs (a power law with energy index alpha=0.98) provides acceptable fits to the X-ray spectra of all six objects. The optical to X-ray spectral indices, alpha_OX, of the X-ray selected BALQSOs, have a mean value of 1.69 +- 0.05, which is similar to that found for X-ray selected and optically selected non-BAL QSOs of similar ultraviolet luminosity. In contrast, optically-selected BALQSOs typically have much larger alpha_OX and so are characterised as being X-ray weak. The results imply that X-ray selection yields intrinsically X-ray bright BALQSOs, but their X-ray sp...

  1. Introduction. Modelling natural action selection.

    Science.gov (United States)

    Prescott, Tony J; Bryson, Joanna J; Seth, Anil K

    2007-09-29

    Action selection is the task of resolving conflicts between competing behavioural alternatives. This theme issue is dedicated to advancing our understanding of the behavioural patterns and neural substrates supporting action selection in animals, including humans. The scope of problems investigated includes: (i) whether biological action selection is optimal (and, if so, what is optimized), (ii) the neural substrates for action selection in the vertebrate brain, (iii) the role of perceptual selection in decision-making, and (iv) the interaction of group and individual action selection. A second aim of this issue is to advance methodological practice with respect to modelling natural action section. A wide variety of computational modelling techniques are therefore employed ranging from formal mathematical approaches through to computational neuroscience, connectionism and agent-based modelling. The research described has broad implications for both natural and artificial sciences. One example, highlighted here, is its application to medical science where models of the neural substrates for action selection are contributing to the understanding of brain disorders such as Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder.

  2. Reaction Selectivity in Heterogeneous Catalysis

    Energy Technology Data Exchange (ETDEWEB)

    Somorjai, Gabor A.; Kliewer, Christopher J.

    2009-02-02

    The understanding of selectivity in heterogeneous catalysis is of paramount importance to our society today. In this review we outline the current state of the art in research on selectivity in heterogeneous catalysis. Current in-situ surface science techniques have revealed several important features of catalytic selectivity. Sum frequency generation vibrational spectroscopy has shown us the importance of understanding the reaction intermediates and mechanism of a heterogeneous reaction, and can readily yield information as to the effect of temperature, pressure, catalyst geometry, surface promoters, and catalyst composition on the reaction mechanism. DFT calculations are quickly approaching the ability to assist in the interpretation of observed surface spectra, thereby making surface spectroscopy an even more powerful tool. HP-STM has revealed three vitally important parameters in heterogeneous selectivity: adsorbate mobility, catalyst mobility, and selective site-blocking. The development of size controlled nanoparticles from 0.8 to 10 nm, of controlled shape, and of controlled bimetallic composition has revealed several important variables for catalytic selectivity. Lastly, DFT calculations may be paving the way to guiding the composition choice for multi-metallic heterogeneous catalysis for the intelligent design of catalysts incorporating the many factors of selectivity we have learned.

  3. Fisheries-induced disruptive selection.

    Science.gov (United States)

    Landi, Pietro; Hui, Cang; Dieckmann, Ulf

    2015-01-21

    Commercial harvesting is recognized to induce adaptive responses of life-history traits in fish populations, in particular by shifting the age and size at maturation through directional selection. In addition to such evolution of a target stock, the corresponding fishery itself may adapt, in terms of fishing policy, technological progress, fleet dynamics, and adaptive harvest. The aim of this study is to assess how the interplay between natural and artificial selection, in the simplest setting in which a fishery and a target stock coevolve, can lead to disruptive selection, which in turn may cause trait diversification. To this end, we build an eco-evolutionary model for a size-structured population, in which both the stock׳s maturation schedule and the fishery׳s harvest rate are adaptive, while fishing may be subject to a selective policy based on fish size and/or maturity stage. Using numerical bifurcation analysis, we study how the potential for disruptive selection changes with fishing policy, fishing mortality, harvest specialization, life-history tradeoffs associated with early maturation, and other demographic and environmental parameters. We report the following findings. First, fisheries-induced disruptive selection is readily caused by commonly used fishing policies, and occurs even for policies that are not specific for fish size or maturity, provided that the harvest is sufficiently adaptive and large individuals are targeted intensively. Second, disruptive selection is more likely in stocks in which the selective pressure for early maturation is naturally strong, provided life-history tradeoffs are sufficiently consequential. Third, when a fish stock is overexploited, fisheries targeting only large individuals might slightly increase sustainable yield by causing trait diversification (even though the resultant yield always remains lower than the maximum sustainable yield that could be obtained under low fishing mortality, without causing disruptive

  4. Selective Audiovisual Semantic Integration Enabled by Feature-Selective Attention.

    Science.gov (United States)

    Li, Yuanqing; Long, Jinyi; Huang, Biao; Yu, Tianyou; Wu, Wei; Li, Peijun; Fang, Fang; Sun, Pei

    2016-01-13

    An audiovisual object may contain multiple semantic features, such as the gender and emotional features of the speaker. Feature-selective attention and audiovisual semantic integration are two brain functions involved in the recognition of audiovisual objects. Humans often selectively attend to one or several features while ignoring the other features of an audiovisual object. Meanwhile, the human brain integrates semantic information from the visual and auditory modalities. However, how these two brain functions correlate with each other remains to be elucidated. In this functional magnetic resonance imaging (fMRI) study, we explored the neural mechanism by which feature-selective attention modulates audiovisual semantic integration. During the fMRI experiment, the subjects were presented with visual-only, auditory-only, or audiovisual dynamical facial stimuli and performed several feature-selective attention tasks. Our results revealed that a distribution of areas, including heteromodal areas and brain areas encoding attended features, may be involved in audiovisual semantic integration. Through feature-selective attention, the human brain may selectively integrate audiovisual semantic information from attended features by enhancing functional connectivity and thus regulating information flows from heteromodal areas to brain areas encoding the attended features.

  5. Natural selection. VII. History and interpretation of kin selection theory.

    Science.gov (United States)

    Frank, S A

    2013-06-01

    Kin selection theory is a kind of causal analysis. The initial form of kin selection ascribed cause to costs, benefits and genetic relatedness. The theory then slowly developed a deeper and more sophisticated approach to partitioning the causes of social evolution. Controversy followed because causal analysis inevitably attracts opposing views. It is always possible to separate total effects into different component causes. Alternative causal schemes emphasize different aspects of a problem, reflecting the distinct goals, interests and biases of different perspectives. For example, group selection is a particular causal scheme with certain advantages and significant limitations. Ultimately, to use kin selection theory to analyse natural patterns and to understand the history of debates over different approaches, one must follow the underlying history of causal analysis. This article describes the history of kin selection theory, with emphasis on how the causal perspective improved through the study of key patterns of natural history, such as dispersal and sex ratio, and through a unified approach to demographic and social processes. Independent historical developments in the multivariate analysis of quantitative traits merged with the causal analysis of social evolution by kin selection.

  6. Molecular Signatures of Natural Selection

    DEFF Research Database (Denmark)

    Nielsen, Rasmus

    2005-01-01

    There is an increasing interest in detecting genes, or genomic regions, that have been targeted by natural selection. The interest stems from a basic desire to learn more about evolutionary processes in humans and other organisms, and from the realization that inferences regarding selection may...... provide important functional information. This review provides a nonmathematical description of the issues involved in detecting selection from DNA sequences and SNP data and is intended for readers who are not familiar with population genetic theory. Particular attention is placed on issues relating...

  7. Selecting Media for Instruction: An Exploratory Study.

    Science.gov (United States)

    Higgins, Norman; Reiser, Robert A.

    1985-01-01

    This study compared media selection decisions novice instructional developers make when using an intuitive selection approach versus Reiser and Gagne's formal selection procedure. Formal selection procedure use results in media selection choices matching those of experienced developers, and more selection factors are considered when novices…

  8. An overview on selection methods

    Directory of Open Access Journals (Sweden)

    J. W. H. Swanepoel

    1982-03-01

    Full Text Available In many studies the experimenter has under consideration several (two or more alternatives, and is studying them in order to determine which is the best (with regard to certain specified criteria of “goodness”. Such an experimenter does not wish basically to test hypotheses, or construct confidence intervals, or perform regression analyses (though these may be appropriate parts of his analysis; he does wish to select the best of several alternatives, and the major part of his analysis should therefore be directed towards this goal. It is precisely for this problem that ranking and selection procedures were developed. This paper presents an overview of some recent work in this field, with emphasis on aspects important to experimenters confronted with selection problems. Fixed sample size and sequential procedures for both the indifference zone and subset formulations of the selection problem are discussed.

  9. Selective Functionalization of Tailored Nanostructures

    NARCIS (Netherlands)

    Slingenbergh, Winand; Boer, Sanne K. de; Cordes, Thorben; Browne, Wesley R.; Feringa, Ben L.; Hoogenboom, Jacob P.; Hosson, Jeff Th.M. De; Dorp, Willem F. van

    2012-01-01

    The controlled positioning of nanostructures with active molecular components is of importance throughout nanoscience and nanotechnology. We present a novel three-step method to produce nanostructures that are selectively decorated with functional molecules. We use fluorophores and nanoparticles to

  10. Ion selectivity of graphene nanopores

    Science.gov (United States)

    Rollings, Ryan C.; Kuan, Aaron T.; Golovchenko, Jene A.

    2016-04-01

    As population growth continues to outpace development of water infrastructure in many countries, desalination (the removal of salts from seawater) at high energy efficiency will likely become a vital source of fresh water. Due to its atomic thinness combined with its mechanical strength, porous graphene may be particularly well-suited for electrodialysis desalination, in which ions are removed under an electric field via ion-selective pores. Here, we show that single graphene nanopores preferentially permit the passage of K+ cations over Cl- anions with selectivity ratios of over 100 and conduct monovalent cations up to 5 times more rapidly than divalent cations. Surprisingly, the observed K+/Cl- selectivity persists in pores even as large as about 20 nm in diameter, suggesting that high throughput, highly selective graphene electrodialysis membranes can be fabricated without the need for subnanometer control over pore size.

  11. Selective Smoothed Finite Element Method

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The paper examines three selective schemes for the smoothed finite element method (SFEM) which was formulated by incorporating a cell-wise strain smoothing operation into the standard compatible finite element method (FEM). These selective SFEM schemes were formulated based on three selective integration FEM schemes with similar properties found between the number of smoothing cells in the SFEM and the number of Gaussian integration points in the FEM. Both scheme 1 and scheme 2 are free of nearly incompressible locking, but scheme 2 is more general and gives better results than scheme 1. In addition, scheme 2 can be applied to anisotropic and nonlinear situations, while scheme 1 can only be applied to isotropic and linear situations. Scheme 3 is free of shear locking. This scheme can be applied to plate and shell problems. Results of the numerical study show that the selective SFEM schemes give more accurate results than the FEM schemes.

  12. Group selection in behavioral evolution.

    Science.gov (United States)

    Rachlin, Howard

    2017-09-09

    How may patterns of behavior change over an organism's lifetime? The answer is that they evolve (behavioral evolution) as species evolve over generations (biological evolution). In biological evolution, under certain conditions, groups of cooperative organisms would be selected over groups of non-cooperative organisms, even when cooperation imposes a cost to individuals. Analogously, in behavioral evolution, patterns of acts may be selected even when each individual act in the pattern is costly. Although there is considerable debate among biologists whether the conditions for group selection are met in biological evolution, it is argued here that they are met in behavioral evolution (as well as in cultural evolution). The article shows how selection of patterns can explain the learning of self-control and altruism. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Random Selection for Drug Screening

    Energy Technology Data Exchange (ETDEWEB)

    Center for Human Reliability Studies

    2007-05-01

    Sampling is the process of choosing some members out of a group or population. Probablity sampling, or random sampling, is the process of selecting members by chance with a known probability of each individual being chosen.

  14. Mode selection in pulsating stars

    CERN Document Server

    Smolec, R

    2013-01-01

    In this review we focus on non-linear phenomena in pulsating stars the mode selection and amplitude limitation. Of many linearly excited modes only a fraction is detected in pulsating stars. Which of them and why (the problem of mode selection) and to what amplitude (the problem of amplitude limitation) are intrinsically non-linear and still unsolved problems. Tools for studying these problems are briefly discussed and our understanding of mode selection and amplitude limitation in selected groups of self-excited pulsators is presented. Focus is put on classical pulsators (Cepheids and RR Lyrae stars) and main sequence variables (delta Scuti and beta Cephei stars). Directions of future studies are briefly discussed.

  15. WMO Selected, Supplemenatary, Auxiliary Ships

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — World Meteorological Organization International List of Selected, Supplementary and Auxiliary Ships, recognized as Publication 47. 1973-1998 editions, gathered from...

  16. Selected Works of AI Shirshov

    CERN Document Server

    Kotchetov, Michail V

    2009-01-01

    Russian mathematician AI Shirshov (1921-1981) was a pioneer in several directions of associative, Lie, Jordan, and alternative algebras, as well as groups and projective planes. This book presents translations of his selected works.

  17. Marketing audit in selected company

    OpenAIRE

    ŠACHTA, Martin

    2014-01-01

    This thesis addresses the implementation of marketing audit in selected companies. For the analysis of the selected engineering company ENGEL Strojirenska ltd. based in the South Bohemian Kaplice. The thesis is divided into an introduction and objectives, literature review, characteristics, implementing marketing audit itself, solution design changes, conclusion and list of references. The literature review is characterized by marketing, micro and macro environments, PEST analysis, Porter's f...

  18. Global Sourcing and Firm Selection

    DEFF Research Database (Denmark)

    Kohler, Wilhelm; Smolka, Marcel

    2014-01-01

    We analyze the sourcing strategies of firms active in the Spanish manufacturing sector. We show that firms that select strategies of vertical integration and of foreign sourcing ex post tend to have been more productive, ex ante, than other firms.......We analyze the sourcing strategies of firms active in the Spanish manufacturing sector. We show that firms that select strategies of vertical integration and of foreign sourcing ex post tend to have been more productive, ex ante, than other firms....

  19. On fast carry select adders

    Science.gov (United States)

    Shamanna, M.; Whitaker, S.

    1992-01-01

    This paper presents an architecture for a high-speed carry select adder with very long bit lengths utilizing a conflict-free bypass scheme. The proposed scheme has almost half the number of transistors and is faster than a conventional carry select adder. A comparative study is also made between the proposed adder and a Manchester carry chain adder which shows that the proposed scheme has the same transistor count, without suffering any performance degradation, compared to the Manchester carry chain adder.

  20. Feature Selection: Algorithms and Challenges

    Institute of Scientific and Technical Information of China (English)

    Xindong Wu; Yanglan Gan; Hao Wang; Xuegang Hu

    2006-01-01

    Feature selection is an active area in data mining research and development. It consists of efforts and contributions from a wide variety of communities, including statistics, machine learning, and pattern recognition. The diversity, on one hand, equips us with many methods and tools. On the other hand, the profusion of options causes confusion. This paper reviews various feature selection methods and identifies research challenges that are at the forefront of this exciting area.

  1. On fast carry select adders

    Science.gov (United States)

    Shamanna, M.; Whitaker, S.

    This paper presents an architecture for a high-speed carry select adder with very long bit lengths utilizing a conflict-free bypass scheme. The proposed scheme has almost half the number of transistors and is faster than a conventional carry select adder. A comparative study is also made between the proposed adder and a Manchester carry chain adder which shows that the proposed scheme has the same transistor count, without suffering any performance degradation, compared to the Manchester carry chain adder.

  2. Selective functionalization of carbon nanotubes

    Science.gov (United States)

    Strano, Michael S. (Inventor); Usrey, Monica (Inventor); Barone, Paul (Inventor); Dyke, Christopher A. (Inventor); Tour, James M. (Inventor); Kittrell, W. Carter (Inventor); Hauge, Robert H. (Inventor); Smalley, Richard E. (Inventor)

    2009-01-01

    The present invention is directed toward methods of selectively functionalizing carbon nanotubes of a specific type or range of types, based on their electronic properties, using diazonium chemistry. The present invention is also directed toward methods of separating carbon nanotubes into populations of specific types or range(s) of types via selective functionalization and electrophoresis, and also to the novel compositions generated by such separations.

  3. A Heckman Selection- t Model

    KAUST Repository

    Marchenko, Yulia V.

    2012-03-01

    Sample selection arises often in practice as a result of the partial observability of the outcome of interest in a study. In the presence of sample selection, the observed data do not represent a random sample from the population, even after controlling for explanatory variables. That is, data are missing not at random. Thus, standard analysis using only complete cases will lead to biased results. Heckman introduced a sample selection model to analyze such data and proposed a full maximum likelihood estimation method under the assumption of normality. The method was criticized in the literature because of its sensitivity to the normality assumption. In practice, data, such as income or expenditure data, often violate the normality assumption because of heavier tails. We first establish a new link between sample selection models and recently studied families of extended skew-elliptical distributions. Then, this allows us to introduce a selection-t (SLt) model, which models the error distribution using a Student\\'s t distribution. We study its properties and investigate the finite-sample performance of the maximum likelihood estimators for this model. We compare the performance of the SLt model to the conventional Heckman selection-normal (SLN) model and apply it to analyze ambulatory expenditures. Unlike the SLNmodel, our analysis using the SLt model provides statistical evidence for the existence of sample selection bias in these data. We also investigate the performance of the test for sample selection bias based on the SLt model and compare it with the performances of several tests used with the SLN model. Our findings indicate that the latter tests can be misleading in the presence of heavy-tailed data. © 2012 American Statistical Association.

  4. Autophagy selectivity through receptor clustering

    Science.gov (United States)

    Rutenberg, Andrew; Brown, Aidan

    Substrate selectivity in autophagy requires an all-or-none cellular response. We focus on peroxisomes, for which autophagy receptor proteins NBR1 and p62 are well characterized. Using computational models, we explore the hypothesis that physical clustering of autophagy receptor proteins on the peroxisome surface provides an appropriate all-or-none response. We find that larger peroxisomes nucleate NBR1 clusters first, and lose them due to competitive coarsening last, resulting in significant size-selectivity. We then consider a secondary hypothesis that p62 inhibits NBR1 cluster formation. We find that p62 inhibition enhances size-selectivity enough that, even if there is no change of the pexophagy rate, the volume of remaining peroxisomes can significantly decrease. We find that enhanced ubiquitin levels suppress size-selectivity, and that this effect is more pronounced for individual peroxisomes. Sufficient ubiquitin allows receptor clusters to form on even the smallest peroxisomes. We conclude that NBR1 cluster formation provides a viable physical mechanism for all-or-none substrate selectivity in pexophagy. We predict that cluster formation is associated with significant size-selectivity. Now at Simon Fraser University.

  5. Salvinorin A reduces mechanical allodynia and spinal neuronal hyperexcitability induced by peripheral formalin injection

    Directory of Open Access Journals (Sweden)

    Guida Francesca

    2012-08-01

    Full Text Available Abstract Background Salvinorin A (SA, the main active component of Salvia Divinorum, is a non-nitrogenous kappa opioid receptor (KOR agonist. It has been shown to reduce acute pain and to exert potent antinflammatory effects. This study assesses the effects and the mode of action of SA on formalin-induced persistent pain in mice. Specifically, the SA effects on long-term behavioural dysfuctions and changes in neuronal activity occurring at spinal level, after single peripheral formalin injection, have been investigated. Moreover, the involvement of microglial and glial cells in formalin-induced chronic pain condition and in SA-mediated effects has been evaluated. Results Formalin induced a significant decrease of mechanical withdrawal threshold at the injected and contralateral paw as well as an increase in the duration and frequency, and a rapid decrease in the onset of evoked activity of the nociceptive neurons 7 days after formalin injection. SA daily treatment significantly reduced mechanical allodynia in KOR and cannabinoid receptor 1 (CB1R sensitive manner. SA treatment also normalized the spinal evoked activity. SA significantly reduced the formalin-mediated microglia and astrocytes activation and modulated pro and anti-inflammatory mediators in the spinal cord. Conclusion SA is effective in reducing formalin-induced mechanical allodynia and spinal neuronal hyperactivity. Our findings suggest that SA reduces glial activation and contributes in the establishment of dysfunctions associated with chronic pain with mechanisms involving KOR and CB1R. SA may provide a new lead compound for developing anti-allodynic agents via KOR and CB1R activation.

  6. Attentional selection by distractor suppression.

    Science.gov (United States)

    Caputo, G; Guerra, S

    1998-03-01

    Selective attention was studied in displays containing singletons popping out for their odd form or color. The target was defined as the form-singleton, the distractor as the color-singleton. The task was to discriminate the length of a longer line inside the target. Target-distractor similarity was controlled using a threshold measurement as dependent variable in experiments in which distractor presence vs absence, bottom-up vs top-down selection (through knowledge of target features), and target-distractor distance were manipulated. The results in the bottom-up condition showed that length threshold was elevated when a distractor was present and that this elevation progressively increased as the number of distractors was increased from one to two. This set-size effect was not accounted by the hypothesis that selective attention intervenes only at the stage of decision before response. Selective attention produced a suppressive surround in which discriminability of neighboring objects was strongly reduced, and a larger surround in which discriminability was reduced by an approximately constant amount. Different results were found in the top-down condition in which target discriminability was unaffected by distractor presence and no effect of target-distractor distance was found. On the other hand, response times in both bottom-up and top-down conditions were slower the shorter the target-distractor distance was. On the basis of the experimental results, selective attention is a parallel process of spatial filtering at an intermediate processing level operating after objects have been segmented. This filtering stage explores high level interactions between objects taking control on combinatorial explosion by operating over only a limited spatial extent: it picks out a selected object and inhibits the neighboring objects; then, non-selected objects are suppressed across the overall image. When no feature-based selection is available in the current behavior, this

  7. Feature-selective attention in healthy old age: a selective decline in selective attention?

    Science.gov (United States)

    Quigley, Cliodhna; Müller, Matthias M

    2014-02-12

    Deficient selection against irrelevant information has been proposed to underlie age-related cognitive decline. We recently reported evidence for maintained early sensory selection when older and younger adults used spatial selective attention to perform a challenging task. Here we explored age-related differences when spatial selection is not possible and feature-selective attention must be deployed. We additionally compared the integrity of feedforward processing by exploiting the well established phenomenon of suppression of visual cortical responses attributable to interstimulus competition. Electroencephalogram was measured while older and younger human adults responded to brief occurrences of coherent motion in an attended stimulus composed of randomly moving, orientation-defined, flickering bars. Attention was directed to horizontal or vertical bars by a pretrial cue, after which two orthogonally oriented, overlapping stimuli or a single stimulus were presented. Horizontal and vertical bars flickered at different frequencies and thereby elicited separable steady-state visual-evoked potentials, which were used to examine the effect of feature-based selection and the competitive influence of a second stimulus on ongoing visual processing. Age differences were found in feature-selective attentional modulation of visual responses: older adults did not show consistent modulation of magnitude or phase. In contrast, the suppressive effect of a second stimulus was robust and comparable in magnitude across age groups, suggesting that bottom-up processing of the current stimuli is essentially unchanged in healthy old age. Thus, it seems that visual processing per se is unchanged, but top-down attentional control is compromised in older adults when space cannot be used to guide selection.

  8. Ion selectivity strategies of sodium channel selectivity filters.

    Science.gov (United States)

    Dudev, Todor; Lim, Carmay

    2014-12-16

    CONSPECTUS: Sodium ion channels selectively transport Na(+) cations across the cell membrane. These integral parts of the cell machinery are implicated in regulating the cardiac, skeletal and smooth muscle contraction, nerve impulses, salt and water homeostasis, as well as pain and taste perception. Their malfunction often results in various channelopathies of the heart, brain, skeletal muscles, and lung; thus, sodium channels are key drug targets for various disorders including cardiac arrhythmias, heart attack, stroke, migraine, epilepsy, pain, cancer, and autoimmune disorders. The ability of sodium channels to discriminate the native Na(+) among other competing ions in the surrounding fluids is crucial for proper cellular functions. The selectivity filter (SF), the narrowest part of the channel's open pore, lined with amino acid residues that specifically interact with the permeating ion, plays a major role in determining Na(+) selectivity. Different sodium channels have different SFs, which vary in the symmetry, number, charge, arrangement, and chemical type of the metal-ligating groups and pore size: epithelial/degenerin/acid-sensing ion channels have generally trimeric SFs lined with three conserved neutral serines and/or backbone carbonyls; eukaryotic sodium channels have EKEE, EEKE, DKEA, and DEKA SFs with an invariant positively charged lysine from the second or third domain; and bacterial voltage-gated sodium (Nav) channels exhibit symmetrical EEEE SFs, reminiscent of eukaryotic voltage-gated calcium channels. How do these different sodium channel SFs achieve high selectivity for Na(+) over its key rivals, K(+) and Ca(2+)? What factors govern the metal competition in these SFs and which of these factors are exploited to achieve Na(+) selectivity in the different sodium channel SFs? The free energies for replacing K(+) or Ca(2+) bound inside different model SFs with Na(+), evaluated by a combination of density functional theory and continuum dielectric

  9. Gravimetric analysis of selecteD types of Biofuels

    Directory of Open Access Journals (Sweden)

    Mikulová Zuzana

    2014-08-01

    Full Text Available Biomass provides a great diversity of input materials and universal use, not only for heat generation but also electricity generation in modern incinerators. For the most eficient use of solid biofuels, it is necessary to know their physico-chemical properties. The work focuses on the gravimetric analysis of selected types of biofuels. This paper presents the results of measurements for moisture content, ash and combustibles in selected solid biofuels. Experiments represent a follow-up to measurements performed to date.

  10. Visuospatial selective attention in chickens.

    Science.gov (United States)

    Sridharan, Devarajan; Ramamurthy, Deepa L; Schwarz, Jason S; Knudsen, Eric I

    2014-05-13

    Voluntary control of attention promotes intelligent, adaptive behaviors by enabling the selective processing of information that is most relevant for making decisions. Despite extensive research on attention in primates, the capacity for selective attention in nonprimate species has never been quantified. Here we demonstrate selective attention in chickens by applying protocols that have been used to characterize visual spatial attention in primates. Chickens were trained to localize and report the vertical position of a target in the presence of task-relevant distracters. A spatial cue, the location of which varied across individual trials, indicated the horizontal, but not vertical, position of the upcoming target. Spatial cueing improved localization performance: accuracy (d') increased and reaction times decreased in a space-specific manner. Distracters severely impaired perceptual performance, and this impairment was greatly reduced by spatial cueing. Signal detection analysis with an "indecision" model demonstrated that spatial cueing significantly increased choice certainty in localizing targets. By contrast, error-aversion certainty (certainty of not making an error) remained essentially constant across cueing protocols, target contrasts, and individuals. The results show that chickens shift spatial attention rapidly and dynamically, following principles of stimulus selection that closely parallel those documented in primates. The findings suggest that the mechanisms that control attention have been conserved through evolution, and establish chickens--a highly visual species that is easily trained and amenable to cutting-edge experimental technologies--as an attractive model for linking behavior to neural mechanisms of selective attention.

  11. Instructive selection and immunological theory.

    Science.gov (United States)

    Lederberg, Joshua

    2002-07-01

    The turning point of modern immunological theory was the advent of the clonal selection theory (Burnet, Talmage - 1957). A useful heuristic in the classification of theoretical models was the contrast of 'instructive' with 'selective' models of the acquisition of information by biological systems. The neo-Darwinian synthesis of the 1940s had consolidated biologists' model of evolution based on prior random variation and natural selection, viz. differential fecundity. While evolution in the large was by then pretty well settled, controversy remained about examples of cellular adaptation to chemical challenges, like induced drug-resistance, enzyme formation and the antibody response. While instructive theories have been on the decline, some clear cut examples can be found of molecular imprinting in the abiotic world, leading, e.g. to the production of specific sorbents. Template-driven assembly, as in DNA synthesis, has remained a paradigm of instructive specification. Nevertheless, the classification may break down with more microscopic scrutiny of the processes of molecular fit of substrates with enzymes, of monomers to an elongating polymer chain, as the reactants often traverse a state space from with activated components are appropriately selected. The same process may be 'instructive' from a holistic, 'selective' from an atomic perspective.

  12. Materials Selection for Aerospace Systems

    Science.gov (United States)

    Arnold, Steven M.; Cebon, David; Ashby, Mike

    2012-01-01

    A systematic design-oriented, five-step approach to material selection is described: 1) establishing design requirements, 2) material screening, 3) ranking, 4) researching specific candidates and 5) applying specific cultural constraints to the selection process. At the core of this approach is the definition performance indices (i.e., particular combinations of material properties that embody the performance of a given component) in conjunction with material property charts. These material selection charts, which plot one property against another, are introduced and shown to provide a powerful graphical environment wherein one can apply and analyze quantitative selection criteria, such as those captured in performance indices, and make trade-offs between conflicting objectives. Finding a material with a high value of these indices maximizes the performance of the component. Two specific examples pertaining to aerospace (engine blades and pressure vessels) are examined, both at room temperature and elevated temperature (where time-dependent effects are important) to demonstrate the methodology. The discussion then turns to engineered/hybrid materials and how these can be effectively tailored to fill in holes in the material property space, so as to enable innovation and increases in performance as compared to monolithic materials. Finally, a brief discussion is presented on managing the data needed for materials selection, including collection, analysis, deployment, and maintenance issues.

  13. Stimulator Selection in SSVEP-Based Spatial Selective Attention Study

    Directory of Open Access Journals (Sweden)

    Songyun Xie

    2016-01-01

    Full Text Available Steady-State Visual Evoked Potentials (SSVEPs are widely used in spatial selective attention. In this process the two kinds of visual simulators, Light Emitting Diode (LED and Liquid Crystal Display (LCD, are commonly used to evoke SSVEP. In this paper, the differences of SSVEP caused by these two stimulators in the study of spatial selective attention were investigated. Results indicated that LED could stimulate strong SSVEP component on occipital lobe, and the frequency of evoked SSVEP had high precision and wide range as compared to LCD. Moreover a significant difference between noticed and unnoticed frequencies in spectrum was observed whereas in LCD mode this difference was limited and selectable frequencies were also limited. Our experimental finding suggested that average classification accuracies among all the test subjects in our experiments were 0.938 and 0.853 in LED and LCD mode, respectively. These results indicate that LED simulator is appropriate for evoking the SSVEP for the study of spatial selective attention.

  14. Measurement Invariance versus Selection Invariance: Is Fair Selection Possible?

    Science.gov (United States)

    Borsman, Denny; Romeijn, Jan-Willem; Wicherts, Jelte M.

    2008-01-01

    This article shows that measurement invariance (defined in terms of an invariant measurement model in different groups) is generally inconsistent with selection invariance (defined in terms of equal sensitivity and specificity across groups). In particular, when a unidimensional measurement instrument is used and group differences are present in…

  15. Model Selection for Pion Photoproduction

    CERN Document Server

    Landay, J; Fernández-Ramírez, C; Hu, B; Molina, R

    2016-01-01

    Partial-wave analysis of meson and photon-induced reactions is needed to enable the comparison of many theoretical approaches to data. In both energy-dependent and independent parametrizations of partial waves, the selection of the model amplitude is crucial. Principles of the $S$-matrix are implemented to different degree in different approaches, but a many times overlooked aspect concerns the selection of undetermined coefficients and functional forms for fitting, leading to a minimal yet sufficient parametrization. We present an analysis of low-energy neutral pion photoproduction using the Least Absolute Shrinkage and Selection Operator (LASSO) in combination with criteria from information theory and $K$-fold cross validation. These methods are not yet widely known in the analysis of excited hadrons but will become relevant in the era of precision spectroscopy. The principle is first illustrated with synthetic data, then, its feasibility for real data is demonstrated by analyzing the latest available measu...

  16. Sexual selection in marine plankton

    DEFF Research Database (Denmark)

    Sichlau, Mie Hylstofte

    . This is the first time that genetic polyandry has been documented in a pelagic copepod. Multiple paternity opens up for the possibility of post-copulatory sexual selection, such as sperm competition and cryptic female choice. We further found that mating was non-random, as we identified superior individuals...... behavioural studies and genetic parentage analyses to examine the fertilization status and occurrence of mate choice and polygamy in the copepod Temora longicornis (Copepoda, Calanoida). The overall objective of my PhD project was to examine the intensity and direction of sexual selection in T. longicornis...... and elucidate the role of sexual selection for the behaviour of individuals, the dynamics of populations, and the functioning of the pelagic ecosystem. I wanted to address the following overarching questions: i) What is the fraction of fertilized females in field and laboratory populations? Is it influenced...

  17. Selection and design of solvents

    DEFF Research Database (Denmark)

    Gani, Rafiqul

    . With increasing interest on issues such as waste, sustainability, environmental impact and green chemistry, the selection and design of solvents have become important problems that need to be addressed during chemical product-process design and development. Systematic methods and tools suitable for selection......Solvents are liquid solutions consisting of one or more chemicals. They have a very wide use and their use is not necessarily restricted to the process industries. This lecture will discuss the different roles and uses of solvents in chemical products and processes that manufacture them...... and design of solvents will be presented together with application examples. The selection problem is defined as finding known chemicals that match the desired functions of a solvent for a specified set of applications. The design problem is defined as finding the molecular structure (or mixture of molecules...

  18. Randomized selection on the GPU

    Energy Technology Data Exchange (ETDEWEB)

    Monroe, Laura Marie [Los Alamos National Laboratory; Wendelberger, Joanne R [Los Alamos National Laboratory; Michalak, Sarah E [Los Alamos National Laboratory

    2011-01-13

    We implement here a fast and memory-sparing probabilistic top N selection algorithm on the GPU. To our knowledge, this is the first direct selection in the literature for the GPU. The algorithm proceeds via a probabilistic-guess-and-chcck process searching for the Nth element. It always gives a correct result and always terminates. The use of randomization reduces the amount of data that needs heavy processing, and so reduces the average time required for the algorithm. Probabilistic Las Vegas algorithms of this kind are a form of stochastic optimization and can be well suited to more general parallel processors with limited amounts of fast memory.

  19. The selection of altruistic behaviour

    CERN Document Server

    Donato, R; Serva, M

    1996-01-01

    Altruistic behaviour is disadvantageous for the individual while is advantageous for its group. If the target of the selection is the individual, one would expect the selection process to lead to populations formed by wholly homogeneous groups, made up of either altruistic or egoistic individuals, where the winning choice depends on the balance beetwen group advantage and individual disadvantage. We show in a simple model that populations formed by inhomogeneous groups can be stabilized in some circumstances. We argue that this condition is realized when there is a relative advantage conferred by the presence of a few altruists to all the members of the group.

  20. The selective therapeutic apheresis procedures.

    Science.gov (United States)

    Sanchez, Amber P; Cunard, Robyn; Ward, David M

    2013-02-01

    Selective apheresis procedures have been developed to target specific molecules, antibodies, or cellular elements in a variety of diseases. The advantage of the selective apheresis procedures over conventional therapeutic plasmapheresis is preservation of other essential plasma components such as albumin, immunoglobulins, and clotting factors. These procedures are more commonly employed in Europe and Japan, and few are available in the USA. Apheresis procedures discussed in this review include the various technologies available for low-density lipoprotein (LDL) apheresis, double filtration plasmapheresis (DFPP), cryofiltration, immunoadsorption procedures, adsorption resins that process plasma, extracorporeal photopheresis, and leukocyte apheresis.

  1. Select Papyri from Danish Collections

    DEFF Research Database (Denmark)

    Christiansen, Thomas

    The thesis, Select Papyri from Danish Collections: Philological and Archaeometric Studies, consists of an introduction, a book, four articles and a rapport on a scientific experiment at EuropeanRadiation Synchrotron Facility(ESRF), Grenoble, France, together with an application for another...

  2. Selecting Copulas for Risk Management

    NARCIS (Netherlands)

    H.J.W.G. Kole (Erik); C.G. Koedijk (Kees); M.J.C.M. Verbeek (Marno)

    2006-01-01

    textabstractCopulas offer financial risk managers a powerful tool to model the dependence between the different elements of a portfolio and are preferable to the traditional, correlation-based approach. In this paper we show the importance of selecting an accurate copula for risk management. We exte

  3. The selective addition of water

    NARCIS (Netherlands)

    Resch, V.; Hanefeld, U.

    2014-01-01

    Water is omnipresent and essential. Yet at the same time it is a rather unreactive molecule. The direct addition of water to C[double bond, length as m-dash]C double bonds is therefore a challenge not answered convincingly. In this perspective we critically evaluate the selectivity and the applicabi

  4. Library Materials: Selection and Processing.

    Science.gov (United States)

    Freeman, Michael; And Others

    This script of a slide-tape presentation, which describes the selection and processing of materials for a university library, includes commentary with indicators for specific slide placement. Distinction is made between books and serial publications and the materials are followed from the ordering decision through processing. The role of the…

  5. Selected Reference Books of 1998.

    Science.gov (United States)

    McIlvaine, Eileen

    1999-01-01

    Reviews a selection of recent scholarly and general reference works under the categories of Periodicals and Newspapers, Philosophy, Literature, Film and Radio, Art and Architecture, Music, Political Science, Women's Studies, and History. A brief summary of new editions of standard works is provided at the end of the articles. (AEF)

  6. Report Literature: Selecting versus Collecting.

    Science.gov (United States)

    Newman, Wilda B.; Amir, Michlean J.

    1978-01-01

    An evaluation of the Applied Physics Laboratory Library was conducted with the view of changing the current collection policy and establishing guidelines for selection. The evaluation included defining the purpose, using a microfiche ordering system, screening items received, guidelines for weeding, microfiche vs paper copy, costs, and…

  7. Variable Selection in Discriminant Analysis.

    Science.gov (United States)

    Huberty, Carl J.; Mourad, Salah A.

    Methods for ordering and selecting variables for discriminant analysis in multiple group comparison or group prediction studies include: univariate Fs, stepwise analysis, learning discriminant function (LDF) variable correlations, communalities, LDF standardized coefficients, and weighted standardized coefficients. Five indices based on distance,…

  8. Dynamic Insurance and Adverse Selection

    NARCIS (Netherlands)

    M.C.W. Janssen (Maarten); V.A. Karamychev (Vladimir)

    2001-01-01

    textabstractWe take a dynamic perspective on insurance markets under adverse selection and study a generalized Rothschild and Stiglitz model where agents may differ with respect to the accidental probability and their expenditure levels in case an accident occurs. We investigate the nature of dynami

  9. Scientists and the Selection Task.

    Science.gov (United States)

    Griggs, Richard A.; Ransdell, Sarah E.

    1986-01-01

    Presents findings of a study of scientists on the Wason four-card selection task, finding little understanding of the effect of disconfirmatory data in assessing conditionals. Found performance influenced by problem content. Explains performance as memory-cueing plus reasoning-by-analogy. (JM)

  10. Selecting Copulas for Risk Management

    NARCIS (Netherlands)

    H.J.W.G. Kole (Erik); C.G. Koedijk (Kees); M.J.C.M. Verbeek (Marno)

    2006-01-01

    textabstractCopulas offer financial risk managers a powerful tool to model the dependence between the different elements of a portfolio and are preferable to the traditional, correlation-based approach. In this paper we show the importance of selecting an accurate copula for risk management. We

  11. Selected Dissemination/Diffusion Strategies.

    Science.gov (United States)

    Schmitt, Marshall L.

    This analysis of selected diffusion and dissemination methods used by developer-demonstrator projects in the National Diffusion Network discusses strategies under the following headings: managing the project, developing materials, disseminating information, conducting awareness sessions, training personnel, using certified trainers, providing…

  12. Selectivity in microemulsion electrokinetic chromatography

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, S; Gabel-Jensen, Charlotte; Honoré Hansen, S

    2000-01-01

    Microemulsion electrokinetic chromatography (MEEKC) is a most promising separation technique providing good selectivity and high separation efficiency of anionic, cationic as well as neutral solutes. In MEEKC lipophilic organic solvents dispersed as tiny droplets in an aqueous buffer by the use...

  13. Sociometry and Classroom Seat Selection.

    Science.gov (United States)

    Hufman, Melody; Barbour, Alton

    Since attraction and close proxemic distances have been found to be associated throughout the study of nonverbal communication, a study was conducted that hypothesized that attraction would be a more important predictor of seat selection than any other variables. Subjects included students enrolled in introductory speech communication classes who…

  14. Evolution: social selection for eccentricity.

    Science.gov (United States)

    Chapuisat, Michel

    2004-12-14

    The dress code of paper wasps, like that of humans, is related to their social habits: species with a flexible nest-founding strategy have highly variable black-and-yellow markings. This color polymorphism facilitates individual recognition and might have been selected to permit complex social interactions.

  15. Selected Leading American Educational Psychologists

    Science.gov (United States)

    Ediger, Marlow

    2015-01-01

    There are selected psychologists who have contributed much toward studying problems in teaching and learning. They have suggested plans from research, carefully conducted, which enable educational practices to be set on more secure and justifiable grounds. The writer will briefly write about ten leaders, although there are salient others.

  16. Modularity, noise, and natural selection.

    Science.gov (United States)

    Marroig, Gabriel; Melo, Diogo A R; Garcia, Guilherme

    2012-05-01

    Most biological systems are formed by component parts that are to some degree interrelated. Groups of parts that are more associated among themselves and are relatively autonomous from others are called modules. One of the consequences of modularity is that biological systems usually present an unequal distribution of the genetic variation among traits. Estimating the covariance matrix that describes these systems is a difficult problem due to a number of factors such as poor sample sizes and measurement errors. We show that this problem will be exacerbated whenever matrix inversion is required, as in directional selection reconstruction analysis. We explore the consequences of varying degrees of modularity and signal-to-noise ratio on selection reconstruction. We then present and test the efficiency of available methods for controlling noise in matrix estimates. In our simulations, controlling matrices for noise vastly improves the reconstruction of selection gradients. We also perform an analysis of selection gradients reconstruction over a New World Monkeys skull database to illustrate the impact of noise on such analyses. Noise-controlled estimates render far more plausible interpretations that are in full agreement with previous results. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.

  17. Bayesian Evidence and Model Selection

    CERN Document Server

    Knuth, Kevin H; Malakar, Nabin K; Mubeen, Asim M; Placek, Ben

    2014-01-01

    In this paper we review the concept of the Bayesian evidence and its application to model selection. The theory is presented along with a discussion of analytic, approximate and numerical techniques. Application to several practical examples within the context of signal processing are discussed.

  18. Variable Selection in Discriminant Analysis.

    Science.gov (United States)

    Huberty, Carl J.; Mourad, Salah A.

    Methods for ordering and selecting variables for discriminant analysis in multiple group comparison or group prediction studies include: univariate Fs, stepwise analysis, learning discriminant function (LDF) variable correlations, communalities, LDF standardized coefficients, and weighted standardized coefficients. Five indices based on distance,…

  19. An Analysis of Brand Selection

    Directory of Open Access Journals (Sweden)

    Kazuhiro Takeyasu†

    2013-09-01

    Full Text Available It is often observed that consumers select upper class brand when they buy next time. Suppose that former buying data and current buying data are gathered. Also suppose that upper brand is located upper in the variable array. Then the transition matrix becomes upper triangular matrix under the supposition that former buying variables are set input and current buying variables are set output. Takeyasu et al. analyzed the brand selection and its matrix structure before. In that paper, products of one genre are analyzed. In this paper, brand selection among multiple genre and its matrix structure are analyzed. Taking an automobile for example, customer brand selection from company A to B or company A to C can be made clear utilizing above stated method. We can confirm not only the preference shift among brands but also the preference shift among companies. This enables building marketing strategy for automobile company much easier. Analyzing such structure provides useful applications. Thus, this proposed approach enables to make effective marketing plan and/or establishing new brand.

  20. Random Selection for Drug Screening

    Energy Technology Data Exchange (ETDEWEB)

    Center for Human Reliability Studies

    2007-05-01

    Simple random sampling is generally the starting point for a random sampling process. This sampling technique ensures that each individual within a group (population) has an equal chance of being selected. There are a variety of ways to implement random sampling in a practical situation.

  1. Selecting materials in product design

    NARCIS (Netherlands)

    Van Kesteren, I.E.H.

    2008-01-01

    This thesis exists of several studies and design steps that resulted in a new material selection technique for user-centred design, which is supported by tools. The tools use examples of materials in products and stimulate the discussions about the user-interaction aspects of those materials desired

  2. Method selection in adaptation research

    NARCIS (Netherlands)

    Werners, Saskia Elisabeth; Loon-Steensma, van Jantsje Mintsje; Oost, Albert Peter

    2016-01-01

    Many methods are available to support adaptation planning. Yet there is little guidance on their selection. A recently developed diagnostic framework offers a structured set of criteria to choose research methods for specific adaptation questions. It has been derived from science-driven cases mos

  3. Selected papers on classical analysis

    CERN Document Server

    Nomizu, Katsumi

    2001-01-01

    This volume contains papers that originally appeared in Japanese in the journal Sūgaku. Ordinarily the papers would appear in the AMS translation of that journal, but to expedite publication, the Society has chosen to publish them as a volume of selected papers. The papers here are in the general area of mathematical analysis as it pertains to free probability theory.

  4. Feature Selection and Effective Classifiers.

    Science.gov (United States)

    Deogun, Jitender S.; Choubey, Suresh K.; Raghavan, Vijay V.; Sever, Hayri

    1998-01-01

    Develops and analyzes four algorithms for feature selection in the context of rough set methodology. Experimental results confirm the expected relationship between the time complexity of these algorithms and the classification accuracy of the resulting upper classifiers. When compared, results of upper classifiers perform better than lower…

  5. Optimal selection for direct mail

    NARCIS (Netherlands)

    Bult, [No Value; Wansbeek, T

    1995-01-01

    Direct marketing (mail) is a growing area of marketing practice, yet the academic journals contain very little research on this topic. The most important issue for direct marketers is how to sample targets from a population for a direct mail campaign. Although some selection methods are described in

  6. Black Holes: A Selected Bibliography.

    Science.gov (United States)

    Fraknoi, Andrew

    1991-01-01

    Offers a selected bibliography pertaining to black holes with the following categories: introductory books; introductory articles; somewhat more advanced articles; readings about Einstein's general theory of relativity; books on the death of stars; articles on the death of stars; specific articles about Supernova 1987A; relevant science fiction…

  7. Acta Electronica Sinica (Selected Articles),

    Science.gov (United States)

    1984-11-07

    ELECTRONICA SINICA’ (Selected Articles) ,_ "_ "-_ CD) .. " -81984 Approved for public release;, distribution unlimitd.. .ts.% .** ** **- ,-*** *o. *;. .s...34 - - - 20 FTD-ID(RST- 1227-84 EDITED TRANSLATION_ FTD-ID(RS )T- k227-84 7 November 1984 MICROFICHE NR: FTD-84-C-001068 ACTA ELECTRONICA SINICA

  8. Orientation selective deep brain stimulation

    Science.gov (United States)

    Lehto, Lauri J.; Slopsema, Julia P.; Johnson, Matthew D.; Shatillo, Artem; Teplitzky, Benjamin A.; Utecht, Lynn; Adriany, Gregor; Mangia, Silvia; Sierra, Alejandra; Low, Walter C.; Gröhn, Olli; Michaeli, Shalom

    2017-02-01

    Objective. Target selectivity of deep brain stimulation (DBS) therapy is critical, as the precise locus and pattern of the stimulation dictates the degree to which desired treatment responses are achieved and adverse side effects are avoided. There is a clear clinical need to improve DBS technology beyond currently available stimulation steering and shaping approaches. We introduce orientation selective neural stimulation as a concept to increase the specificity of target selection in DBS. Approach. This concept, which involves orienting the electric field along an axonal pathway, was tested in the corpus callosum of the rat brain by freely controlling the direction of the electric field on a plane using a three-electrode bundle, and monitoring the response of the neurons using functional magnetic resonance imaging (fMRI). Computational models were developed to further analyze axonal excitability for varied electric field orientation. Main results. Our results demonstrated that the strongest fMRI response was observed when the electric field was oriented parallel to the axons, while almost no response was detected with the perpendicular orientation of the electric field relative to the primary fiber tract. These results were confirmed by computational models of the experimental paradigm quantifying the activation of radially distributed axons while varying the primary direction of the electric field. Significance. The described strategies identify a new course for selective neuromodulation paradigms in DBS based on axonal fiber orientation.

  9. Selection strategies for improved biocatalysts

    NARCIS (Netherlands)

    Boersma, Ykelien L.; Droge, Melloney J.; Quax, Wim J.

    2007-01-01

    Enzymes have become an attractive alternative to conventional catalysts in numerous industrial processes. However, their properties do not always meet the criteria of the application of interest. Directed evolution is a powerful tool for adapting the characteristics of an enzyme. However, selection

  10. Heterogeneous catalysis: Uniformity begets selectivity

    Science.gov (United States)

    Yang, Dong; Gates, Bruce C.

    2017-07-01

    A Pd4 cluster, supported by a metal-organic framework and formed by post-synthesis methods, shows high catalytic activity and selectivity for carbene-mediated reactions. This crystallographically precise material may lead to a large class of catalysts.

  11. Graft selection in cerebral revascularization.

    Science.gov (United States)

    Baaj, Ali A; Agazzi, Siviero; van Loveren, Harry

    2009-05-01

    Cerebral revascularization constitutes an important treatment modality in the management of complex aneurysms, carotid occlusion, tumor, and moyamoya disease. Graft selection is a critical step in the planning of revascularization surgery, and depends on an understanding of graft and regional hemodynamics, accessibility, and patency rates. The goal of this review is to highlight some of these properties.

  12. Optimal selection for direct mail

    NARCIS (Netherlands)

    Bult, [No Value; Wansbeek, T

    1995-01-01

    Direct marketing (mail) is a growing area of marketing practice, yet the academic journals contain very little research on this topic. The most important issue for direct marketers is how to sample targets from a population for a direct mail campaign. Although some selection methods are described in

  13. Selection arena in Aspergillus nidulans

    NARCIS (Netherlands)

    Bruggeman, J.; Debets, A.J.M.; Hoekstra, R.F.

    2004-01-01

    The selection arena hypothesis states that overproduction of zygotes-a widespread phenomenon in animals and plants-can be explained as a mechanism of progeny choice. As a similar mechanism, the ascomycetous fungus Aspergillus nidulans may overproduce dikaryotic fruit initials, hereafter called dikar

  14. Molecular Components of Catalytic Selectivity

    Energy Technology Data Exchange (ETDEWEB)

    Somorjai, Gabor A.; Park, Jeong Y.

    2008-07-02

    Selectivity, that is, to produce one molecule out of many other thermodynamically feasible product molecules, is the key concept to develop 'clean manufacturing' processes that do not produce byproducts (green chemistry). Small differences in potential energy barriers for elementary reaction steps control which reaction channel is more likely to yield the desired product molecule (selectivity), instead of the overall activation energy for the reaction that controls turnover rates (activity). Recent studies have demonstrated the atomic- or molecular-level tailoring of parameters such as the surface structures of active sites that give rise to nanoparticle size and shape dependence of turnover rates and reaction selectivities. Here, we highlight seven molecular components that influence reaction selectivities. These include: surface structure, adsorbate-induced restructuring, adsorbate mobility, reaction intermediates, surface composition, charge transport, and oxidation states for model metal single crystal and colloid nanoparticle catalysts. We show examples of their functioning and describe in-situ instruments that permit us to investigate their roles in surface reactions.

  15. Strategic Vision: A Selected Bibliography

    Science.gov (United States)

    2008-03-01

    Journal 19 (Spring 2005): 59-66. ProQuest 27 BIBLIOGRAPHIES Costa , Mark R., comp. Transformation: A Selected Bibliography. Carlisle Barracks: U.S. Army War...SecurityStrategy07.pdf Phillips, Joan T., comp. Future. Maxwell Air Force Base: Muir S. Fairchild Research Information Center, November 2006. http

  16. Environmental Pollution, A Selective Bibliography.

    Science.gov (United States)

    Clearinghouse for Federal Scientific and Technical Information, Springfield, VA.

    This bibliography on environmental pollution is comprised primarily of reports of federally sponsored research by such departments and agencies as HEW, Interior, AEC, NASA, Defense, Transportation, and others. The reports were selected from Clearinghouse announcement journals during the period 1968 through April 1970. The bibliography contains…

  17. Sales Tax Compliance and Audit Selection

    OpenAIRE

    Murray, Matthew N.

    1995-01-01

    Uses sample selection estimation techniques to identify systematic audit selection rules and determinants of sales tax underreporting. Though based on data from only one state (Tennessee), outcomes are useful in developing and evaluating audit selection results.

  18. Selective decontamination and antibiotic resistance in ICUs

    NARCIS (Netherlands)

    Plantinga, Nienke L.; Bonten, Marc J. M.|info:eu-repo/dai/nl/123144337

    2015-01-01

    Selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD) have been associated with reduced mortality and lower ICU-acquired bacteremia and ventilator-associated pneumonia rates in areas with low levels of antibiotic resistance. However, the effect of selective

  19. Rewards teach visual selective attention.

    Science.gov (United States)

    Chelazzi, Leonardo; Perlato, Andrea; Santandrea, Elisa; Della Libera, Chiara

    2013-06-07

    Visual selective attention is the brain function that modulates ongoing processing of retinal input in order for selected representations to gain privileged access to perceptual awareness and guide behavior. Enhanced analysis of currently relevant or otherwise salient information is often accompanied by suppressed processing of the less relevant or salient input. Recent findings indicate that rewards exert a powerful influence on the deployment of visual selective attention. Such influence takes different forms depending on the specific protocol adopted in the given study. In some cases, the prospect of earning a larger reward in relation to a specific stimulus or location biases attention accordingly in order to maximize overall gain. This is mediated by an effect of reward acting as a type of incentive motivation for the strategic control of attention. In contrast, reward delivery can directly alter the processing of specific stimuli by increasing their attentional priority, and this can be measured even when rewards are no longer involved, reflecting a form of reward-mediated attentional learning. As a further development, recent work demonstrates that rewards can affect attentional learning in dissociable ways depending on whether rewards are perceived as feedback on performance or instead are registered as random-like events occurring during task performance. Specifically, it appears that visual selective attention is shaped by two distinct reward-related learning mechanisms: one requiring active monitoring of performance and outcome, and a second one detecting the sheer association between objects in the environment (whether attended or ignored) and the more-or-less rewarding events that accompany them. Overall this emerging literature demonstrates unequivocally that rewards "teach" visual selective attention so that processing resources will be allocated to objects, features and locations which are likely to optimize the organism's interaction with the

  20. Industrial Selection and Growth Industrial Selection and Growth

    Directory of Open Access Journals (Sweden)

    German Echecopar

    1999-03-01

    Full Text Available The paper provides an argument for how selective industrial policies (targeting can produce faster productivity growth. A model is developed to show that when learning externalities are present, targeting can increase the amount of learning that is produced and shared within the targeted sector. This effect will raise the sectoral and the economy-wide average productivity growth rates. The paper also discusses how targeting can speed output growth by raising the incentives to learn and by reducing investment risk. The paper provides an argument for how selective industrial policies (targeting can produce faster productivity growth. A model is developed to show that when learning externalities are present, targeting can increase the amount of learning that is produced and shared within the targeted sector. This effect will raise the sectoral and the economy-wide average productivity growth rates. The paper also discusses how targeting can speed output growth by raising the incentives to learn and by reducing investment risk.

  1. A Hybrid Feature Subset Selection using Metrics and Forward Selection

    Directory of Open Access Journals (Sweden)

    K. Fathima Bibi

    2015-04-01

    Full Text Available The aim of this study is to design a Feature Subset Selection Technique that speeds up the Feature Selection (FS process in high dimensional datasets with reduced computational cost and great efficiency. FS has become the focus of much research on decision support system areas for which data with tremendous number of variables are analyzed. Filters and wrappers are proposed techniques for the feature subset selection process. Filters make use of association based approach but wrappers adopt classification algorithms to identify important features. Filter method lacks the ability of minimization of simplification error while wrapper method burden weighty computational resource. To pull through these difficulties, a hybrid approach is proposed combining both filters and wrappers. Filter approach uses a permutation of ranker search methods and a wrapper which improves the learning accurateness and obtains a lessening in the memory requirements and finishing time. The UCI machine learning repository was chosen to experiment the approach. The classification accuracy resulted from our approach proves to be higher.

  2. Gamma-ray-selected AGN

    Science.gov (United States)

    Giommi, Paolo

    2016-08-01

    The gamma-ray band is the most energetic part of the electromagnetic spectrum. As such it is also where selection effects are most severe, as it can only be reached by the most extreme non-thermal AGN. Blazars, with their emission dominated by non-thermal blue-shifted radiation arising in a relativistic jet pointed in the direction of the observer, naturally satisfy this though requirement. For this reason, albeit these sources are intrisically very rare (orders of magnitude less abundant than radio quiet AGN of the same optical magnitude) they almost completely dominate the extragalactic gamma-ray and very high energy sky. I will discuss the emission of different types of blazars and the selection effects that are at play in the gamma-ray band based on recent results from the current generation of gamma-ray astronomy satellites, ground-based Cherenkov telescopes, and Monte Carlo simulations.

  3. Cadaveric donor selection and management.

    Science.gov (United States)

    Studer, Sean M; Orens, Jonathan B

    2006-10-01

    While there is little doubt that proper donor selection is extremely important to achieve good outcomes from transplantation, there are only limited data regarding the current criteria utilized to select the "ideal donor". Importantly, there are not enough donor lungs available for all of those in need. Until an adequate supply of donor organs exists, lives will be lost on the transplant waiting list. While efforts have been made to increase donor awareness, additional transplants can be realized by improving donor utilization. This can be achieved by active participation of transplant teams in donor management and by utilizing "extended criteria" organs. Further studies are needed to assess the impact of using "extended criteria" donors, as this practice could result in increased posttransplant morbidity and mortality. This article summarizes the approach to identification of potential lung donors, optimal donor management, and the clinical importance of various donor factors upon recipient outcomes.

  4. Entropic criterion for model selection

    Science.gov (United States)

    Tseng, Chih-Yuan

    2006-10-01

    Model or variable selection is usually achieved through ranking models according to the increasing order of preference. One of methods is applying Kullback-Leibler distance or relative entropy as a selection criterion. Yet that will raise two questions, why use this criterion and are there any other criteria. Besides, conventional approaches require a reference prior, which is usually difficult to get. Following the logic of inductive inference proposed by Caticha [Relative entropy and inductive inference, in: G. Erickson, Y. Zhai (Eds.), Bayesian Inference and Maximum Entropy Methods in Science and Engineering, AIP Conference Proceedings, vol. 707, 2004 (available from arXiv.org/abs/physics/0311093)], we show relative entropy to be a unique criterion, which requires no prior information and can be applied to different fields. We examine this criterion by considering a physical problem, simple fluids, and results are promising.

  5. Knowledge Acquisition for Content Selection

    CERN Document Server

    Reiter, E R; Osman, L; Roff, Y; Reiter, Ehud; Cawsey, Alison; Osman, Liesl; Roff, Yvonne

    1997-01-01

    An important part of building a natural-language generation (NLG) system is knowledge acquisition, that is deciding on the specific schemas, plans, grammar rules, and so forth that should be used in the NLG system. We discuss some experiments we have performed with KA for content-selection rules, in the context of building an NLG system which generates health-related material. These experiments suggest that it is useful to supplement corpus analysis with KA techniques developed for building expert systems, such as structured group discussions and think-aloud protocols. They also raise the point that KA issues may influence architectural design issues, in particular the decision on whether a planning approach is used for content selection. We suspect that in some cases, KA may be easier if other constructive expert-system techniques (such as production rules, or case-based reasoning) are used to determine the content of a generated text.

  6. Production Systems and Supplier Selection

    DEFF Research Database (Denmark)

    Pedraza-Acosta, Isabel; Pilkington, Alan; Barnes, David

    2016-01-01

    Purpose: This paper presents a combined multi-phase supplier selection model. The process repeatedly revisits the criteria and sourcing decision as the development process continues. This enables a structured adoption of product and production system innovation from strategic suppliers, where...... strategic stamping suppliers. Findings: Our contribution is the multi-phased production and product innovation process. This is an advance from traditional supplier selection and also an extension of ideas of supplier-located product development as it includes production system development, and complements...... the literature on working with strategic suppliers. Specifically, we explicitly articulate the previously unreported issue of whether a supplier chosen for its innovation capabilities at the start of the new product development process will also be the most appropriate supplier during the production system...

  7. Rabi N. Bhattacharya selected papers

    CERN Document Server

    Waymire, Edward

    2016-01-01

    This volume presents some of the most influential papers published by Rabi N. Bhattacharya, along with commentaries from international experts, demonstrating his knowledge, insight, and influence in the field of probability and its applications. For more than three decades, Bhattacharya has made significant contributions in areas ranging from theoretical statistics via analytical probability theory, Markov processes, and random dynamics to applied topics in statistics, economics, and geophysics. Selected reprints of Bhattacharya’s papers are divided into three sections: Modes of Approximation, Large Times for Markov Processes, and Stochastic Foundations in Applied Sciences. The accompanying articles by the contributing authors not only help to position his work in the context of other achievements, but also provide a unique assessment of the state of their individual fields, both historically and for the next generation of researchers. Rabi N. Bhattacharya: Selected Papers will be a valuable resource for yo...

  8. Statistical learning and selective inference.

    Science.gov (United States)

    Taylor, Jonathan; Tibshirani, Robert J

    2015-06-23

    We describe the problem of "selective inference." This addresses the following challenge: Having mined a set of data to find potential associations, how do we properly assess the strength of these associations? The fact that we have "cherry-picked"--searched for the strongest associations--means that we must set a higher bar for declaring significant the associations that we see. This challenge becomes more important in the era of big data and complex statistical modeling. The cherry tree (dataset) can be very large and the tools for cherry picking (statistical learning methods) are now very sophisticated. We describe some recent new developments in selective inference and illustrate their use in forward stepwise regression, the lasso, and principal components analysis.

  9. Interaction intensity and pollinator-mediated selection.

    Science.gov (United States)

    Trunschke, Judith; Sletvold, Nina; Ågren, Jon

    2017-02-27

    In animal-pollinated plants, the opportunity for selection and the strength of pollinator-mediated selection are expected to increase with the degree of pollen limitation. However, whether differences in pollen limitation can explain variation in pollinator-mediated and net selection among animal-pollinated species is poorly understood. In the present study, we quantified pollen limitation, variance in relative fitness and pollinator-mediated selection on five traits important for pollinator attraction (flowering start, plant height, flower number, flower size) and pollination efficiency (spur length) in natural populations of 12 orchid species. Pollinator-mediated selection was quantified by subtracting estimates of selection gradients for plants receiving supplemental hand-pollination from estimates obtained for open-pollinated control plants. Mean pollen limitation ranged from zero to 0.96. Opportunity for selection, pollinator-mediated selection and net selection were all positively related to pollen limitation, whereas nonpollinator-mediated selection was not. Opportunity for selection varied five-fold, strength of pollinator-mediated selection varied three-fold and net selection varied 1.5-fold among species. Supplemental hand-pollination reduced both opportunity for selection and selection on floral traits. The results show that the intensity of biotic interactions is an important determinant of the selection regime, and indicate that the potential for pollinator-mediated selection and divergence in floral traits is particularly high in species that are strongly pollen-limited.

  10. Thermophysical Properties of Selected Rocks.

    Science.gov (United States)

    1974-04-01

    Thermal Condutivity (K) (W m-4 K- 1) 300 2.497 400 2.258 500 2.035 600 1.825 700 1.645 800 1.481 900 1.345 1000 1.252 *No selections were made for...WORDS (Continue on revese side it necessay and identify by block number) *Thermophysical properties-- *Rocks --- Thermal conductivity --- Thermal ...diffusivity --- Thermal linear expansion --- Specif ic heat --- Basalt --- Dacite--Dunite --- Gabbro --- Granite--- *Granodiorite --- Limestone --- Marble

  11. Selection of LHCb Physics Results

    Directory of Open Access Journals (Sweden)

    Schmidt Burkhard

    2013-05-01

    Full Text Available LHCb is a dedicated flavour physics experiment at the LHC searching for physics beyond the Standard Model through precision measurements of CP-violating observables and the study of very rare decays of beauty- and charm-flavoured hadrons. In this article a selection of recent LHCb results is presented. Unless otherwise stated, the results are based on an integrated luminosity of 1 fb−1 accumulated during the year 2011 at √s = 7 TeV.

  12. Patient selection for liver transplantation.

    Science.gov (United States)

    Carrion, Andres F; Aye, Lydia; Martin, Paul

    2013-08-01

    Improved outcomes in liver transplant recipients reflect advances in surgical technique, post-operative care, immunosuppression as well as better selection of potential candidates. The pre-transplant evaluation is a multidisciplinary process intended to recognize and treat important comorbid conditions that may impair outcomes during the peri- and post-transplant periods. Important psychosocial issues should also be ascertained and tackled early during the pre-transplant evaluation with an overarching intention to improve the success of liver transplantation.

  13. Information Selection in Intelligence Processing

    Science.gov (United States)

    2011-12-01

    problem of overload.” As another example, Whaley (Whaley, 1974) argues that one of the causes for the Pearl Harbor and Barbarossa strategic surprises is...which becomes more and more important as the Internet evolves. The IR problem and the information selection problem share some similar...all the algorithms tend more towards exploration: the temperature parameter in Softmax is higher (0.12 instead of 0.08), the delta for the VDBE

  14. Selected Declassified Chinese Diplomatic Archives

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Since the gradual declassification of China’s diplomatic archives beginning in January 2004, a great number of confidential historical archives have been unveiled to the public, providing experts and scholars with first-hand information of great value, thus facilitating the deepening of international studies on a solid base. For the benefit of our readers, China International Studies will print on a selective basis valuable declassified archives at irregular intervals.

  15. A New Wavelength Selective Photoreceiver

    Institute of Scientific and Technical Information of China (English)

    LIU Kai; HUANG Yongqing; REN Xiaomin; LI Jianxin; GUO Wei

    2000-01-01

    A new kind of wavelength selective photoreceiver is proposed. It was constructed by a Fabry-Perot (F-P) etalon filter and a resonant cavity enhanced (RCE) photodetector. The photoreceiver′s spectral response is determined by the F-P etalon filter with a FWHM of less than 4 nm. Moreover, with such a photoreceiver, the transmission loss of the F-P etalon filter can be compensated to some extent. And this will benefit its applications.

  16. Ion selectivity of graphene nanopores

    OpenAIRE

    Rollings, Ryan C.; Kuan, Aaron T.; Golovchenko, Jene A.

    2016-01-01

    As population growth continues to outpace development of water infrastructure in many countries, desalination (the removal of salts from seawater) at high energy efficiency will likely become a vital source of fresh water. Due to its atomic thinness combined with its mechanical strength, porous graphene may be particularly well-suited for electrodialysis desalination, in which ions are removed under an electric field via ion-selective pores. Here, we show that single graphene nanopores prefer...

  17. Brand management of selected brand

    OpenAIRE

    2011-01-01

    This thesis addresses the subject of brand management. My main objective was to summarize the issue of brand management and apply the acquired knowledge on the selected brand of food products on the Czech market, i.e. to assess its current management and the current situation and where appropriate, propose recommendations for the future. I use the case study method, the method of survey and analysis of primary and secondary data. The theoretical part deals with the concept of brand, its featu...

  18. Biomaterial Selection for Tooth Regeneration

    OpenAIRE

    2011-01-01

    Biomaterials are native or synthetic polymers that act as carriers for drug delivery or scaffolds for tissue regeneration. When implanted in vivo, biomaterials should be nontoxic and exert intended functions. For tooth regeneration, biomaterials have primarily served as a scaffold for (1) transplanted stem cells and/or (2) recruitment of endogenous stem cells. This article critically synthesizes our knowledge of biomaterial use in tooth regeneration, including the selection of native and/or s...

  19. Optimal Contracting under Adverse Selection

    DEFF Research Database (Denmark)

    Lenells, Jonatan; Stea, Diego; Foss, Nicolai Juul

    2015-01-01

    We study a model of adverse selection, hard and soft information, and mentalizing ability--the human capacity to represent others' intentions, knowledge, and beliefs. By allowing for a continuous range of different information types, as well as for different means of acquiring information, we dev...... of that information. This strategy affects the properties of the optimal contract, which grows closer to the first best. This research provides insights into the implications of mentalizing for agency theory....

  20. Smart Data Selection (SDS) Brief

    Science.gov (United States)

    2014-10-21

    Developing the capability to notify operators when data demonstrate abnormal behavior 15. SUBJECT TERMS Spectrum, Aeronautical telemetry, algorithm...bandwidth, Integrated Networked Enhanced Telemetry (iNET), Smart Data Selection (SDS), Pulse Code modulation (PCM) 16. SECURITY CLASSIFICATION OF...Efficient Algorithm • PCM Compression Enhancement • Benefits to T&E Project Description (/) ~ ;;:,... ~ 0 8 ~ & ~əNott,C# iThe dominant inherent nature

  1. Selective electrophilic activation of alkanes

    Energy Technology Data Exchange (ETDEWEB)

    Sommer, J.; Bukala, J. (Universite Louis Pasteur, Strasbourg (France))

    1993-07-01

    One major drawback for the direct use of alkanes as chemicals is their chemical inertness toward most of the usual reagents. For this reason, costly, large-scale refinery operations such as catalytic reforming and vapocracking are needed, which necessitate the use of noble metal catalysts and/or high temperature to activate the strong C-H and C-C bonds and yield the primary chemical building blocks such as ethylene, propylene, butadiene, benzene, toluene, and xylene. In response to the challenge to use more economically a larger share of alkanes, and increasing number of research groups are working on the activation functionalization processes of the saturated hydrocarbon C-H bond. The goal is to overcome smoothly and selectively the chemical inertness of the starting (paraffinic) material. A book and special issue have been published recently on this subject. Protonated alkanes are reaction intermediates in superacid-catalyzed protolysis. Protonation occurs on all C-C and C-H [sigma]-bonds independently of the further reactivity of the protonated alkane as confirmed by using [sup 2]H labeled superacids. Direct and selective C-H bond protolysis is limited to tertiary alkanes whereas linear alkanes undergo less selective C-C bond cleavage. 31 refs., 3 figs.

  2. Dysprosium selective potentiometric membrane sensor

    Energy Technology Data Exchange (ETDEWEB)

    Zamani, Hassan Ali, E-mail: haszamani@yahoo.com [Department of Applied Chemistry, Mashhad Branch, Islamic Azad University, Mashhad (Iran, Islamic Republic of); Faridbod, Farnoush; Ganjali, Mohammad Reza [Center of Excellence in Electrochemistry, Faculty of Chemistry, University of Tehran, Tehran (Iran, Islamic Republic of)

    2013-03-01

    A novel Dy(III) ion-selective PVC membrane sensor was made using a new synthesized organic compound, 3,4-diamino-N Prime -((pyridin-2-yl)methylene)benzohydrazide (L) as an excellent sensing element. The electrode showed a Nernstian slope of 19.8 {+-} 0.6 mV per decade in a wide concentration range of 1.0 Multiplication-Sign 10{sup -6}-1.0 Multiplication-Sign 10{sup -2} mol L{sup -1}, a detection limit of 5.5 Multiplication-Sign 10{sup -7} mol L{sup -1}, a short conditioning time, a fast response time (< 10 s), and high selectivity towards Dy(III) ion in contrast to other cations. The proposed sensor was successfully used as an indicator electrode in the potentiometric titration of Dy(III) ions with EDTA. The membrane sensor was also applied to the F{sup -} ion indirect determination of some mouth washing solutions and to the Dy{sup 3+} determination in binary mixtures. Highlights: Black-Right-Pointing-Pointer The novelty of this work is based on the high affinity of the ionophore toward the Dy{sup 3+} ions. Black-Right-Pointing-Pointer This technique is very simple, fast and inexpensive and it is not necessary to use sophisticated equipment. Black-Right-Pointing-Pointer The newly developed sensor is superior to the formerly reported Dy{sup 3+} sensors in terms of selectivity.

  3. Model selection for pion photoproduction

    Science.gov (United States)

    Landay, J.; Döring, M.; Fernández-Ramírez, C.; Hu, B.; Molina, R.

    2017-01-01

    Partial-wave analysis of meson and photon-induced reactions is needed to enable the comparison of many theoretical approaches to data. In both energy-dependent and independent parametrizations of partial waves, the selection of the model amplitude is crucial. Principles of the S matrix are implemented to a different degree in different approaches; but a many times overlooked aspect concerns the selection of undetermined coefficients and functional forms for fitting, leading to a minimal yet sufficient parametrization. We present an analysis of low-energy neutral pion photoproduction using the least absolute shrinkage and selection operator (LASSO) in combination with criteria from information theory and K -fold cross validation. These methods are not yet widely known in the analysis of excited hadrons but will become relevant in the era of precision spectroscopy. The principle is first illustrated with synthetic data; then, its feasibility for real data is demonstrated by analyzing the latest available measurements of differential cross sections (d σ /d Ω ), photon-beam asymmetries (Σ ), and target asymmetry differential cross sections (d σT/d ≡T d σ /d Ω ) in the low-energy regime.

  4. Aflatoxins in selected Thai commodities.

    Science.gov (United States)

    Tansakul, Natthasit; Limsuwan, Sasithorn; Böhm, Josef; Hollmann, Manfred; Razzazi-Fazeli, Ebrahim

    2013-01-01

    Aflatoxin (AF) B1, B2, G1 and G2 were determined in 120 samples of selected Thai commodities including unpolished rice, unpolished glutinous rice, chilli powder, whole dried chilli pods and raw peanut. The mean concentrations of the total AFs for analysed samples were 0.16, 25.43, 14.18, 6.62 and 1.43 µg kg(-1) with positive incidences of 4%, 20%, 97%, 37% and 30%, respectively. Quantitative analysis was performed using HPLC equipped with post-column derivatisation and fluorescence detection. Sample clean-up was carried out using immunoaffinity columns for selective enrichment of AFs. The method was validated by using certified reference material, which showed recoveries over 85%. The limit of detections (LODs) and limit of quantifications (LOQs) were in a range between 0.01-0.11 µg kg(-1) and 0.03-0.38 µg kg(-1), respectively. The results clearly demonstrated that AFs were detectable in different matrices. Chilli powder was found to have the highest level of AFs contamination followed by chilli pods, peanut and rice, respectively. However, among the selected commodities, unpolished rice contained only trace levels of AFB1 and AFB2. With regard to the fact that AFs are a natural contaminant in commodities, this report calls to attention the regular monitoring and effective control of food commodities to prevent health hazards.

  5. Toddlers Selectively Help Fair Agents

    Directory of Open Access Journals (Sweden)

    Luca Surian

    2017-06-01

    Full Text Available Previous research showed that infants and toddlers are inclined to help prosocial agents and assign a positive valence to fair distributions. Also, they expect that positive and negative actions directed toward distributors will conform to reciprocity principles. This study investigates whether toddlers are selective in helping others, as a function of others’ previous distributive actions. Toddlers were presented with real-life events in which two actresses distributed resources either equally or unequally between two puppets. Then, they played together with a ball that accidentally fell to the ground and asked participants to help them to retrieve it. Participants preferred to help the actress who performed equal distributions. This finding suggests that by the second year children’s prosocial actions are modulated by their emerging sense of fairness.HighlightsToddlers (mean age = 25 months are selective in helping distributors.Toddlers prefer helping a fair rather than an unfair distributor.Toddlers’ selective helping provides evidence for an early sense of fairness.

  6. Supplier Selection: An Intelligent Approach

    Science.gov (United States)

    Poddar, A.; Ray, A.

    2014-04-01

    The aim of this research is to develop a generic model of intelligence and cognitive science-based method that can play an active role in selecting the best supplier in the supply chain management system. In this paper, an intelligent system was conceived for prediction of the best supplier from the set of suppliers in the supply chain management system. Initially, the proposed system incorporates the tangible and intangible data as inputs to the system in the fuzzy environment and acts as the source case. The target case consists of several criteria that influence the supplier selection process. The system calculates the similarities between the source and target cases and decides the best supplier by using fuzzy rule-based system. Finally, the weights of each supplier optimize the order quantities in the unstructured environment. The proposed expert system is superior to the traditional supplier selection and allocation of the ordered quantities and assists inexperienced users in predicting the best supplier within the shortest possible time.

  7. Enhancing Automated Test Selection in Probabilistic Networks

    NARCIS (Netherlands)

    Sent, D.; van der Gaag, L.C.; Bellazzi, R; Abu-Hanna, A; Hunter, J

    2007-01-01

    Most test-selection algorithms currently in use with probabilistic networks select variables myopically, that is, test variables are selected sequentially, on a one-by-one basis, based upon expected information gain. While myopic test selection is not realistic for many medical applications, non-myo

  8. Selective memories: infants' encoding is enhanced in selection via suppression.

    Science.gov (United States)

    Markant, Julie; Amso, Dima

    2013-11-01

    The present study examined the hypothesis that inhibitory visual selection mechanisms play a vital role in memory by limiting distractor interference during item encoding. In Experiment 1a we used a modified spatial cueing task in which 9-month-old infants encoded multiple category exemplars in the contexts of an attention orienting mechanism involving suppression (i.e. inhibition of return, IOR) versus one that does not (i.e. facilitation). At test, infants in the IOR condition showed both item-specific learning and abstraction of broader category information. In contrast, infants in the facilitation condition did not discriminate across novel and familiar test items. Experiment 1b confirmed that the learning observed in the IOR condition was specific to spatial cueing of attention and was not due to timing differences across the IOR and facilitation conditions. In Experiment 2, we replicated the results of Experiment 1, using a within-subjects design to explicitly examine learning and memory encoding in the context of concurrent suppression. These data show that developing inhibitory selective attention enhances efficacy of memory encoding for subsequent retrieval. Furthermore, these results highlight the importance of considering interactions between developing attention and memory systems.

  9. Microhydrodynamics principles and selected applications

    CERN Document Server

    Kim, Sangtae; Brenner, Howard

    1991-01-01

    Microhydrodynamics: Principles and Selected Applications presents analytical and numerical methods for describing motion of small particles suspended in viscous fluids. The text first covers the fundamental principles of low-Reynolds-number flow, including the governing equations and fundamental theorems; the dynamics of a single particle in a flow field; and hydrodynamic interactions between suspended particles. Next, the book deals with the advances in the mathematical and computational aspects of viscous particulate flows that point to innovations for large-scale simulations on parallel co

  10. Selected papers on optomechanical design

    Science.gov (United States)

    O'Shea, Donald C.

    The papers included in this volume deal with a variety of topics in optical and optoelectronic science, engineering, and technology under the following headings: design, materials, tolerancing and specification, mounting, mechanical analysis, thermal analysis, stabilization, baffling, assembly and alignment, and scanning. Particular topics discussed include selection of materials and processes for metal optics, trends and limits in the production of optical elements and optical systems, aerospace mounts for down-to-earth optics, and thermal effects in optical systems. Papers are also presented on integrating Nd:YAG lasers into optical systems, line-of-sight steering and stabilization, and motors and control systems for rotating mirror deflectors.

  11. Selected readings in chemical kinetics

    CERN Document Server

    Back, Margaret H

    2013-01-01

    Selected Readings in Chemical Kinetics covers excerpts from 12 papers in the field of general and gas-phase kinetics. The book discusses papers on the laws of connexion between the conditions of a chemical change and its amount; on the reaction velocity of the inversion of the cane sugar by acids; and the calculation in absolute measure of velocity constants and equilibrium constants in gaseous systems. The text then tackles papers on simple gas reactions; on the absolute rate of reactions in condensed phases; on the radiation theory of chemical action; and on the theory of unimolecular reacti

  12. Quantum interaction. Revised selected papers

    Energy Technology Data Exchange (ETDEWEB)

    Song, Dawei; Zhang, Peng; Wang, Lei [Aberdeen Univ. (United Kingdom). School of Computing; Melucci, Massimo [Padua Univ., Padova (Italy). Dept. of Information Engineering; Frommholz, Ingo [Bedfordshire Univ. (United Kingdom); Arafat, Sachi (eds.) [Glasgow Univ. (United Kingdom). School of Computing Science

    2011-07-01

    This book constitutes the thoroughly refereed post-conference proceedings of the 5th International Symposium on Quantum Interaction, QI 2011, held in Aberdeen, UK, in June 2011. The 26 revised full papers and 6 revised poster papers, presented together with 1 tutorial and 1 invited talk were carefully reviewed and selected from numerous submissions during two rounds of reviewing and improvement. The papers show the cross-disciplinary nature of quantum interaction covering topics such as computation, cognition, mechanics, social interaction, semantic space and information representation and retrieval. (orig.)

  13. Microhydrodynamics principles and selected applications

    CERN Document Server

    Kim, Sangtae

    2005-01-01

    ""This book is well organized and comprehensive . . . an eloquent and enduring statement of significant hydrodynamic principles."" - AIChE JournalMicrohydrodynamics concerns the flow and related phenomena pertinent to the motion of small particles suspended in viscous fluids. This text focuses on determining the motion of a particle or particles through a viscous fluid in bounded and unbounded flow. Its central theme is the mobility relation between particle motion and forces.Microhydrodynamics: Principles and Selected Applications functions as a manual that explains methods for solving partic

  14. Selected papers from ESSDERC 2014

    Science.gov (United States)

    Bez, Roberto; Meneghesso, Gaudenzio; Pavan, Paolo; Zanoni, Enrico

    2015-11-01

    This special issue of Solid State Electronics includes 28 paper selected from the best presentations given at the 44th European Solid-State Device Research Conference (ESSDERC 2014, September 22-26, 2014 - Venice, Italy). These papers cover different topics in the research on solid-state devices. These topics are used also to organize the conference presentations in 7 tracks: Advanced CMOS: Devices, Process and Integration; Microwave, Opto and Power Solid-State Devices; Modeling and Simulation; Characterization, Reliability and Yield; Advanced and Emerging Memories; MEMS, NEMS, Bio-sensors and Display Technologies; Emerging non-CMOS Devices and Technologies.

  15. SELECTED FEATURES OF POLISH FARMERS

    Directory of Open Access Journals (Sweden)

    Grzegorz Spychalski

    2013-12-01

    Full Text Available The paper presents results of the research carried out among farm owners in Wielkopolskie voivodeship referring to selected features of social capital. The author identifies and estimates impact of some socio-professional factors on social capital quality and derives statistical conclusion. As a result there is a list of economic policy measures facilitating rural areas development in this aspect. The level of education, civic activity and tendency for collective activity are main conditions of social capital quality in Polish rural areas.

  16. Selective catalytic hydrodehalogenation of chloronitrobenzenes

    Energy Technology Data Exchange (ETDEWEB)

    Nesterov, M.A.; Chizhova, M.M.; Sharf, V.Z.

    1987-02-20

    They have synthesized new, active, and highly selective metal complex catalysts derived from palladium salts immobilized on silica gel modified by Schiff bases of heterocyclic aldehydes. The rate of the dechlorination of chloronitrobenzenes using these catalysts is 3-40 mole/min g-at Pd and the yield of nitrobenzene is virtually quantitative. The best results were obtained by using palladium complexes with silica gel modified by pyridyl-4-, thienyl-2-, and pyrryl-2-aldiminopropyl groups. The initial rate for the conversion of chloronitrobenzene on these catalysts is 38, 29, and 21 mole/min x g-at Pd.

  17. Generic maximum likely scale selection

    DEFF Research Database (Denmark)

    Pedersen, Kim Steenstrup; Loog, Marco; Markussen, Bo

    2007-01-01

    The fundamental problem of local scale selection is addressed by means of a novel principle, which is based on maximum likelihood estimation. The principle is generally applicable to a broad variety of image models and descriptors, and provides a generic scale estimation methodology. The focus...... on second order moments of multiple measurements outputs at a fixed location. These measurements, which reflect local image structure, consist in the cases considered here of Gaussian derivatives taken at several scales and/or having different derivative orders....

  18. Selected soil thermal conductivity models

    Directory of Open Access Journals (Sweden)

    Rerak Monika

    2017-01-01

    Full Text Available The paper presents collected from the literature models of soil thermal conductivity. This is a very important parameter, which allows one to assess how much heat can be transferred from the underground power cables through the soil. The models are presented in table form, thus when the properties of the soil are given, it is possible to select the most accurate method of calculating its thermal conductivity. Precise determination of this parameter results in designing the cable line in such a way that it does not occur the process of cable overheating.

  19. THE FEATURE SUBSET SELECTION ALGORITHM

    Institute of Scientific and Technical Information of China (English)

    LiuYongguo; LiXueming; 等

    2003-01-01

    The motivation of data mining is how to extract effective information from huge data in very large database.However,some redundant irrelevant attributes,which result in low performance and high computing complexity,are included in the very large database in general.So,Feature Selection(FSS)becomes one important issue in the field of data mining.In this letter,an Fss model based on the filter approach is built,which uses the simulated annealing gentic algorithm.Experimental results show that convergence and stability of this algorithm are adequately achieved.

  20. THE FEATURE SUBSET SELECTION ALGORITHM

    Institute of Scientific and Technical Information of China (English)

    Liu Yongguo; Li Xueming; Wu Zhongfu

    2003-01-01

    The motivation of data mining is how to extract effective information from huge data in very large database. However, some redundant and irrelevant attributes, which result in low performance and high computing complexity, are included in the very large database in general.So, Feature Subset Selection (FSS) becomes one important issue in the field of data mining. In this letter, an FSS model based on the filter approach is built, which uses the simulated annealing genetic algorithm. Experimental results show that convergence and stability of this algorithm are adequately achieved.

  1. Feature Selection in Scientific Applications

    Energy Technology Data Exchange (ETDEWEB)

    Cantu-Paz, E; Newsam, S; Kamath, C

    2004-02-27

    Numerous applications of data mining to scientific data involve the induction of a classification model. In many cases, the collection of data is not performed with this task in mind, and therefore, the data might contain irrelevant or redundant features that affect negatively the accuracy of the induction algorithms. The size and dimensionality of typical scientific data make it difficult to use any available domain information to identify features that discriminate between the classes of interest. Similarly, exploratory data analysis techniques have limitations on the amount and dimensionality of the data that can be effectively processed. In this paper, we describe applications of efficient feature selection methods to data sets from astronomy, plasma physics, and remote sensing. We use variations of recently proposed filter methods as well as traditional wrapper approaches where practical. We discuss the importance of these applications, the general challenges of feature selection in scientific datasets, the strategies for success that were common among our diverse applications, and the lessons learned in solving these problems.

  2. Selected papers in hydrologic sciences

    Science.gov (United States)

    A collection of short topical papers providing significant results of hydrologic studies by the U.S. Geological Survey, Department of the Interior, has been published as “Selected Papers in the Hydrologic Sciences, Volume 1” (Water-Supply Paper 2262). Edited by Eric L. Meyer, “Selected Papers in the Hydrologic Sciences“ is a new journal-type publication that will be a part of the existing U.S. Geological Survey Water-Supply Paper series. The “journal” is aimed at meeting the widespread public and professional interest of the hydrologic community in timely results from hydrologic studies derived from federal research programs, federal-state cooperative programs, and some work done on behalf of other federal agencies.This first volume, comprising eight papers, addresses a broad array of topics covering sediment chemistry, pesticides, toxic metals, and streamflow characteristics. Included are papers on a technique to measure oxygen in the root zone of saturated and unsaturated soils; measurement of surface runoff and collection of sediment samples from small areas; organic carbon in volcanic ash from Mount St. Helens, Washington; organochlorine pesticide and polychlorinated biphenyl in the Schuylkill River, Pennsylvania; interference of cadmium carbonate precipitation in the determination of cation exchange separation factors; confidence limtis for determining concentrations of tracer particles in sediment samples; determination of aquatic humic substances in natural water; and use of channel cross-section properties for estimating streamflow characteristics.

  3. Filter selection using genetic algorithms

    Science.gov (United States)

    Patel, Devesh

    1996-03-01

    Convolution operators act as matched filters for certain types of variations found in images and have been extensively used in the analysis of images. However, filtering through a bank of N filters generates N filtered images, consequently increasing the amount of data considerably. Moreover, not all these filters have the same discriminatory capabilities for the individual images, thus making the task of any classifier difficult. In this paper, we use genetic algorithms to select a subset of relevant filters. Genetic algorithms represent a class of adaptive search techniques where the processes are similar to natural selection of biological evolution. The steady state model (GENITOR) has been used in this paper. The reduction of filters improves the performance of the classifier (which in this paper is the multi-layer perceptron neural network) and furthermore reduces the computational requirement. In this study we use the Laws filters which were proposed for the analysis of texture images. Our aim is to recognize the different textures on the images using the reduced filter set.

  4. Visible Spectrum Incandescent Selective Emitter

    Energy Technology Data Exchange (ETDEWEB)

    Sonsight Inc.

    2004-04-30

    The purpose of the work performed was to demonstrate the feasibility of a novel bi-layer selective emitter. Selective emitters are incandescent radiant bodies with emissivities that are substantially larger in a selected part of the radiation spectrum, thereby significantly shifting their radiated spectral distribution from that of a blackbody radiating at the same temperature. The major research objectives involved answering the following questions: (1) What maximum VIS/NIR radiant power and emissivity ratios can be attained at 2650 K? (2) What is the observed emitter body life and how does its performance vary with time? (3) What are the design tradeoffs for a dual heating approach in which both an internally mounted heating coil and electrical resistance self-heating are used? (4) What are the quantitative improvements to be had from utilizing a bi-layer emitter body with a low emissivity inner layer and a partially transmissive outer layer? Two approaches to obtaining selective emissivity were investigated. The first was to utilize large optical scattering within an emitter material with a spectral optical absorption that is much greater within the visible spectrum than that within the NIR. With this approach, an optically thick emitter can radiate almost as if optically thin because essentially, scattering limits the distance below the surface from which significant amounts of internally generated radiation can emerge. The performance of thin emitters was also investigated (for optically thin emitters, spectral emissivity is proportional to spectral absorptivity). These emitters were fabricated from thin mono-layer emitter rods as well as from bi-layer rods with a thin emitter layer mounted on a substrate core. With an initially estimated energy efficiency of almost three times that of standard incandescent bulbs, a number of energy, economic and environmental benefits such as less energy use and cost, reduced CO{sub 2} emissions, and no mercury contamination

  5. G protein activation by endomorphins in the mouse periaqueductal gray matter.

    Science.gov (United States)

    Narita, M; Mizoguchi, H; Narita, M; Dun, N J; Hwang, B H; Endoh, T; Suzuki, T; Nagase, H; Suzuki, T; Tseng, L F

    2000-01-01

    The midbrain periaqueductal gray matter (PAG) is an important brain region for the coordination of mu-opioid-induced pharmacological actions. The present study was designed to determine whether newly isolated mu-opioid peptide endomorphins can activate G proteins through mu-opioid receptors in the PAG by monitoring the binding to membranes of the non-hydrolyzable analog of GTP, guanosine-5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS). An autoradiographic [(35)S]GTPgammaS binding study showed that both endomorphin-1 and -2 produced similar anatomical distributions of activated G proteins in the mouse midbrain region. In the mouse PAG, endomorphin-1 and -2 at concentrations from 0.001 to 10 microM increased [(35)S]GTPgammaS binding in a concentration-dependent manner and reached a maximal stimulation of 74.6+/-3.8 and 72.3+/-4.0%, respectively, at 10 microM. In contrast, the synthetic selective mu-opioid receptor agonist [D-Ala(2),NHPhe(4), Gly-ol]enkephalin (DAMGO) had a much greater efficacy and produced a 112.6+/-5.1% increase of the maximal stimulation. The receptor specificity of endomorphin-stimulated [(35)S]GTPgammaS binding was verified by coincubating membranes with endomorphins in the presence of specific mu-, delta- or kappa-opioid receptor antagonists. Coincubation with selective mu-opioid receptor antagonists beta-funaltrexamine or D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH(2) (CTOP) blocked both endomorphin-1 and-2-stimulated [(35)S]GTPgammaS binding. In contrast, neither delta- nor kappa-opioid receptor antagonist had any effect on the [(35)S]GTPgammaS binding stimulated by either endomorphin-1 or -2. These findings indicate that both endomorphin-1 and -2 increase [(35)S]GTPgammaS binding by selectively stimulating mu-opioid receptors with intrinsic activity less than that of DAMGO and suggest that these new endogenous ligands might be partial agonists for mu-opioid receptors in the mouse PAG.

  6. Selective networks and recognition automata.

    Science.gov (United States)

    Reeke, G N; Edelman, G M

    1984-01-01

    The results we have presented demonstrate that a network based on a selective principle can function in the absence of forced learning or an a priori program to give recognition, classification, generalization, and association. While Darwin II is not a model of any actual nervous system, it does set out to solve one of the same problems that evolution had to solve--the need to form categories in a bottom-up manner from information in the environment, without incorporating the assumptions of any particular observer. The key features of the model that make this possible are (1) Darwin II incorporates selective networks whose initial specificities enable them to respond without instruction to unfamiliar stimuli; (2) degeneracy provides multiple possibilities of response to any one stimulus, at the same time providing functional redundancy against component failure; (3) the output of Darwin II is a pattern of response, making use of the simultaneous responses of multiple degenerate groups to avoid the need for very high specificity and the combinatorial disaster that would imply; (4) reentry within individual networks vitiates the limitations described by Minsky and Papert for a class of perceptual automata lacking such connections; and (5) reentry between intercommunicating networks with different functions gives rise to new functions, such as association, that either one alone could not display. The two kinds of network are roughly analogous to the two kinds of category formation that people use: Darwin, corresponding to the exemplar description of categories, and Wallace, corresponding to the probabilistic matching description of categories. These principles lead to a new class of pattern-recognizing machine of which Darwin II is just an example. There are a number of obvious extensions to this work that we are pursuing. These include giving Darwin II the capability to deal with stimuli that are in motion, an ability that probably precedes the ability of biological

  7. Selected recent results from AMANDA

    CERN Document Server

    Andrés, E; Bai, X; Barouch, G; Barwick, S W; Bay, R C; Becker, K H; Bergström, L; Bertrand, D; Bierenbaum, D; Biron, A; Booth, J; Botner, O; Bouchta, A; Boyce, M M; Carius, S; Chen, A; Chirkin, D; Conrad, J; Cooley, J; Costa, C G S; Cowen, D F; Dailing, J; Dalberg, E; De Young, T R; Desiati, P; Dewulf, J P; Doksus, P; Edsjö, J; Ekstrom, P; Erlandsson, B; Feser, T; Gaug, M; Goldschmidt, A; Goobar, A; Gray, L; Haase, H; Hallgren, A; Halzen, F; Hanson, K; Hardtke, R; He, Y D; Hellwig, M; Heukenkamp, H; Hill, G C; Hulth, P O; Hundertmark, S; Jacobsen, J; Kandhadai, V; Karle, A; Kim, J; Koci, B; Köpke, L; Kowalski, M; Leich, H; Leuthold, M; Lindahl, P; Liubarsky, I; Loaiza, P; Lowder, D M; Ludvig, J; Madsen, J; Marciniewski, P; Matis, H S; Mihályi, A; Mikolajski, T; Miller, T C; Minaeva, Y; Miocinovic, P; Mock, P C; Morse, R; Neunhoffer, T; Newcomer, F M; Niessen, P; Nygren, D R; Ogelman, H; Heros, C P D L; Porrata, R; Price, P B; Rawlins, K; Reed, C; Rhode, W; Richards, A; Richter, S; Martino, J R; Romenesko, P; Ross, D; Rubinstein, H; Sander, H G; Scheider, T; Schmidt, T; Schneider, D; Schneider, E; Schwarzl, R; Silvestri, A; Solarz, M; Spiczak, G M; Spiering, C; Starinsky, N; Steele, D; Steffen, P; Stokstad, R G; Streicher, O; Sun, A; Taboada, I; Thollander, L; Thon, T; Tilav, S; Usechak, N; Donckt, M V; Walck, C; Weinheimer, C; Wiebusch, C; Wischnewski, R; Wissing, H; Woschnagg, K; Wu, W; Yodh, G; Young, S

    2001-01-01

    We present a selection of results based on data taken in 1997 with the 302-PMT Antarctic Muon and Neutrino Detector Array-B10 ("AMANDA-B10") array. Atmospheric neutrinos created in the northern hemisphere are observed indirectly through their charged current interactions which produce relativistic, Cherenkov-light-emitting upgoing muons in the South Pole ice cap. The reconstructed angular distribution of these events is in good agreement with expectation and demonstrates the viability of this ice-based device as a neutrino telescope. Studies of nearly vertical upgoing muons limit the available parameter space for WIMP dark matter under the assumption that WIMPS are trapped in the earth's gravitational potential well and annihilate with one another near the earth's center.

  8. Optimal Contracting under Adverse Selection

    DEFF Research Database (Denmark)

    Lenells, Jonatan; Stea, Diego; Foss, Nicolai Juul

    2015-01-01

    We study a model of adverse selection, hard and soft information, and mentalizing ability--the human capacity to represent others' intentions, knowledge, and beliefs. By allowing for a continuous range of different information types, as well as for different means of acquiring information, we dev...... of that information. This strategy affects the properties of the optimal contract, which grows closer to the first best. This research provides insights into the implications of mentalizing for agency theory....... develop a model that captures how principals differentially obtain information on agents. We show that principals that combine conventional data collection techniques with mentalizing benefit from a synergistic effect that impacts both the amount of information that is accessed and the overall cost...

  9. Electromagnetic Properties of Selected Hexaferrites

    Directory of Open Access Journals (Sweden)

    Maritn Soka

    2008-01-01

    Full Text Available Ba(Sr(Me12+Me24+xFe12-xO19 hexagonal ferrites preparation with substitution ratio of 0.0 x 0.6. The iron ionswere substituted by selected cation combinations (divalent Me12+= Ni, Zn, Sn, Co and tetravalent Me24+= Ti, Zr, Ru ions.The samples were synthesised by high energy milling and metallorganic precursor method. A special attention was focused toresults obtained for (ZnTix substitutions.. The changes of coercivity HC were chosen as a evaluation criterion of anisotropyvariation. Simultaneously with the magnetic properties, the dielectric parameters were also tested. Two dielectric relaxationprocesses were detected in Ba - Sr ferrite. Our results showed probably a ferroelectric behaviour of some ferrite samples.

  10. Traveling waves of selective sweeps

    CERN Document Server

    Durrett, Rick

    2009-01-01

    The goal of cancer genome sequencing projects is to determine the genetic alterations that cause common cancers. Many malignancies arise during the clonal expansion of a benign tumor which motivates the study of recurrent selective sweeps in an exponentially growing population. To better understand this process, Beerenwinkel et al.(2007) consider a Wright-Fisher model in which cells from an exponentially growing population accumulate advantageous mutations. Simulations show a traveling wave in which the time of the first k-fold mutant, $\\tau_k$, is approximately linear in $k$ and heuristics are used to obtain formulas for $E\\tau_k$. Here, we consider the analogous problem for the Moran model and prove that as the mutation rate $\\mu\\to 0$, $\\tau_k \\sim c_k \\log(1/\\mu)$, where the $c_k$ can be computed explicitly.

  11. Selective Laser Trabeculoplasty: An Overview.

    Science.gov (United States)

    Jha, Bhaskar; Bhartiya, Shibal; Sharma, Reetika; Arora, Tarun; Dada, Tanuj

    2012-01-01

    Given the obvious quality of life concerns with medical and surgical lowering of intraocular pressure (IOP), lasers have received considerable attention as a therapeutic modality for glaucoma. Selective laser trabeculoplasty (SLT) is increasingly being used in clinical practice as both the primary procedure and as an adjunct to medical and surgical therapy. Preliminary published evidence suggests that SLT is an effective, compliance-free, repeatable and safe therapeutic modality having only minor, transient, self-limiting or easily controlled side effects with no sequelae. This review attempts a broad overview of the current knowledge of its mechanism, efficacy, indications and limitations, point out the knowledge lacunae that still exist with respect to this highly promising technology which has captured the attention of glaucoma surgeons all over the world.

  12. Human development recruiting and selection

    Directory of Open Access Journals (Sweden)

    Maksimović Marijana

    2002-01-01

    Full Text Available Along with the development of trends towards internationalization and globalization, human resource management and, especially, international human resource management, attracted overall theoretical and practical interest. International environment is complex, made of numerous elements like social organization, laws, education, values and attitudes, religion language, politics, material and technological culture. In multicultural environment, strategic activities could be multiplied through economical political, cultural, social and technological spheres of action, making the recruitment, selection and successful resource allocation in the international human resource management a real challenge for top management. In international human resource management practice, several approaches to the recruitment have differentiated, playing the key roles in hiring talented individuals and retaining efficient workforce KW resources, labor force, recruiting, managers, education

  13. Selecting Operations for Assembler Encoding

    Directory of Open Access Journals (Sweden)

    Tomasz Praczyk

    2010-04-01

    Full Text Available Assembler Encoding is a neuro-evolutionary method in which a neural network is represented in the form of a simple program called Assembler Encoding Program. The task of the program is to create the so-called Network Definition Matrix which maintains all the information necessary to construct the network. To generate Assembler Encoding Programs and the subsequent neural networks evolutionary techniques are used.
    The performance of Assembler Encoding strongly depends on operations used in Assembler Encoding Programs. To select the most effective operations, experiments in the optimization and the predator-prey problem were carried out. In the experiments, Assembler Encoding Programs equipped with different types of operations were tested. The results of the tests are presented at the end of the paper.

  14. Selective catalytic oxidation of ammonia

    Energy Technology Data Exchange (ETDEWEB)

    Leppaelahti, J.; Koljonen, T. [VTT Energy, Espoo (Finland)

    1996-12-31

    In the combustion of fossil fuels, the principal source of nitrogen oxides is nitrogen bound in the fuel structure. In gasification, a large part of fuel nitrogen forms NH{sub 3}, which may form nitrogen oxides during gas combustion. If NH{sub 3} and other nitrogen species could be removed from hot gas, the NO emission could be considerably reduced. However, relatively little attention has been paid to finding new means of removing nitrogen compounds from the hot gasification gas. The possibility of selectively oxidizing NH{sub 3} to N{sub 2} in the hot gasification has been studied at VTT Energy. The largest NH{sub 3} reductions have been achieved by catalytic oxidation on aluminium oxides. (author) (4 refs.)

  15. Vacuum Selection on Axionic Landscapes

    CERN Document Server

    Wang, Gaoyuan

    2015-01-01

    We compute the distribution of minima that are reached dynamically on multi-field axionic landscapes, both numerically and analytically. Such landscapes are well suited for inflationary model building due to the presence of shift symmetries and possible alignment effects (the KNP mechanism). The resulting distribution of dynamically reached minima differs considerably from the naive expectation based on counting all vacua. These differences are more pronounced in the presence of many fields due to dynamical selection effects: while low lying minima are preferred as fields roll down the potential, trajectories are also more likely to get trapped by one of the many nearby minima. We show that common analytic arguments based on random matrix theory in the large $D$-limit to estimate the distribution of minima are insufficient for quantitative arguments pertaining to the dynamically reached ones. This discrepancy is not restricted to axionic potentials. We provide an empirical expression for the expectation value...

  16. Minimization over randomly selected lines

    Directory of Open Access Journals (Sweden)

    Ismet Sahin

    2013-07-01

    Full Text Available This paper presents a population-based evolutionary optimization method for minimizing a given cost function. The mutation operator of this method selects randomly oriented lines in the cost function domain, constructs quadratic functions interpolating the cost function at three different points over each line, and uses extrema of the quadratics as mutated points. The crossover operator modifies each mutated point based on components of two points in population, instead of one point as is usually performed in other evolutionary algorithms. The stopping criterion of this method depends on the number of almost degenerate quadratics. We demonstrate that the proposed method with these mutation and crossover operations achieves faster and more robust convergence than the well-known Differential Evolution and Particle Swarm algorithms.

  17. SELECTED DETERMINANTS OF DEMOGRAPHIC SAFETY

    Directory of Open Access Journals (Sweden)

    Stanisława Ostasiewicz

    2016-09-01

    Full Text Available The article presents, in a simplifi ed manner, selected theories of population to explain the current trends of population development in Poland and throughout the world. The aim of the article is to present the demographic threats that have emerged in the last eighty years. Prognosticated age structures have also been predicted. Signifi cant diff erences between the structure of the population now and the future have been indicated, particularly regarding the ageing of the population. Against the background of global transformations analyzes of changes in Poland have been conducted. The comparison shows that changes in Poland are highly analogous to transformations around the world, such as declining birth rates and increasing life expectancy. These changes cause ageing of the population, which could result in the collapse of the functioning of the labor market and the pension system as it currently exists.

  18. Selective dissolution in binary alloys

    Science.gov (United States)

    McCall, Carol Rene

    Corrosion is an important issue in the design of engineering alloys. De-alloying is an aspect of alloy corrosion related to the selective dissolution of one or more of the components in an alloy. The work reported herein focuses on the topic of de-alloying specific to single-phase binary noble metal alloy systems. The alloy systems investigated were gold-silver and gold-copper. The onset of a bulk selective dissolution process is typically marked by a critical potential whereby the more reactive component in the alloy begins dissolving from the bulk, leading to the formation of a bi-continuous solid-void morphology. The critical potential was investigated for the entire composition range of gold-silver alloys. The results presented herein include the formulation of an expression for critical potential as a function of both alloy and electrolyte composition. Results of the first investigation of underpotential deposition (UPD) on alloys are also presented herein. These results were implemented as an analytical tool to provide quantitative measurements of the surface evolution of gold during de-alloying. The region below the critical potential was investigated in terms of the compositional evolution of the alloy surface. Below the critical potential, there is a competition between the dissolution of the more reactive alloying constituent (either silver or copper) and surface diffusion of gold that serves to cover dissolution sites and prevent bulk dissolution. By holding the potential at a prescribed value below the critical potential, a time-dependent gold enrichment occurs on the alloy surface leading to passivation. A theoretical model was developed to predict the surface enrichment of gold based on the assumption of layer-by-layer dissolution of the more reactive alloy constituent. The UPD measurements were used to measure the time-dependent surface gold concentration and the results agreed with the predictions of the theoretical model.

  19. ServCat Document Selection Guidelines

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — The ServCat document selection guidelines were developed for selecting appropriate documents to upload into ServCat. When beginning to upload documents into ServCat,...

  20. Maximizing crossbred performance through purebred genomic selection

    DEFF Research Database (Denmark)

    Esfandyari, Hadi; Sørensen, Anders Christian; Bijma, Piter

    2015-01-01

    Background In livestock production, many animals are crossbred, with two distinct advantages: heterosis and breed complementarity. Genomic selection (GS) can be used to select purebred parental lines for crossbred performance (CP). Dominance being the likely genetic basis of heterosis, explicitly...

  1. Handling Resource Oscillations Through Selective Misinformation

    Science.gov (United States)

    Klein, Mark; Metzler, Richard; Bar-Yam, Yaneer

    When resource consumers select among competing providers based on delayed information, inefficient oscillations in resource utilization can emerge. This paper describes an approach, based on selective stochastic resource request rejection, for dealing with this emergent dysfunction.

  2. Selecting Trade Books for Elementary Science Units.

    Science.gov (United States)

    Rop, Charles J.; Rop, Sheri K.

    2001-01-01

    Explains the importance of using well-chosen trade books for stimulating student interest and motivation in the natural world. Discusses how to assess and select trade books. Lists selected trade books on the life cycles of plants. (YDS)

  3. Tonic inhibitory control exerted by opioid peptides in the paraventricular nuclei of the hypothalamus on regional hemodynamic activity in rats.

    Science.gov (United States)

    Lessard, Andrée; Bachelard, Hélène

    2002-07-01

    1. Systemic and regional cardiovascular changes were measured following bilateral microinjection of specific and selective opioid-receptor antagonists into the paraventricular nuclei of the hypothalamus (PVN) of awake, freely moving rats. 2. PVN microinjection of increasing doses of the specific opioid antagonist naloxone - methiodide (1 - 5.0 nmol), or a selective mu-opioid receptor antagonist, beta-funaltrexamine (0.05 - 0.5 nmol), evoked important cardiovascular changes characterized by small and transient increases in heart rate (HR) and mean arterial pressure (MAP), vasoconstriction in renal and superior mesenteric vascular beds and vasodilation in the hindquarter vascular bed. 3. No significant cardiovascular changes were observed following PVN administration of the highly selective delta-opioid-receptor antagonist, ICI 174864 (0.1 - 1 nmol), or the selective kappa-opioid-receptor antagonist, nor-binaltorphine (0.1 - 1 nmol). 4. Most of the cardiovascular responses to naloxone (3 nmol) and beta-funaltrexamine (0.5 nmol) were attenuated or abolished by an i.v. treatment with a specific vasopressin V(1) receptor antagonist. 5. These results suggest that endogenous opioid peptides and mu-type PVN opioid receptors modulate a tonically-active central depressor pathway acting on systemic and regional haemodynamic systems. Part of this influence could involve a tonic inhibition of vasopressin release.

  4. Automatic Algorithm Selection for Complex Simulation Problems

    CERN Document Server

    Ewald, Roland

    2012-01-01

    To select the most suitable simulation algorithm for a given task is often difficult. This is due to intricate interactions between model features, implementation details, and runtime environment, which may strongly affect the overall performance. An automated selection of simulation algorithms supports users in setting up simulation experiments without demanding expert knowledge on simulation. Roland Ewald analyzes and discusses existing approaches to solve the algorithm selection problem in the context of simulation. He introduces a framework for automatic simulation algorithm selection and

  5. Adaptation, teleology, and selection by consequences

    OpenAIRE

    Ringen, Jon D.

    1993-01-01

    This paper presents and defends the view that reinforcement and natural selection are selection processes, that selection processes are neither mechanistic nor teleological, and that mentalistic and vitalistic processes are teleological but not mechanistic. The differences between these types of processes are described and used in discussing the conceptual and methodological significance of “selection type theories” and B. F. Skinner's radical behaviorist view that “operant behavior is the fi...

  6. CARBON DIOXIDE SEPARATION BY SELECTIVE PERMEATION.

    Science.gov (United States)

    CARBON DIOXIDE , SEPARATION), (*PERMEABILITY, CARBON DIOXIDE ), POROUS MATERIALS, SILICON COMPOUNDS, RUBBER, SELECTION, ADSORPTION, TEMPERATURE, PRESSURE, POLYMERS, FILMS, PLASTICS, MEMBRANES, HUMIDITY.

  7. In-Place Randomized Slope Selection

    DEFF Research Database (Denmark)

    Blunck, Henrik; Vahrenhold, Jan

    2006-01-01

    Slope selection, i.e. selecting the slope with rank k among all 􀀀n 2lines induced by a collection P of points, results in a widely used robust estimator for linefitting. In this paper, we demonstrate that it is possible to perform slope selection in expected O(n·log2 n) time using only...

  8. 15 CFR 2301.18 - Selection process.

    Science.gov (United States)

    2010-01-01

    ... 15 Commerce and Foreign Trade 3 2010-01-01 2010-01-01 false Selection process. 2301.18 Section 2301.18 Commerce and Foreign Trade Regulations Relating to Telecommunications and Information NATIONAL... PROGRAM Evaluation and Selection Process § 2301.18 Selection process. (a) The PTFP Director will...

  9. Selective decontamination and antibiotic resistance in ICUs

    NARCIS (Netherlands)

    Plantinga, Nienke L.; Bonten, Marc J. M.

    2015-01-01

    Selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD) have been associated with reduced mortality and lower ICU-acquired bacteremia and ventilator-associated pneumonia rates in areas with low levels of antibiotic resistance. However, the effect of selective deco

  10. MIS-based sensors with hydrogen selectivity

    Science.gov (United States)

    Li; ,Dongmei; Medlin, J. William; McDaniel, Anthony H.; Bastasz, Robert J.

    2008-03-11

    The invention provides hydrogen selective metal-insulator-semiconductor sensors which include a layer of hydrogen selective material. The hydrogen selective material can be polyimide layer having a thickness between 200 and 800 nm. Suitable polyimide materials include reaction products of benzophenone tetracarboxylic dianhydride 4,4-oxydianiline m-phenylene diamine and other structurally similar materials.

  11. Maximizing Crossbred Performance through Purebred Genomic Selection

    DEFF Research Database (Denmark)

    Esfandyari, Hadi; Sørensen, Anders Christian; Bijma, Pieter

    Genomic selection (GS) can be used to select purebreds for crossbred performance (CP). As dominance is the likely genetic basis of heterosis, explicitly including dominance in the GS model may be beneficial for selection of purebreds for CP, when estimating allelic effects from pure line data...

  12. Selective Maintenance Model Considering Time Uncertainty

    OpenAIRE

    Le Chen; Zhengping Shu; Yuan Li; Xuezhi Lv

    2012-01-01

    This study proposes a selective maintenance model for weapon system during mission interval. First, it gives relevant definitions and operational process of material support system. Then, it introduces current research on selective maintenance modeling. Finally, it establishes numerical model for selecting corrective and preventive maintenance tasks, considering time uncertainty brought by unpredictability of maintenance procedure, indetermination of downtime for spares and difference of skil...

  13. 5 CFR 720.206 - Selection guidelines.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Selection guidelines. 720.206 Section 720... guidelines. This subpart sets forth requirements for a recruitment program, not a selection program... procedures and criteria must be consistent with the Uniform Guidelines on Employee Selection Procedures...

  14. Stepwise Variable Selection in Factor Analysis.

    Science.gov (United States)

    Kano, Yutaka; Harada, Akira

    2000-01-01

    Takes several goodness-of-fit statistics as measures of variable selection and develops backward elimination and forward selection procedures in exploratory factor analysis. A newly developed variable selection program, SEFA, can print several fit measures for a current model and models obtained by removing an internal variable or adding an…

  15. Inbreeding in genome-wide selection

    NARCIS (Netherlands)

    Daetwyler, H.D.; Villanueva, B.; Bijma, P.; Woolliams, J.A.

    2007-01-01

    Traditional selection methods, such as sib and best linear unbiased prediction (BLUP) selection, which increased genetic gain by increasing accuracy of evaluation have also led to an increased rate of inbreeding per generation (¿FG). This is not necessarily the case with genome-wide selection, which

  16. 45 CFR 1217.4 - Selection procedure.

    Science.gov (United States)

    2010-10-01

    ... Director's review. (b) Selection. VISTA volunteer leaders will be selected by the Regional Director (or his... VISTA VOLUNTEER LEADER § 1217.4 Selection procedure. (a) Nomination. Candidates may be nominated in writing to the Regional Director by the Program Officer or the State Program Director in whose area the...

  17. A Submodularity Framework for Data Subset Selection

    Science.gov (United States)

    2013-09-01

    evaluate novel data subset selection algorithms that are based on the framework of submodular functions, a class of mathematical functions that have...data selection to the problems of automatic speech recognition (ASR) and machine translation (MT). Data subset selection algorithms were used to

  18. Methods for Selecting Phage Display Antibody Libraries.

    Science.gov (United States)

    Jara-Acevedo, Ricardo; Diez, Paula; Gonzalez-Gonzalez, Maria; Degano, Rosa Maria; Ibarrola, Nieves; Gongora, Rafael; Orfao, Alberto; Fuentes, Manuel

    2016-01-01

    The selection process aims sequential enrichment of phage antibody display library in clones that recognize the target of interest or antigen as the library undergoes successive rounds of selection. In this review, selection methods most commonly used for phage display antibody libraries have been comprehensively described.

  19. The spatial patterns of directional phenotypic selection

    KAUST Repository

    Siepielski, Adam M.

    2013-09-12

    Local adaptation, adaptive population divergence and speciation are often expected to result from populations evolving in response to spatial variation in selection. Yet, we lack a comprehensive understanding of the major features that characterise the spatial patterns of selection, namely the extent of variation among populations in the strength and direction of selection. Here, we analyse a data set of spatially replicated studies of directional phenotypic selection from natural populations. The data set includes 60 studies, consisting of 3937 estimates of selection across an average of five populations. We performed meta-analyses to explore features characterising spatial variation in directional selection. We found that selection tends to vary mainly in strength and less in direction among populations. Although differences in the direction of selection occur among populations they do so where selection is often weakest, which may limit the potential for ongoing adaptive population divergence. Overall, we also found that spatial variation in selection appears comparable to temporal (annual) variation in selection within populations; however, several deficiencies in available data currently complicate this comparison. We discuss future research needs to further advance our understanding of spatial variation in selection. © 2013 John Wiley & Sons Ltd/CNRS.

  20. In-Place Randomized Slope Selection

    DEFF Research Database (Denmark)

    Blunck, Henrik; Vahrenhold, Jan

    2006-01-01

    Slope selection, i.e. selecting the slope with rank k among all 􀀀n 2lines induced by a collection P of points, results in a widely used robust estimator for linefitting. In this paper, we demonstrate that it is possible to perform slope selection in expected O(n·log2 n) time using only...

  1. Hydrogen Selective Exfoliated Zeolite Membranes

    Energy Technology Data Exchange (ETDEWEB)

    Tsapatsis, Michael [Univ. of Minnesota, Minneapolis, MN (United States). Department of Chemical Engineering and Materials Science; Daoutidis, Prodromos [Univ. of Minnesota, Minneapolis, MN (United States). Department of Chemical Engineering and Materials Science; Elyassi, Bahman [Univ. of Minnesota, Minneapolis, MN (United States). Department of Chemical Engineering and Materials Science; Lima, Fernando [Univ. of Minnesota, Minneapolis, MN (United States). Department of Chemical Engineering and Materials Science; Iyer, Aparna [Univ. of Minnesota, Minneapolis, MN (United States). Department of Chemical Engineering and Materials Science; Agrawal, Kumar [Univ. of Minnesota, Minneapolis, MN (United States). Department of Chemical Engineering and Materials Science; Sabnis, Sanket [Univ. of Minnesota, Minneapolis, MN (United States). Department of Chemical Engineering and Materials Science

    2015-04-06

    The objective of this project was to develop and evaluate an innovative membrane technology at process conditions that would be representative of Integrated Gasification Combined Cycle (IGCC) advanced power generation with pre-combustion capture of carbon dioxide (CO2). This research focused on hydrogen (H2)-selective zeolite membranes that could be utilized to separate conditioned syngas into H2-rich and CO2-rich components. Both experiments and process design and optimization calculations were performed to evaluate the concept of ultra-thin membranes made from zeolites nanosheets. In this work, efforts in the laboratory were made to tackle two fundamental challenges in application of zeolite membranes in harsh industrial environments, namely, membrane thickness and membrane stability. Conventional zeolite membranes have thicknesses in the micron range, limiting their performance. In this research, we developed a method for fabrication of ultimately thin zeolite membranes based on zeolite nanosheets. A range of layered zeolites (MWW, RWR, NSI structure types) suitable for hydrogen separation was successfully exfoliated to their constituent nanosheets. Further, membranes were made from one of these zeolites, MWW, to demonstrate the potential of this group of materials. Moreover, long-term steam stability of these zeolites (up to 6 months) was investigated in high concentrations of steam (35 mol% and 95 mole%), high pressure (10 barg), and high temperatures (350 °C and 600 °C) relevant to conditions of water-gas-shift and steam methane reforming reactions. It was found that certain nanosheets are stable, and that stability depends on the concentration of structural defects. Additionally, models that represent a water-gas-shift (WGS) membrane reactor equipped with the zeolite membrane were developed for systems studies. These studies had the aim of analyzing the effect of the membrane reactor integration into IGCC plants

  2. SLS Test Stand Site Selection

    Science.gov (United States)

    Crowe, Kathryn; Williams, Michael

    2015-01-01

    Test site selection is a critical element of the design, development and production of a new system. With the advent of the new Space Launch System (SLS), the National Aeronautics and Space Administration (NASA) had a number of test site selection decisions that needed to be made early enough in the Program to support the planned Launch Readiness Date (LRD). This case study focuses on decisions that needed to be made in 2011 and 2012 in preparation for the April 2013 DPMC decision about where to execute the Main Propulsion Test that is commonly referred to as "Green Run." Those decisions relied upon cooperative analysis between the Program, the Test Lab and Center Operations. The SLS is a human spaceflight vehicle designed to carry a crew farther into space than humans have previously flown. The vehicle consists of four parts: the crew capsule, the upper stage, the core stage, and the first stage solid rocket boosters. The crew capsule carries the astronauts, while the upper stage, the core stage, and solid rocket boosters provide thrust for the vehicle. In other words, the stages provide the "lift" part of the lift vehicle. In conjunction with the solid rocket boosters, the core stage provides the initial "get-off-the-ground" thrust to the vehicle. The ignition of the four core stage engines and two solid rocket boosters is the first step in the launch portion of the mission. The solid rocket boosters burn out after about 2 minutes of flight, and are then jettisoned. The core stage provides thrust until the vehicle reaches a specific altitude and speed, at which point the core stage is shut off and jettisoned, and the upper stage provides vehicle thrust for subsequent mission trajectories. The integrated core stage primarily consists of a liquid oxygen tank, a liquid hydrogen tank, and the four core stage engines. For the SLS program, four RS-25 engines were selected as the four core stage engines. The RS-25 engine is the same engine that was used for Space

  3. Selective Insulin Resistance in Adipocytes*

    Science.gov (United States)

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

    2015-01-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

  4. Polystyrene Based Silver Selective Electrodes

    Directory of Open Access Journals (Sweden)

    Shiva Agarwal

    2002-06-01

    Full Text Available Silver(I selective sensors have been fabricated from polystyrene matrix membranes containing macrocycle, Me6(14 diene.2HClO4 as ionophore. Best performance was exhibited by the membrane having a composition macrocycle : Polystyrene in the ratio 15:1. This membrane worked well over a wide concentration range 5.0×10-6–1.0×10-1M of Ag+ with a near-Nernstian slope of 53.0 ± 1.0 mV per decade of Ag+ activity. The response time of the sensor is <15 s and the membrane can be used over a period of four months with good reproducibility. The proposed electrode works well in a wide pH range 2.5-9.0 and demonstrates good discriminating power over a number of mono-, di-, and trivalent cations. The sensor has also been used as an indicator electrode in the potentiometric titration of silver(II ions against NaCl solution. The sensor can also be used in non-aqueous medium with no significant change in the value of slope or working concentration range for the estimation of Ag+ in solution having up to 25% (v/v nonaqueous fraction.

  5. Selective insulin resistance in adipocytes.

    Science.gov (United States)

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H; Fazakerley, Daniel J; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C; Coster, Adelle C F; Stöckli, Jacqueline; James, David E

    2015-05-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Torsional Phacoemulsification and Tip Selection

    Directory of Open Access Journals (Sweden)

    Fırat Helvacıoğlu

    2014-10-01

    Full Text Available One of the recent advances in cataract surgery is torsional phacoemulsification. It was developed to increase the efficacy of ultrasonic emulsification. In torsional phacoemulsification, the torsional movement of the tip is translated to side-to-side cutting action with the aid of bent phaco tips. Lens material is cut in both directions, rather than only during a forward stroke. The efficiency of this technique is further enhanced by an improvement in followability provided by the inherent non-repulsive nature of the side-to-side motion. Tip selection is very important for the efficiency of torsional phacoemulsification. Theoretically, there are 2 ways to enhance the cutting efficiency of the tip. First is the stroke length; the 22-degree bent 30-degree Kelman mini-flared tip cuts longer than the 12-degree bent 30-degree mini-flared Kelman tip. Second is the angulation or bevel; the higher the degree (45 degrees, the better cutting efficiency. Retrospective analyses of the previously published clinical studies clearly demonstrated that the efficacy of the torsional phacoemulsification has positive correlation with both the aperture angles and neck angles of the tips. (Turk J Ophthalmol 2014; 44: 392-5

  7. Selective laser trabeculoplasty: current perspectives

    Directory of Open Access Journals (Sweden)

    Leahy KE

    2015-05-01

    Full Text Available Kate E Leahy,1 Andrew JR White1–3 1Westmead Hospital, Westmead, NSW, Australia; 2Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia; 3Save Sight Institute, University of Sydney, Sydney, NSW, Australia Abstract: Selective laser trabeculoplasty (SLT has been used in the treatment of glaucoma for just over a decade. Here, we review the current literature in terms of suggested mechanism, efficacy, method of treatment, predictors of success, adverse events, repeatability, and cost of SLT. The exact mechanism by which SLT lowers intraocular pressure (IOP remains unknown although circumstantial evidence has come in many forms in relation to structural alteration; oxidative stress and inflammatory responses; tight junction integrity; proliferative responses; and microbubble formation. SLT is as effective as argon laser trabeculoplasty and medications in reducing IOP in glaucoma and ocular hypertension. The treatment is not uniformly effective in all eyes, and its IOP-lowering effect decreases over time. High pretreatment IOP is the strongest predictor of success; however, significant pressure reduction has also been shown in normal-tension glaucoma and in patients already taking multiple antiglaucoma drops. Mild, transient adverse effects are common. Transient IOP spikes usually resolve quickly with or without antiglaucoma treatment but may be problematic in pigmented angles. The limited available evidence suggests SLT is repeatable and cost-effective for the treatment of glaucoma and ocular hypertension. Keywords: glaucoma, SLT, ocular hypertension, intraocular pressure

  8. Selection criteria for dental radiography

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-07-01

    The Faculty of General Dental Practitioners (UK) has a declared commitment to 'improving the standards of patient care'. By the provision of standards and guidelines it aims to help the profession to achieve this goal. Standards and guidelines are simply tools a dentist may use to improve treatment planning and care outcomes. The Self-Assessment Manual and Standards, SAMS, first published in 1991, is now well known to the profession and has become a frequently quoted source in clinical audit and quality assurance initiatives. Since its publication the scientific methodology of systematic reviews of the literature has progressed dramatically and this book is based on these developments. Evidence-based care is well established in medicine and dentistry and these selection criteria and guidelines follow these established protocols by basing advice on the available scientific evidence wherever possible. This book's purpose is a practical one, it is not intended to be limiting or restrictive but to be useful in the decision-making process. This is the first in a series of standards documents from the FGDP(UK) which are based on reviews of the scientific literature and employ the Scottish Intercollegiate Guideline Network (SIGN) methodology for guideline production. They are not constraints but an aid to effective treatment planning and patient care.

  9. Selection of image acquisition methods

    Science.gov (United States)

    Donnelly, Joseph J.

    1991-05-01

    A comprehensive picture archiving and communications system (PACS), such as the medical diagnostic imaging support (MDIS) system, consists of several interrelated sub systems. The image acquisition subsystem is the means by which images are introduced into the system and as such it is analogous to the ''eyes'' of the system. Images from digital modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are readily transferable to a PACS since they are acquired in a digital format. Conventional film based analog images are particularly challenging since at no point in their production or display do they exist in an electronic form suitable for transfer to the MDIS system. In recent years, commercial high resolution film digitizers and computed radiology (CR) devices have become available. These devices now provide us with the means to capture conventional radiographic images in a format suitable for transfer to a PACS. Through the careful selection of acquisition devices we can now design an image acquisition subsystem tailored to meet our clinical needs.

  10. Biomaterial selection for tooth regeneration.

    Science.gov (United States)

    Yuan, Zhenglin; Nie, Hemin; Wang, Shuang; Lee, Chang Hun; Li, Ang; Fu, Susan Y; Zhou, Hong; Chen, Lili; Mao, Jeremy J

    2011-10-01

    Biomaterials are native or synthetic polymers that act as carriers for drug delivery or scaffolds for tissue regeneration. When implanted in vivo, biomaterials should be nontoxic and exert intended functions. For tooth regeneration, biomaterials have primarily served as a scaffold for (1) transplanted stem cells and/or (2) recruitment of endogenous stem cells. This article critically synthesizes our knowledge of biomaterial use in tooth regeneration, including the selection of native and/or synthetic polymers, three-dimensional scaffold fabrication, stem cell transplantation, and stem cell homing. A tooth is a complex biological organ. Tooth loss represents the most common organ failure. Tooth regeneration encompasses not only regrowth of an entire tooth as an organ, but also biological restoration of individual components of the tooth including enamel, dentin, cementum, or dental pulp. Regeneration of tooth root represents perhaps more near-term opportunities than the regeneration of the whole tooth. In the adult, a tooth owes its biological vitality, arguably more, to the root than the crown. Biomaterials are indispensible for the regeneration of tooth root, tooth crown, dental pulp, or an entire tooth.

  11. Vacuum selection on axionic landscapes

    Science.gov (United States)

    Wang, Gaoyuan; Battefeld, Thorsten

    2016-04-01

    We compute the distribution of minima that are reached dynamically on multi-field axionic landscapes, both numerically and analytically. Such landscapes are well suited for inflationary model building due to the presence of shift symmetries and possible alignment effects (the KNP mechanism). The resulting distribution of dynamically reached minima differs considerably from the naive expectation based on counting all vacua. These differences are more pronounced in the presence of many fields due to dynamical selection effects: while low lying minima are preferred as fields roll down the potential, trajectories are also more likely to get trapped by one of the many nearby minima. We show that common analytic arguments based on random matrix theory in the large D-limit to estimate the distribution of minima are insufficient for quantitative arguments pertaining to the dynamically reached ones. This discrepancy is not restricted to axionic potentials. We provide an empirical expression for the expectation value of such dynamically reached minimas' height and argue that the cosmological constant problem is not alleviated in the absence of anthropic arguments. We further comment on the likelihood of inflation on axionic landscapes in the large D-limit.

  12. Selected Natural Materials in History

    Institute of Scientific and Technical Information of China (English)

    Julian F.V.Vincent

    2005-01-01

    @@ 1 Technology of natural materials Early man used conveniently shaped stones as tools."Workshop" areas have been found with large numbers of stones, some showing signs of being worked[1].However, organic materials like wood will decay under normal wet conditions in the presence of oxygen, so we won't find the same sort of evidence for wooden tools. It is safe to assume that early man used sticks as probes and clubs, and maybe even for making some sort of nestlike protection against the elements and predators, since we see chimpanzees and other animals doing this sort of thing. So wood, and almost certainly other plant materials such as fibrous leaves, and bone and other materials gleaned from dead animals, would be used from the earliest times. We need to know this in order to establish the idea that Man can be expected to have a long history of the use and manipulation of natural materials. This needs skills in choosing materials for certain uses on the basis of their mechanical properties,whether those properties are to do with the ease of shaping the material or the effectiveness of that material in use. Occasionally the material was chosen simply because it was readily available. If we find that a particular material was always used for a certain job, it's reasonable to deduce that Man was exerting materials selection criteria through experience.

  13. Europa Lander Material Selection Considerations

    Energy Technology Data Exchange (ETDEWEB)

    Tappan, Alexander S. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Heller, Mellisa [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2017-01-10

    Energetic materials (EMs, explosives, pyrotechnics, propellants) provide high-power output of high temperature reaction products. These products can be solid, liquid, or gaseous during reaction or after the products have equilibrated with the surroundings. For example, high explosives typically consist of carbon, hydrogen, nitrogen, and oxygen bonded within a single molecule, and produce almost exclusively gaseous products. Conversely, intermetallics consist of physical mixtures of metals and metalloids, and produce almost exclusively condensed products. Other materials such as pyrotechnics and propellants have intermediate behavior. All energetic materials react in a self-propagating manner that after ignition, does not necessarily require energy input from the surroundings. The range of reaction velocities can range from mm/s for intermetallics, to km/s for high explosives. Energetic material selection depends on numerous requirements specific to the needs of a system. High explosives are used for applications where high pressure gases are necessary for pushing or fracturing materials (e.g., rock, metal) or creating shock waves or air blast. Propellants are used to produce moderate-pressure, high-temperature products without a shock wave. Pyrotechnics are used to produce numerous effects including: high-temperature products, gases, light, smoke, sound, and others. Thermites are used to produce heat, high-temperature products, materials, and other effects that require condensed products. Intermetallics are used to produce high-temperature condensed products and materials, with very little gas production. Numerous categories of energetic materials exist with overlapping definitions, effects, and properties.

  14. A Selection Method for COTS Systems

    DEFF Research Database (Denmark)

    Hedman, Jonas

    new skills and methods supporting the process of evaluating and selecting information systems. This paper presents a method for selecting COTS systems. The method includes the following phases: problem framing, requirements and appraisal, and selection of systems. The idea and distinguishing feature...... the selection of COTS systems as viewing COTS systems as a ‘mean' to reach organizational ‘ends' is different from the mainstream view of information systems development, which view information systems development as a problem solving process, and the underlying ontological view in other COTS selection methods...

  15. Innovation During the Supplier Selection Process

    DEFF Research Database (Denmark)

    Pilkington, Alan; Pedraza, Isabel

    2014-01-01

    Established ideas on supplier selection have not moved much from the original premise of how to choose between bidders. Whilst we have added many different tools and refinements to choose between alternative suppliers, its nature has not evolved. We move the original selection process approach...... observed through an ethnographic embedded researcher study has refined the selection process and has two selection stages one for first supply covering tool/process developed and another later for resupply of mature parts. We report the details of the process, those involved, the criteria employed...... and identify benefits and weaknesses of this enhanced selection process....

  16. Natural Selection in the Great Apes.

    Science.gov (United States)

    Cagan, Alexander; Theunert, Christoph; Laayouni, Hafid; Santpere, Gabriel; Pybus, Marc; Casals, Ferran; Prüfer, Kay; Navarro, Arcadi; Marques-Bonet, Tomas; Bertranpetit, Jaume; Andrés, Aida M

    2016-12-01

    Natural selection is crucial for the adaptation of populations to their environments. Here, we present the first global study of natural selection in the Hominidae (humans and great apes) based on genome-wide information from population samples representing all extant species (including most subspecies). Combining several neutrality tests we create a multi-species map of signatures of natural selection covering all major types of natural selection. We find that the estimated efficiency of both purifying and positive selection varies between species and is significantly correlated with their long-term effective population size. Thus, even the modest differences in population size among the closely related Hominidae lineages have resulted in differences in their ability to remove deleterious alleles and to adapt to changing environments. Most signatures of balancing and positive selection are species-specific, with signatures of balancing selection more often being shared among species. We also identify loci with evidence of positive selection across several lineages. Notably, we detect signatures of positive selection in several genes related to brain function, anatomy, diet and immune processes. Our results contribute to a better understanding of human evolution by putting the evidence of natural selection in humans within its larger evolutionary context. The global map of natural selection in our closest living relatives is available as an interactive browser at http://tinyurl.com/nf8qmzh. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  17. Natural Selection in the Great Apes

    Science.gov (United States)

    Cagan, Alexander; Theunert, Christoph; Laayouni, Hafid; Santpere, Gabriel; Pybus, Marc; Casals, Ferran; Prüfer, Kay; Navarro, Arcadi; Marques-Bonet, Tomas; Bertranpetit, Jaume; Andrés, Aida M.

    2016-01-01

    Natural selection is crucial for the adaptation of populations to their environments. Here, we present the first global study of natural selection in the Hominidae (humans and great apes) based on genome-wide information from population samples representing all extant species (including most subspecies). Combining several neutrality tests we create a multi-species map of signatures of natural selection covering all major types of natural selection. We find that the estimated efficiency of both purifying and positive selection varies between species and is significantly correlated with their long-term effective population size. Thus, even the modest differences in population size among the closely related Hominidae lineages have resulted in differences in their ability to remove deleterious alleles and to adapt to changing environments. Most signatures of balancing and positive selection are species-specific, with signatures of balancing selection more often being shared among species. We also identify loci with evidence of positive selection across several lineages. Notably, we detect signatures of positive selection in several genes related to brain function, anatomy, diet and immune processes. Our results contribute to a better understanding of human evolution by putting the evidence of natural selection in humans within its larger evolutionary context. The global map of natural selection in our closest living relatives is available as an interactive browser at http://tinyurl.com/nf8qmzh. PMID:27795229

  18. Anisotropic selection in cellular genetic algorithms

    CERN Document Server

    Simoncini, David; Collard, Philippe; Clergue, Manuel

    2008-01-01

    In this paper we introduce a new selection scheme in cellular genetic algorithms (cGAs). Anisotropic Selection (AS) promotes diversity and allows accurate control of the selective pressure. First we compare this new scheme with the classical rectangular grid shapes solution according to the selective pressure: we can obtain the same takeover time with the two techniques although the spreading of the best individual is different. We then give experimental results that show to what extent AS promotes the emergence of niches that support low coupling and high cohesion. Finally, using a cGA with anisotropic selection on a Quadratic Assignment Problem we show the existence of an anisotropic optimal value for which the best average performance is observed. Further work will focus on the selective pressure self-adjustment ability provided by this new selection scheme.

  19. Rough set-based feature selection method

    Institute of Scientific and Technical Information of China (English)

    ZHAN Yanmei; ZENG Xiangyang; SUN Jincai

    2005-01-01

    A new feature selection method is proposed based on the discern matrix in rough set in this paper. The main idea of this method is that the most effective feature, if used for classification, can distinguish the most number of samples belonging to different classes. Experiments are performed using this method to select relevant features for artificial datasets and real-world datasets. Results show that the selection method proposed can correctly select all the relevant features of artificial datasets and drastically reduce the number of features at the same time. In addition, when this method is used for the selection of classification features of real-world underwater targets,the number of classification features after selection drops to 20% of the original feature set, and the classification accuracy increases about 6% using dataset after feature selection.

  20. Involvement of peripheral mu opioid receptors in scratching behavior in mice.

    Science.gov (United States)

    Yamamoto, Atsuki; Sugimoto, Yukio

    2010-12-15

    Pruritus is a common adverse effect of opioid treatment. However, the mechanism by which pruritus is induced by opioid administration is unclear. In this study, we examined the effects of the intradermal injection of loperamide, a peripherally restricted opioid receptor agonist, on the itch sensation. When injected intradermally into the rostral part of the back in mice, loperamide elicited scratching behavior. We also examined the effects of the selective mu opioid receptor agonist [d-Ala², N-Me-Phe⁴, Gly⁵-ol]-enkephalin acetate (DAMGO), the selective delta opioid receptor agonist [d-Pen(2,5)]-enkephalin (DPDPE), and the selective kappa opioid receptor agonist U-50488H on scratching behavior in mice in order to determine which subtype is involved in opioid-induced pruritus. Following intradermal injection into the rostral part of the back in mice, DAMGO elicited scratching behavior, while DPDPE and U-50488H did not. This suggests that peripheral mu opioid activation elicits the itch sensation. Next, we focused on the treatment of opioid-induced itch sensation without central adverse effects. Naloxone methiodide is a peripherally restricted opioid receptor antagonist. In the present study, naloxone methiodide significantly suppressed scratching behavior induced by loperamide and DAMGO. These findings suggest that mu opioid receptors play a primary role in peripheral pruritus and that naloxone methiodide may represent a possible remedy for opioid-induced itching.

  1. Antidepressant-like effect of endomorphin-1 and endomorphin-2 in mice.

    Science.gov (United States)

    Fichna, Jakub; Janecka, Anna; Piestrzeniewicz, Mariola; Costentin, Jean; do Rego, Jean-Claude

    2007-04-01

    Endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2)) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH(2)) are two recently isolated mu-opioid selective peptides with a potent antinociceptive activity, involved in a number of physiological processes, including food intake, vasomotricity, sexual behavior, as well as neuroendocrine and cardiorespiratory functions. The neuroanatomical distribution of endomorphins prompted us to study their antidepressant activity in two animal behavioral models of depression: forced-swimming and tail-suspension tests. In both tests, the intracerebroventricular (i.c.v.) injection of either endomorphin-1 or endomorphin-2 significantly decreased the duration of immobility, interpreted as an expression of 'behavioral despair', which could be related to the depression syndrome. These effects of endomorphins did not result from the stimulation of the animal motor activity. We have also demonstrated that the antidepressant-like effect of endomorphins was antagonized by the universal opioid antagonist, naloxone and the mu-opioid receptor selective antagonist, beta-funaltrexamine. In contrast, this effect was not antagonized by delta- and kappa-opioid receptor selective antagonists, naltrindole and nor-binaltorphimine, respectively. The results of the present study demonstrate that endomorphin-1 and endomorphin-2 produce potent antidepressant-like effects after i.c.v. injection in mice. We may suggest that endomorphins and the mu-opioid receptors might be involved in the physiopathology of depressive disorders, and that the endomorphinergic system could serve as a novel target for the development of antidepressant drugs.

  2. Food selection for endurance sports.

    Science.gov (United States)

    Houtkooper, L

    1992-09-01

    1) The body requires at least 40 nutrients that are classified into six groups: protein, carbohydrate, fat, vitamin, mineral, and water. These nutrients cannot be made in the body and so they must be supplied from solid or liquid foods. 2) Fat, carbohydrate, and protein contain energy that is measured in units called kilocalories. Alcohol also contains kilocalories, but is not a recommended energy source for endurance exercise. 3) Foods in endurance sports training programs should provide adequate fluids to prevent dehydration; energy intake that is high in carbohydrate, low in fat, adequate in protein, and that maintains desirable body weight and desirable proportions of fat and lean weight; and sufficient amounts of vitamins and minerals. 4) Six categories of food types form the fundamentals of good diets for endurance exercise training and include: fruits, vegetables, grains-legumes, lean meats, low-fat milk products, and fats-sweets. Vegetarian diets include all food type categories except meat and/or milk products. 5) Fat and carbohydrate content of foods in each food type category varies greatly because of how foods are prepared. 6) The Food Pyramid and Sports Food Swap are guides for selecting foods that provide recommended amounts of essential nutrients for endurance exercise. 7) Before, during, and after endurance exercise, food intake should include adequate amounts of easily digestible, high carbohydrate foods that are familiar and psychologically satisfying. 8) Easily digestible high carbohydrate liquid or solid foods should be eaten soon after exercise is stopped to maximize rates of glycogen replacement. 9) Dehydration can be prevented by adequate fluid intake before, during, and after exercise. 10) Any food plan should be tested before a competition to find out how well that plan works for an athlete.

  3. Cannabis Epidemiology: A Selective Review

    Science.gov (United States)

    Anthony, James C.; Lopez-Quintero, Catalina; Alshaarawy, Omayma

    2017-01-01

    Background Globally, the most widely used set of compounds among the internationally regulated drugs is cannabis. Objective To review evidence from epidemiological research on cannabis, organized in relation to this field’s five main rubrics: quantity, location, causes, mechanisms, and prevention/control. Method The review covers a selection of evidence from standardized population surveys, official statistics, and governmental reports, as well as published articles and books identified via MEDLINE, Web of Science, and Google Scholar as of July 2016. Results In relation to quantity, an estimated 3% to 5% of the world population is thought to have tried a cannabis product, with at least one fairly recent use, mainly extra-medical and outside boundaries of prescribed use. Among cannabis users in the United States, roughly one in 7–8 has engaged in medical marijuana use. In relation to location, prevalence proportions reveal important variations across countries and between subgroups within countries. Regarding causes and mechanisms of starting to use cannabis, there is no compelling integrative and replicable conceptual model or theoretical formulation. Most studies of mechanisms have focused upon a ‘gateway sequence’ and person-to-person diffusion, with some recent work on disability-adjusted life years. A brief review of cannabis use consequences, as well as prevention and control strategies is also provided. Conclusion At present, we know much about the frequency and occurrence of cannabis use, with too little replicable definitive evidence with respect to the other main rubrics. Given a changing regulatory environment for cannabis products, new institutions such as an independent International Cannabis Products Safety Commission may be required to produce evidence required to weigh benefits versus costs. It is not clear that government sponsored research will be sufficient to meet consumer demand for balanced points of view and truly definitive evidence

  4. Optimizing Site Selection for HEDS

    Science.gov (United States)

    Marshall, J. R.

    1999-01-01

    MSP 2001 will be conducting environmental assessment for the Human exploration and Development of Space (HEDS) Program in order to safeguard future human exploration of the planet, in addition to geological studies being addressed by the APEX payload. In particular, the MECA experiment (see other abstracts, this volume), will address chemical toxicity of the soil, the presence of adhesive or abrasive soil dust components, and the geoelectrical-triboelectrical character of the surface environment. The attempt will be to quantify hazards to humans and machinery structures deriving from compounds that poison, corrode, abrade, invade (lungs or machinery), contaminate, or electrically interfere with the human presence. The DART experiment, will also address the size and electrical nature of airborne dust. Photo-imaging of the local scene with RAC and Pancam will be able to assess dust raising events such as local thermal vorticity-driven dust devils. The need to introduce discussion of HEDS landing site requirements stems from potential conflict, but also potential synergism with other '01 site requirements. In-situ Resource Utilization (ISRU) mission components desire as much solar radiation as possible, with some very limited amount of dust available; the planetary-astrobiology mission component desires sufficient rock abundance without inhibiting rover activities (and an interesting geological niche if available), the radiation component may again have special requirements, as will the engineers concerned with mission safety and mission longevity. The '01 mission affords an excellent opportunity to emphasize HEDS landing site requirements, given the constraint that both recent missions (Pathfinder, Mars '98) and future missions (MSP '03 & '05) have had or will have strong geological science drivers in the site selection process. What type of landing site best facilitates investigation of the physical, chemical, and behavioral properties of soil and dust? There are

  5. The ABSTRACTS OF SELECTED ARTICLES

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    The Appreciation of RMB, the Behavior of Firms and the Export Trade: A Case Study Based on the Enterprise Data of a Large Specimen between 2005 and 2009 In this article, we have constructed a simplified dynamic discrete choice model to analyze, within the framework of the maximization of profit, the two-stage decision of firm' s export behavior and the effect of the exchange rate. We have, by the means of the specimen data on China' s industrial enterprises between 2005 and 2009 and by the use of Heckman selection model, evaluated the general impact of the appreciation of RMB (AORMB) on the export trade and the structural impact. The results of our study indicate that the AORMB has generated significant negative shock to firm ' s export through extensive margins and intensive margins. Meanwhile, the difference in operation strategy of heteroge- neous firms has resulted in the fact that the AORMB can hardly achieve the expected purpose of the survival of the fit- test; instead it has interrupted the optimization of the adjustment in the optimization of the structure of the main body of the export trade. The AORMB has, in a certain degree, driven the industry structure of export to develop to a higher phase. However, such positive effects have mainly rooted in the contribution of foreign-funded enterprises, but this pos- itive role has restricted the growth space of the local enterprises in the advanced manufacturing industry. Under the cir- cumstance of high uncertainty in foreign and domestic economy, in order to guarantee the steady transition of the eco- nomic transition, the AORMB should be slowed for the time being, and other more pertinent measures should be adopt- ed to drive the upgrade of the export trade and the adjustment of economic structure.

  6. Expression of {mu}, {kappa}, and {delta} opioid receptor messenger RNA in the human CNS: a {sup 33}P in situ hybridization study

    Energy Technology Data Exchange (ETDEWEB)

    Peckys, D.; Landwehrmeyer, G.B. [Department of Neurology, Albert-Ludwigs-University Freiburg, Neurozentrum, Breisacherstrasse 64, D-79106 Freiburg (Germany)

    1999-02-01

    The existence of at least three opioid receptor types, referred to as {mu}, {kappa}, and {delta}, is well established. Complementary DNAs corresponding to the pharmacologically defined {mu}, {kappa}, and {delta} opioid receptors have been isolated in various species including man. The expression patterns of opioid receptor transcripts in human brain has not been established with a cellular resolution, in part because of the low apparent abundance of opioid receptor messenger RNAs in human brain. To visualize opioid receptor messenger RNAs we developed a sensitive in situ hybridization histochemistry method using {sup 33}P-labelled RNA probes. In the present study we report the regional and cellular expression of {mu}, {kappa}, and {delta} opioid receptor messenger RNAs in selected areas of the human brain. Hybridization of the different opioid receptor probes resulted in distinct labelling patterns. For the {mu} and {kappa} opioid receptor probes, the most intense regional signals were observed in striatum, thalamus, hypothalamus, cerebral cortex, cerebellum and certain brainstem areas as well as the spinal cord. The most intense signals for the {delta} opioid receptor probe were found in cerebral cortex. Expression of opioid receptor transcripts was restricted to subpopulations of neurons within most regions studied demonstrating differences in the cellular expression patterns of {mu}, {kappa}, and {delta} opioid receptor messenger RNAs in numerous brain regions. The messenger RNA distribution patterns for each opioid receptor corresponded in general to the distribution of opioid receptor binding sites as visualized by receptor autoradiography. However, some mismatches, for instance between {mu} opioid receptor receptor binding and {mu} opioid receptor messenger RNA expression in the anterior striatum, were observed. A comparison of the distribution patterns of opioid receptor messenger RNAs in the human brain and that reported for the rat suggests a homologous

  7. Opioid binding sites in the guinea pig and rat kidney: Radioligand homogenate binding and autoradiography

    Energy Technology Data Exchange (ETDEWEB)

    Dissanayake, V.U.; Hughes, J.; Hunter, J.C. (Parke-Davis Research Unit, Addenbrookes Hospital Site, Cambridge (England))

    1991-07-01

    The specific binding of the selective {mu}-, {delta}-, and {kappa}-opioid ligands (3H)(D-Ala2,MePhe4,Gly-ol5)enkephalin ((3H) DAGOL), (3H)(D-Pen2,D-Pen5)enkephalin ((3H)DPDPE), and (3H)U69593, respectively, to crude membranes of the guinea pig and rat whole kidney, kidney cortex, and kidney medulla was investigated. In addition, the distribution of specific 3H-opioid binding sites in the guinea pig and rat kidney was visualized by autoradiography. Homogenate binding and autoradiography demonstrated the absence of {mu}- and {kappa}-opioid binding sites in the guinea pig kidney. No opioid binding sites were demonstrable in the rat kidney. In the guinea pig whole kidney, cortex, and medulla, saturation studies demonstrated that (3H)DPDPE bound with high affinity (KD = 2.6-3.5 nM) to an apparently homogeneous population of binding sites (Bmax = 8.4-30 fmol/mg of protein). Competition studies using several opioid compounds confirmed the nature of the {delta}-opioid binding site. Autoradiography experiments demonstrated that specific (3H)DPDPE binding sites were distributed radially in regions of the inner and outer medulla and at the corticomedullary junction of the guinea pig kidney. Computer-assisted image analysis of saturation data yielded KD values (4.5-5.0 nM) that were in good agreement with those obtained from the homogenate binding studies. Further investigation of the {delta}-opioid binding site in medulla homogenates, using agonist ((3H)DPDPE) and antagonist ((3H)diprenorphine) binding in the presence of Na+, Mg2+, and nucleotides, suggested that the {delta}-opioid site is linked to a second messenger system via a GTP-binding protein. Further studies are required to establish the precise localization of the {delta} binding site in the guinea pig kidney and to determine the nature of the second messenger linked to the GTP-binding protein in the medulla.

  8. New insights into selected-area deposition of diamond films by means of selective seeding

    CERN Document Server

    LiuHongWu; Gao Chun Xi; Han Yong; Luo Ji Feng; Zou Guang Tian; Wen Chao

    2002-01-01

    Polycrystalline diamond films have been patterned on a polished Si substrate by means of selective seeding via hot-filament chemical vapour deposition. In addition to the process of selective seeding, the CH sub 4 /H sub 2 concentration and the sizes of the patterns have effects on the selectivity. The mechanism of selective growth of diamond is also discussed in this paper.

  9. Selection of phytotoxin producing rhizobacteria

    Directory of Open Access Journals (Sweden)

    Daniel D.C. Carvalho

    2011-09-01

    Full Text Available In order to select phytotoxin producing rhizobacteria to control weed plants, twenty five bacterial strains previously isolated from the rhizospheres of various plants were grown in a liquid medium and, after cell removal by centrifugation, the liquid phases were freeze-dried and the products were extracted with ethyl acetate/methanol. The extracts were concentrated to dryness under vacuum and dissolved in water and sucrose solution to be submitted to in vitro assays of lettuce (Lactuca sativa L. seed germination and wheat (Triticum aestivum L. coleoptile growth. Although most samples affected coleoptile growth, only those from four strains reduced lettuce seed germination. Two strains of Bacillus cereus, one strain of B. pumilus and one of Stenotrophoonas altophilia were the most promising microorganisms for producing phytotoxin and, consequently, for the development of new weed control products.Com o objetivo de selecionar rizobactérias produtoras de fitotoxinas para uso no controle de plantas daninhas, vinte e cinco isolados bacterianos previamente obtidos das rizosferas de diferentes plantas foram cultivados em meio líquido e, após remoção das células por centrifugação, as fases líquidas foram liofilizadas e os resíduos obtidos foram submetidos à extração com acetato de etila/metanol. Os extratos foram concentrados sob vácuo até secura e dissolvidos em água e solução de sacarose para serem submetidos a testes in vitro de germinação de sementes de alface (Lactuca sativa L. e de crescimento de coleóptilos de trigo (Triticum aestivum L.. Embora a maior parte das amostras tenha desfavorecido o crescimento dos coleóptilos de trigo, somente as provenientes de quatro isolados reduziram a germinação das sementes de alface. Dois isolados de Bacillus cereus, um isolado de B. pumilus e um de Stenotrophomonas maltophilia foram os microrganismos mais promissores para a produção de fitotoxinas, com possibilidade de uso no

  10. Selective serotonin reuptake inhibitor exposure.

    Science.gov (United States)

    Fitzgerald, Kevin T; Bronstein, Alvin C

    2013-02-01

    Many antidepressants inhibit serotonin or norepinephrine reuptake or both to achieve their clinical effect. The selective serotonin reuptake inhibitor class of antidepressants (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are as effective as tricyclic antidepressants in treatment of major depression with less significant side effects. As a result, they have become the largest class of medications prescribed to humans for depression. They are also used to treat obsessive-compulsive disorder, panic disorders, alcoholism, obesity, migraines, and chronic pain. An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety. SSRIs act specifically on synaptic serotonin concentrations by blocking its reuptake in the presynapse and increasing levels in the presynaptic membrane. Clinical signs of SSRI overdose result from excessive amounts of serotonin in the central nervous system. These signs include nausea, vomiting, mydriasis, hypersalivation, and hyperthermia. Clinical signs are dose dependent and higher dosages may result in the serotonin syndrome that manifests itself as ataxia, tremors, muscle rigidity, hyperthermia, diarrhea, and seizures. Current studies reveal no increase in appearance of any specific clinical signs of serotonin toxicity with regard to any SSRI medication. In people, citalopram has been reported to have an increased risk of electrocardiographic abnormalities. Diagnosis of SSRI poisoning is based on history, clinical signs, and response to therapy. No single clinical test is currently available to confirm SSRI toxicosis. The goals of treatment in this intoxication are to support the animal, prevent further absorption of the drug, support the central nervous system, control hyperthermia, and halt any seizure activity. The relative safety of the SSRIs in overdose despite the occurrence of serotonin syndrome makes them

  11. Model selection bias and Freedman's paradox

    Science.gov (United States)

    Lukacs, P.M.; Burnham, K.P.; Anderson, D.R.

    2010-01-01

    In situations where limited knowledge of a system exists and the ratio of data points to variables is small, variable selection methods can often be misleading. Freedman (Am Stat 37:152-155, 1983) demonstrated how common it is to select completely unrelated variables as highly "significant" when the number of data points is similar in magnitude to the number of variables. A new type of model averaging estimator based on model selection with Akaike's AIC is used with linear regression to investigate the problems of likely inclusion of spurious effects and model selection bias, the bias introduced while using the data to select a single seemingly "best" model from a (often large) set of models employing many predictor variables. The new model averaging estimator helps reduce these problems and provides confidence interval coverage at the nominal level while traditional stepwise selection has poor inferential properties. ?? The Institute of Statistical Mathematics, Tokyo 2009.

  12. IDENTIFICATION AND SELECTION OF SIX SIGMA PROJECTS

    Directory of Open Access Journals (Sweden)

    Abdalhkeim FA. Flifel

    2017-04-01

    Full Text Available Six Sigma is a well-structured and proven methodology for improving organizational performance. It helps achieving the goals of the organization through the use of project-driven approach. The implementation of Six sigma approach depends on proper identification and selection of projects, moreover, the selection of right Six sigma projects is one of the critical success factors of six sigma efforts. The paper provides the sources for the identification of potential projects, top down and bottom up approaches, the process of selection of projects, guidelines that assist the selection of appropriate projects, selection criteria which must be precisely chosen in accordance with the objectives, needs and capabilities of the organization as well as sophisticated techniques and tools recommended in the literature for the selection of projects.

  13. Parental selection of children's sexual orientation.

    Science.gov (United States)

    Greenberg, A S; Bailey, J M

    2001-08-01

    As we learn more about the causes of sexual orientation, the likelihood increases that parents will one day be able to select the orientation of their children. This possibility (at least that of selecting for heterosexuality) has generated a great deal of concern among supporters of homosexual rights, with such selection being widely condemned as harmful and morally repugnant. Notwithstanding this widespread condemnation, and even assuming, as we do, that homosexuality is entirely acceptable morally, allowing parents, by means morally unproblematic in themselves, to select for heterosexuality would be morally acceptable. This is because allowing parents to select their children's sexual orientation would further parent's freedom to raise the sort of children they wish to raise and because selection for heterosexuality may benefit parents and children and is unlikely to cause significant harm.

  14. Asymmetric Information – Adverse Selection Problem

    Directory of Open Access Journals (Sweden)

    Dumitru MARIN

    2007-01-01

    Full Text Available The present paper makes an introduction in the contract theory starting with the definitions of asymmetric information and some of the problems that generate: moral hazard and adverse selection. We provide an insight of the latest empirical studies in adverse selection in different markets. An adverse selection model, based on Rothchild and Stiglitz is also present to give a perspective of the theoretical framework.

  15. Spectral Selectivity Applied To Hybrid Concentration Systems

    Science.gov (United States)

    Hamdy, M. A.; Luttmann, F.; Osborn, D. E.; Jacobson, M. R.; MacLeod, H. A.

    1985-12-01

    The efficiency of conversion of concentrated solar energy can be improved by separating the solar spectrum into portions matched to specific photoquantum processes and the balance used for photothermal conversion. The basic approaches of spectrally selective beam splitters are presented. A detailed simulation analysis using TRNSYS is developed for a spectrally selective hybrid photovoltaic/photothermal concentrating system. The analysis shows definite benefits to a spectrally selective approach.

  16. (Z)-Selective Takai olefination of salicylaldehydes

    Science.gov (United States)

    Galloway, Warren R J D; Sore, Hannah F; Goodman, Jonathan M

    2017-01-01

    The Takai olefination (or Takai reaction) is a method for the conversion of aldehydes to vinyl iodides, and has seen widespread implementation in organic synthesis. The reaction is usually noted for its high (E)-selectivity; however, herein we report the highly (Z)-selective Takai olefination of salicylaldehyde derivatives. Systematic screening of related substrates led to the identification of key factors responsible for this surprising inversion of selectivity, and enabled the development of a modified mechanistic model to rationalise these observations.

  17. Fundamental Vocabulary Selection Based on Word Familiarity

    Science.gov (United States)

    Sato, Hiroshi; Kasahara, Kaname; Kanasugi, Tomoko; Amano, Shigeaki

    This paper proposes a new method for selecting fundamental vocabulary. We are presently constructing the Fundamental Vocabulary Knowledge-base of Japanese that contains integrated information on syntax, semantics and pragmatics, for the purposes of advanced natural language processing. This database mainly consists of a lexicon and a treebank: Lexeed (a Japanese Semantic Lexicon) and the Hinoki Treebank. Fundamental vocabulary selection is the first step in the construction of Lexeed. The vocabulary should include sufficient words to describe general concepts for self-expandability, and should not be prohibitively large to construct and maintain. There are two conventional methods for selecting fundamental vocabulary. The first is intuition-based selection by experts. This is the traditional method for making dictionaries. A weak point of this method is that the selection strongly depends on personal intuition. The second is corpus-based selection. This method is superior in objectivity to intuition-based selection, however, it is difficult to compile a sufficiently balanced corpora. We propose a psychologically-motivated selection method that adopts word familiarity as the selection criterion. Word familiarity is a rating that represents the familiarity of a word as a real number ranging from 1 (least familiar) to 7 (most familiar). We determined the word familiarity ratings statistically based on psychological experiments over 32 subjects. We selected about 30,000 words as the fundamental vocabulary, based on a minimum word familiarity threshold of 5. We also evaluated the vocabulary by comparing its word coverage with conventional intuition-based and corpus-based selection over dictionary definition sentences and novels, and demonstrated the superior coverage of our lexicon. Based on this, we conclude that the proposed method is superior to conventional methods for fundamental vocabulary selection.

  18. Selection on Moral Hazard in Health Insurance

    Science.gov (United States)

    Einav, Liran; Finkelstein, Amy; Ryan, Stephen; Schrimpf, Paul

    2012-01-01

    We use employee-level panel data from a single firm to explore the possibility that individuals may select insurance coverage in part based on their anticipated behavioral (“moral hazard”) response to insurance, a phenomenon we label “selection on moral hazard.” Using a model of plan choice and medical utilization, we present evidence of heterogeneous moral hazard as well as selection on it, and explore some of its implications. For example, we show that, at least in our context, abstracting from selection on moral hazard could lead to over-estimates of the spending reduction associated with introducing a high-deductible health insurance option. PMID:24748682

  19. Selection decisions among reindeer herders in Finland

    Directory of Open Access Journals (Sweden)

    Kirsi Muuttoranta

    2011-04-01

    Full Text Available Selection of breeding animals is a tool to improve the revenues in animal production. Information about selection practices and criteria are essential in assessing the possibilities for systematic selection schemes. Attitudes of reindeer herders towards use of selection in improving production were investigated by means of interviews. We interviewed the managers of reindeer herding cooperatives concerning their selection decisions. Fortyfive out of 56 managers answered to the semi-structured questionnaire. Among herding operations, selection of breeding animals was regarded by managers as critical for calf’s autumn weight and survival. The main selection criteria were calf’s health, vigour, body size and muscularity, dam or dam line, and maternal care. Hair quality and hair length were important as well, while such often quoted traits as antler characteristics, e.g. early shedding of antler velvet and thick antler bases, were unimportant. The results show that reindeer herders i acknowledge the importance and effects of selective breeding, and ii have empirical knowledge to list the most important selection criteria.

  20. Selective Photo-Initiated Electrophoretic Separator Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Physical Optics Corporation (POC) proposes to develop a Selective Photoinitiated Electrophoretic Separator (SPIES) System to address NASA's volatile gas separation...