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Sample records for partial inverse agonist

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

    NARCIS (Netherlands)

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

    1991-01-01

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

  2. AC-3933, a benzodiazepine partial inverse agonist, improves memory performance in MK-801-induced amnesia mouse model.

    Science.gov (United States)

    Hashimoto, Takashi; Iwamura, Yoshihiro

    2016-05-01

    AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N-methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK-801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

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

  4. Sulfoximines as potent RORγ inverse agonists.

    Science.gov (United States)

    Ouvry, Gilles; Bihl, Franck; Bouix-Peter, Claire; Christin, Olivier; Defoin-Platel, Claire; Deret, Sophie; Feret, Christophe; Froude, David; Hacini-Rachinel, Feriel; Harris, Craig S; Hervouet, Catherine; Lafitte, Guillaume; Luzy, Anne-Pascale; Musicki, Branislav; Orfila, Danielle; Parnet, Veronique; Pascau, Coralie; Pascau, Jonathan; Pierre, Romain; Raffin, Catherine; Rossio, Patricia; Spiesse, Delphine; Taquet, Nathalie; Thoreau, Etienne; Vatinel, Rodolphe; Vial, Emmanuel; Hennequin, Laurent F

    2018-05-01

    Progress in the identification of suitable RORγ inverse agonists as clinical candidates has been hampered by the high lipophilicity that seems required for high potency on this nuclear receptor. In this context, we decided to focus on the replacement of the hydroxymethyl group found on known modulators to determine if more polarity could be tolerated in this position. SAR of the replacement of this moiety is presented in this article leading to the identification of sulfoximine derivatives as potent modulators with pharmacological activity in the in vivo mouse Imiquimod psoriasis model. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2017-01-01

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

  6. Evaluation of partial beta-adrenoceptor agonist activity.

    Science.gov (United States)

    Lipworth, B J; Grove, A

    1997-01-01

    A partial beta-adrenoceptor (beta-AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a beta-AR agonist with higher intrinsic activity. In vivo partial beta-AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (beta 1/beta 2), inotropicity (beta 1) or peripheral vasodilatation and finger tremor (beta 2). beta-AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, beta-AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (beta 1) and potassium (beta 2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a beta-adrenoceptor blocker with partial beta 1-AR agonist activity compared with a beta-adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using beta-AR blocking drugs with partial beta 1-AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between beta 2-AR partial agonist activity and endogenous adrenergic activity. For predominantly beta 2-AR agonist such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly beta 2-AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. beta 2-AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether

  7. Nicotine receptor partial agonists for smoking cessation

    Directory of Open Access Journals (Sweden)

    Kate Cahill

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

  8. Nicotine receptor partial agonists for smoking cessation.

    Science.gov (United States)

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

    2012-04-18

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

  9. Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists.

    Science.gov (United States)

    Wang, Yonghui; Yang, Ting; Liu, Qian; Ma, Yingli; Yang, Liuqing; Zhou, Ling; Xiang, Zhijun; Cheng, Ziqiang; Lu, Sijie; Orband-Miller, Lisa A; Zhang, Wei; Wu, Qianqian; Zhang, Kathleen; Li, Yi; Xiang, Jia-Ning; Elliott, John D; Leung, Stewart; Ren, Feng; Lin, Xichen

    2015-09-01

    A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as RORγt inverse agonists was discovered. Binding mode analysis of a RORγt partial agonist (2c) revealed by co-crystal structure in RORγt LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the RORγt LBD. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 3m with a pIC50 of 8.0. Selected compounds in the series showed reasonable activity in Th17 cell differentiation assay as well as low intrinsic clearance in mouse liver microsomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2010-11-01

    Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility. © 2010 American Academy of Forensic Sciences.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-09-17

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

  12. Inverse problems for partial differential equations

    CERN Document Server

    Isakov, Victor

    2017-01-01

    This third edition expands upon the earlier edition by adding nearly 40 pages of new material reflecting the analytical and numerical progress in inverse problems in last 10 years. As in the second edition, the emphasis is on new ideas and methods rather than technical improvements. These new ideas include use of the stationary phase method in the two-dimensional elliptic problems and of multi frequencies\\temporal data to improve stability and numerical resolution. There are also numerous corrections and improvements of the exposition throughout. This book is intended for mathematicians working with partial differential equations and their applications, physicists, geophysicists, and financial, electrical, and mechanical engineers involved with nondestructive evaluation, seismic exploration, remote sensing, and various kinds of tomography. Review of the second edition: "The first edition of this excellent book appeared in 1998 and became a standard reference for everyone interested in analysis and numerics of...

  13. Blockade of alcohol's amnestic activity in humans by an alpha5 subtype benzodiazepine receptor inverse agonist.

    Science.gov (United States)

    Nutt, David J; Besson, Marie; Wilson, Susan J; Dawson, Gerard R; Lingford-Hughes, Anne R

    2007-12-01

    Alcohol produces many subjective and objective effects in man including pleasure, sedation, anxiolysis, plus impaired eye movements and memory. In human volunteers we have used a newly available GABA-A/benzodiazepine receptor inverse agonist that is selective for the alpha5 subtype (a5IA) to evaluate the role of this subtype in mediating these effects of alcohol on the brain. After pre-treatment with a5IA, we found almost complete blockade of the marked impairment caused by alcohol (mean breath concentration 150mg/100ml) of word list learning and partial but non-significant reversal of subjective sedation without effects on other measures such as intoxication, liking, and slowing of eye movements. This action was not due to alterations in alcohol kinetics and so provides the first proof of concept that selectively decreasing GABA-A receptor function at a specific receptor subtype can offset some actions of alcohol in humans. It also supports growing evidence for a key role of the alpha5 subtype in memory. Inverse agonists at other GABA-A receptor subtypes may prove able to reverse other actions of alcohol, and so offer a new approach to understanding the actions of alcohol in the human brain and in the treatment of alcohol related disorders in humans.

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

    Science.gov (United States)

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

    2017-09-01

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

  15. Inverse semigroups the theory of partial symmetries

    CERN Document Server

    Lawson, Mark V

    1998-01-01

    Symmetry is one of the most important organising principles in the natural sciences. The mathematical theory of symmetry has long been associated with group theory, but it is a basic premise of this book that there are aspects of symmetry which are more faithfully represented by a generalization of groups called inverse semigroups. The theory of inverse semigroups is described from its origins in the foundations of differential geometry through to its most recent applications in combinatorial group theory, and the theory tilings.

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

    Science.gov (United States)

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

    2006-02-14

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

  17. Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor.

    Science.gov (United States)

    Lin, Wenwei; Yang, Lei; Chai, Sergio C; Lu, Yan; Chen, Taosheng

    2016-01-27

    Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer cells to chemotherapeutic drugs. We recently reported a novel CAR inhibitor/inverse agonist CINPA1 (11). Here, we have obtained or designed 54 analogs of CINPA1 and used a time-resolved fluorescence resonance energy transfer (TR-FRET) assay to evaluate their CAR inhibition potency. Many of the 54 analogs showed CAR inverse agonistic activities higher than those of CINPA1, which has an IC50 value of 687 nM. Among them, 72 has an IC50 value of 11.7 nM, which is about 59-fold more potent than CINPA1 and over 10-fold more potent than clotrimazole (an IC50 value of 126.9 nM), the most potent CAR inverse agonist in a biochemical assay previously reported by others. Docking studies provide a molecular explanation of the structure-activity relationship (SAR) observed experimentally. To our knowledge, this effort is the first chemistry endeavor in designing and identifying potent CAR inverse agonists based on a novel chemical scaffold, leading to 72 as the most potent CAR inverse agonist so far. The 54 chemicals presented are novel and unique tools for characterizing CAR's function, and the SAR information gained from these 54 analogs could guide future efforts to develop improved CAR inverse agonists. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  18. Preclinical evaluation of SMM-189, a cannabinoid receptor 2-specific inverse agonist.

    Science.gov (United States)

    Presley, Chaela; Abidi, Ammaar; Suryawanshi, Satyendra; Mustafa, Suni; Meibohm, Bernd; Moore, Bob M

    2015-08-01

    Cannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune-related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3',5'-dichloro-2,6-dihydroxy-biphenyl-4-yl)-phenyl-methanone (SMM-189) and the characterization of the beneficial effects of SMM-189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM-189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM-189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM-189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.

  19. Generalized concentration addition: a method for examining mixtures containing partial agonists.

    Science.gov (United States)

    Howard, Gregory J; Webster, Thomas F

    2009-08-07

    Environmentally relevant toxic exposures often consist of simultaneous exposure to multiple agents. Methods to predict the expected outcome of such combinations are critical both to risk assessment and to an accurate judgment of whether combinations are synergistic or antagonistic. Concentration addition (CA) has commonly been used to assess the presence of synergy or antagonism in combinations of similarly acting chemicals, and to predict effects of combinations of such agents. CA has the advantage of clear graphical interpretation: Curves of constant joint effect (isoboles) must be negatively sloped straight lines if the mixture is concentration additive. However, CA cannot be directly used to assess combinations that include partial agonists, although such agents are of considerable interest. Here, we propose a natural extension of CA to a functional form that may be applied to mixtures including full agonists and partial agonists. This extended definition, for which we suggest the term "generalized concentration addition," encompasses linear isoboles with slopes of any sign. We apply this approach to the simple example of agents with dose-response relationships described by Hill functions with slope parameter n=1. The resulting isoboles are in all cases linear, with negative, zero and positive slopes. Using simple mechanistic models of ligand-receptor systems, we show that the same isobole pattern and joint effects are generated by modeled combinations of full and partial agonists. Special cases include combinations of two full agonists and a full agonist plus a competitive antagonist.

  20. Development of CINPA1 analogs as novel and potent inverse agonists of constitutive androstane receptor

    OpenAIRE

    Lin, Wenwei; Yang, Lei; Chai, Sergio C.; Lu, Yan; Chen, Taosheng

    2015-01-01

    Constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) are master regulators of endobiotic and xenobiotic metabolism and disposition. Because CAR is constitutively active in certain cellular contexts, inhibiting CAR might reduce drug-induced hepatotoxicity and resensitize drug-resistant cancer cells to chemotherapeutic drugs. We recently reported a novel CAR inhibitor/inverse agonist CINPA1 (11). Here, we have obtained or designed 54 analogs of CINPA1 and used a ti...

  1. Xamoterol, a new selective beta-1-adrenoceptor partial agonist, in the treatment of postural hypotension

    DEFF Research Database (Denmark)

    Mehlsen, J; Trap-Jensen, J

    1986-01-01

    Three patients severely disabled from postural hypotension were treated with xamoterol, a selective beta-1-adrenoceptor antagonist with a high degree of partial agonist activity. Oral treatment (200 mg b.i.d.) was chosen on the basis of the effects of acute intravenous administration of xamoterol...... and pindolol, a non-selective beta-adrenoceptor antagonist with partial agonist activity. In these patients pindolol had a predominantly antagonist effect, whereas xamoterol had a predominantly agonist effect after intravenous administration. Oral treatment was carried out with placebo control in a single......, supine). During the placebo period (2 weeks) heart rate decreased to pretreatment levels and mean blood pressure was reduced by only 14 mmHg. The patients reported substantial improvement in their condition during active medication. Xamoterol seems to be a useful alternative in the treatment of postural...

  2. High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist

    DEFF Research Database (Denmark)

    Holst, Birgitte; Cygankiewicz, Adam; Jensen, Tine Halkjaer

    2003-01-01

    Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake. By measuring inositol phosphate turnover or by using a reporter assay for transcriptional activity controlled by cAMP-responsive elements, the ghrelin receptor showed strong, ligand......-independent signaling in transfected COS-7 or human embryonic kidney 293 cells. Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further. In contrast, the low potency ghrelin antagonist, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P was surprisingly...... found to be a high potency (EC50 = 5.2 nm) full inverse agonist as it decreased the constitutive signaling of the ghrelin receptor down to that observed in untransfected cells. The homologous motilin receptor functioned as a negative control as it did not display any sign of constitutive activity...

  3. Anxiogenic properties of an inverse agonist selective for α3 subunit-containing GABAA receptors

    OpenAIRE

    Atack, John R; Hutson, Peter H; Collinson, Neil; Marshall, George; Bentley, Graham; Moyes, Christopher; Cook, Susan M; Collins, Ian; Wafford, Keith; McKernan, Ruth M; Dawson, Gerard R

    2005-01-01

    α3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABAA receptors containing an α3 rather than an α1, α2 or α5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of α3IA are most probably mediated by the α3 subtype.α3IA has good CNS penetration in rats and mice as measured using a [3H]Ro 15-1788 in vivo bi...

  4. A Novel Selective Inverse Agonist of the CB2 Receptor as a Radiolabeled Tool Compound for Kinetic Binding Studies.

    Science.gov (United States)

    Martella, Andrea; Sijben, Huub; Rufer, Arne C; Grether, Uwe; Fingerle, Juergen; Ullmer, Christoph; Hartung, Thomas; IJzerman, Adriaan P; van der Stelt, Mario; Heitman, Laura H

    2017-10-01

    The endocannabinoid system, and in particular the cannabinoid type 2 receptor (CB2R), raised the interest of many medicinal chemistry programs for its therapeutic relevance in several (patho)physiologic processes. However, the physico-chemical properties of tool compounds for CB2R (e.g., the radioligand [ 3 H]CP55,940) are not optimal, despite the research efforts in developing effective drugs to target this system. At the same time, the importance of drug-target binding kinetics is growing since the kinetic binding profile of a ligand may provide important insights for the resulting in vivo efficacy. In this context we synthesized and characterized [ 3 H]RO6957022, a highly selective CB2R inverse agonist, as a radiolabeled tool compound. In equilibrium and kinetic binding experiments [ 3 H]RO6957022 showed high affinity for human CB2R with fast association ( k on ) and moderate dissociation ( k off ) kinetics. To demonstrate the robustness of [ 3 H]RO6957022 binding, affinity studies were carried out for a wide range of CB2R reference ligands, spanning the range of full, partial, and inverse agonists. Finally, we used [ 3 H]RO6957022 to study the kinetic binding profiles (i.e., k on and k off values) of selected synthetic and endogenous (i.e., 2-arachidonoylglycerol, anandamide, and noladin ether) CB2R ligands by competition association experiments. All tested ligands, and in particular the endocannabinoids, displayed distinct kinetic profiles, shedding more light on their mechanism of action and the importance of association rates in the determination of CB2R affinity. Altogether, this study shows that the use of a novel tool compound, i.e., [ 3 H]RO6957022, can support the development of novel ligands with a repertoire of kinetic binding profiles for CB2R. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  5. Inverse agonist and neutral antagonist actions of synthetic compounds at an insect 5-HT1 receptor.

    Science.gov (United States)

    Troppmann, B; Balfanz, S; Baumann, A; Blenau, W

    2010-04-01

    5-Hydroxytryptamine (5-HT) has been shown to control and modulate many physiological and behavioural functions in insects. In this study, we report the cloning and pharmacological properties of a 5-HT(1) receptor of an insect model for neurobiology, physiology and pharmacology. A cDNA encoding for the Periplaneta americana 5-HT(1) receptor was amplified from brain cDNA. The receptor was stably expressed in HEK 293 cells, and the functional and pharmacological properties were determined in cAMP assays. Receptor distribution was investigated by RT-PCR and by immunocytochemistry using an affinity-purified polyclonal antiserum. The P. americana 5-HT(1) receptor (Pea5-HT(1)) shares pronounced sequence and functional similarity with mammalian 5-HT(1) receptors. Activation with 5-HT reduced adenylyl cyclase activity in a dose-dependent manner. Pea5-HT(1) was expressed as a constitutively active receptor with methiothepin acting as a neutral antagonist, and WAY 100635 as an inverse agonist. Receptor mRNA was present in various tissues including brain, salivary glands and midgut. Receptor-specific antibodies showed that the native protein was expressed in a glycosylated form in membrane samples of brain and salivary glands. This study marks the first pharmacological identification of an inverse agonist and a neutral antagonist at an insect 5-HT(1) receptor. The results presented here should facilitate further analyses of 5-HT(1) receptors in mediating central and peripheral effects of 5-HT in insects.

  6. SB265610 is an allosteric, inverse agonist at the human CXCR2 receptor

    Science.gov (United States)

    Bradley, ME; Bond, ME; Manini, J; Brown, Z; Charlton, SJ

    2009-01-01

    Background and purpose: In several previous studies, the C-X-C chemokine receptor (CXCR)2 antagonist 1-(2-bromo-phenyl)-3-(7-cyano-3H-benzotriazol-4-yl)-urea (SB265610) has been described as binding competitively with the endogenous agonist. This is in contrast to many other chemokine receptor antagonists, where the mechanism of antagonism has been described as allosteric. Experimental approach: To determine whether it displays a unique mechanism among the chemokine receptor antagonists, the mode of action of SB265610 was investigated at the CXCR2 receptor using radioligand and [35S]-GTPγS binding approaches in addition to chemotaxis of human neutrophils. Key results: In equilibrium saturation binding studies, SB265610 depressed the maximal binding of [125I]-interleukin-8 ([125I]-IL-8) without affecting the Kd. In contrast, IL-8 was unable to prevent binding of [3H]-SB265610. Kinetic binding experiments demonstrated that this was not an artefact of irreversible or slowly reversible binding. In functional experiments, SB265610 caused a rightward shift of the concentration-response curves to IL-8 and growth-related oncogene α, but also a reduction in maximal response elicited by each agonist. Fitting these data to an operational allosteric ternary complex model suggested that, once bound, SB265610 completely blocks receptor activation. SB265610 also inhibited basal [35S]-GTPγS binding in this preparation. Conclusions and implications: Taken together, these data suggest that SB265610 behaves as an allosteric inverse agonist at the CXCR2 receptor, binding at a region distinct from the agonist binding site to prevent receptor activation, possibly by interfering with G protein coupling. PMID:19422399

  7. Successful treatment of dopamine dysregulation syndrome with dopamine D2 partial agonist antipsychotic drug

    Directory of Open Access Journals (Sweden)

    Mizushima Jin

    2012-07-01

    Full Text Available Abstract Dopamine dysregulation syndrome (DDS consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson’s disease (PD. Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system.

  8. The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

    OpenAIRE

    Sirohi, Sunil; Dighe, Shveta V.; Madia, Priyanka A.; Yoburn, Byron C.

    2009-01-01

    Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was exa...

  9. Ghrelin receptor inverse agonists: identification of an active peptide core and its interaction epitopes on the receptor

    DEFF Research Database (Denmark)

    Holst, Birgitte; Lang, Manja; Brandt, Erik

    2006-01-01

    [D-Arg1,D-Phe5,D-Trp7,9,Leu11]Substance P functions as a low-potency antagonist but a high-potency full inverse agonist on the ghrelin receptor. Through a systematic deletion and substitution analysis of this peptide, the C-terminal carboxyamidated pentapeptide wFwLX was identified as the core...... structure, which itself displayed relatively low inverse agonist potency. Mutational analysis at 17 selected positions in the main ligand-binding crevice of the ghrelin receptor demonstrated that ghrelin apparently interacts only with residues in the middle part of the pocket [i.e., between transmembrane...... upon both AspII:20 and GluIII:09. The identified pharmacophore can possibly serve as the basis for targeted discovery of also nonpeptide inverse agonists for the ghrelin receptor....

  10. Antibodies against the melanocortin-4 receptor act as inverse agonists in vitro and in vivo.

    Science.gov (United States)

    Peter, Jean-Christophe; Nicholson, Janet R; Heydet, Déborah; Lecourt, Anne-Catherine; Hoebeke, Johan; Hofbauer, Karl G

    2007-06-01

    Functionally active antibodies (Abs) against central G-protein-coupled receptors have not yet been reported. We selected the hypothalamic melanocortin-4 receptor (MC4-R) as a target because of its crucial role in the regulation of energy homeostasis. A 15 amino acid sequence of the N-terminal (NT) domain was used as an antigen. This peptide showed functional activity in surface plasmon resonance experiments and in studies on HEK-293 cells overexpressing the human MC4-R (hMC4-R). Rats immunized against the NT peptide produced specific antibodies, which were purified and characterized in vitro. In HEK-293 cells, rat anti-NT Abs showed specific immunofluorescence labeling of hMC4-R. They reduced the production of cAMP under basal conditions and after stimulation with a synthetic MC4-R agonist. Rats immunized against the NT peptide developed a phenotype consistent with MC4-R blockade, that is, increased food intake and body weight, increased liver and fat pad weight, and elevated plasma triglycerides. In a separate experiment in rats, an increase in food intake could be produced after injection of purified Abs into the third ventricle. Similar results were obtained in rats injected with anti-NT Abs raised in rabbits. Our data show for the first time that active immunization of rats against the NT sequence of the MC4-R results in specific Abs, which appear to stimulate food intake by acting as inverse agonists in the hypothalamus.

  11. In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist.

    Science.gov (United States)

    Panayi, Fany; Sors, Aurore; Bert, Lionel; Martin, Brigitte; Rollin-Jego, Gaelle; Billiras, Rodolphe; Carrié, Isabelle; Albinet, Karine; Danober, Laurence; Rogez, Nathalie; Thomas, Jean-Yves; Pira, Luigi; Bertaina-Anglade, Valérie; Lestage, Pierre

    2017-05-15

    S 38093, a novel histamine H3 receptor inverse agonist, was tested in a series of neurochemical and behavioral paradigms designed to evaluate its procognitive and arousal properties. In intracerebral microdialysis studies performed in rats, S 38093 dose-dependently increased histamine extracellular levels in the prefrontal cortex and facilitated cholinergic transmission in the prefrontal cortex and hippocampus of rats after acute and chronic administration (10mg/kg i.p.). Acute oral administration of S 38093 at 0.1mg/kg significantly improved spatial working memory in rats in the Morris water maze test. The compound also displayed cognition enhancing properties in the two-trial object recognition task in rats, in a natural forgetting paradigm at 0.3 and 1mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3mg/kg p.o. The property of S 38093 to promote episodic memory was confirmed in a social recognition test in rats at 0.3 and 1mg/kg i.p. Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10mg/kg i.p., S 38093 significantly reduced slow wave sleep delta power and induced at the highest dose a delay in sleep latency. S 38093 at 10mg/kg p.o. also decreased the barbital-induced sleeping time in rats. Taken together these data indicate that S 38093, a novel H3 inverse agonist, displays cognition enhancing at low doses and arousal properties at higher doses in rodents. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Microstrip natural wave spectrum mathematical model using partial inversion method

    International Nuclear Information System (INIS)

    Pogarsky, S.A.; Litvinenko, L.N.; Prosvirnin, S.L.

    1995-01-01

    It is generally agreed that both microstrip lines itself and different discontinuities based on microstrips are the most difficult problem for accurate electrodynamic analysis. Over the last years much has been published about principles and accurate (or full wave) methods of microstrip lines investigations. The growing interest for this problem may be explained by the microstrip application in the millimeter-wave range for purpose of realizing interconnects and a variety of passive components. At these higher operating rating frequencies accurate component modeling becomes more critical. A creation, examination and experimental verification of the accurate method for planar electrodynamical structures natural wave spectrum investigations are the objects of this manuscript. The moment method with partial inversion operator method using may be considered as a basical way for solving this problem. This method is outlook for accurate analysis of different planar discontinuities in microstrip: such as step discontinuities, microstrip turns, Y- and X-junctions and etc., substrate space steps dielectric constants and other anisotropy types

  13. PPARγ partial agonist GQ-16 strongly represses a subset of genes in 3T3-L1 adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Milton, Flora Aparecida [Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília (Brazil); Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States); Cvoro, Aleksandra [Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States); Amato, Angelica A. [Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília (Brazil); Sieglaff, Douglas H.; Filgueira, Carly S.; Arumanayagam, Anithachristy Sigamani [Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States); Caro Alves de Lima, Maria do; Rocha Pitta, Ivan [Laboratório de Planejamento e Síntese de Fármacos – LPSF, Universidade Federal de Pernambuco (Brazil); Assis Rocha Neves, Francisco de [Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília (Brazil); Webb, Paul, E-mail: pwebb@HoustonMethodist.org [Genomic Medicine, Houston Methodist Research Institute, Houston, TX (United States)

    2015-08-28

    Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists that improve insulin resistance but trigger side effects such as weight gain, edema, congestive heart failure and bone loss. GQ-16 is a PPARγ partial agonist that improves glucose tolerance and insulin sensitivity in mouse models of obesity and diabetes without inducing weight gain or edema. It is not clear whether GQ-16 acts as a partial agonist at all PPARγ target genes, or whether it displays gene-selective actions. To determine how GQ-16 influences PPARγ activity on a gene by gene basis, we compared effects of rosiglitazone (Rosi) and GQ-16 in mature 3T3-L1 adipocytes using microarray and qRT-PCR. Rosi changed expression of 1156 genes in 3T3-L1, but GQ-16 only changed 89 genes. GQ-16 generally showed weak effects upon Rosi induced genes, consistent with partial agonist actions, but a subset of modestly Rosi induced and strongly repressed genes displayed disproportionately strong GQ-16 responses. PPARγ partial agonists MLR24 and SR1664 also exhibit disproportionately strong effects on transcriptional repression. We conclude that GQ-16 displays a continuum of weak partial agonist effects but efficiently represses some negatively regulated PPARγ responsive genes. Strong repressive effects could contribute to physiologic actions of GQ-16. - Highlights: • GQ-16 is an insulin sensitizing PPARγ ligand with reduced harmful side effects. • GQ-16 displays a continuum of weak partial agonist activities at PPARγ-induced genes. • GQ-16 exerts strong repressive effects at a subset of genes. • These inhibitor actions should be evaluated in models of adipose tissue inflammation.

  14. PPARγ partial agonist GQ-16 strongly represses a subset of genes in 3T3-L1 adipocytes

    International Nuclear Information System (INIS)

    Milton, Flora Aparecida; Cvoro, Aleksandra; Amato, Angelica A.; Sieglaff, Douglas H.; Filgueira, Carly S.; Arumanayagam, Anithachristy Sigamani; Caro Alves de Lima, Maria do; Rocha Pitta, Ivan; Assis Rocha Neves, Francisco de; Webb, Paul

    2015-01-01

    Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists that improve insulin resistance but trigger side effects such as weight gain, edema, congestive heart failure and bone loss. GQ-16 is a PPARγ partial agonist that improves glucose tolerance and insulin sensitivity in mouse models of obesity and diabetes without inducing weight gain or edema. It is not clear whether GQ-16 acts as a partial agonist at all PPARγ target genes, or whether it displays gene-selective actions. To determine how GQ-16 influences PPARγ activity on a gene by gene basis, we compared effects of rosiglitazone (Rosi) and GQ-16 in mature 3T3-L1 adipocytes using microarray and qRT-PCR. Rosi changed expression of 1156 genes in 3T3-L1, but GQ-16 only changed 89 genes. GQ-16 generally showed weak effects upon Rosi induced genes, consistent with partial agonist actions, but a subset of modestly Rosi induced and strongly repressed genes displayed disproportionately strong GQ-16 responses. PPARγ partial agonists MLR24 and SR1664 also exhibit disproportionately strong effects on transcriptional repression. We conclude that GQ-16 displays a continuum of weak partial agonist effects but efficiently represses some negatively regulated PPARγ responsive genes. Strong repressive effects could contribute to physiologic actions of GQ-16. - Highlights: • GQ-16 is an insulin sensitizing PPARγ ligand with reduced harmful side effects. • GQ-16 displays a continuum of weak partial agonist activities at PPARγ-induced genes. • GQ-16 exerts strong repressive effects at a subset of genes. • These inhibitor actions should be evaluated in models of adipose tissue inflammation

  15. Modulation of Autophagy by a Small Molecule Inverse Agonist of ERRα Is Neuroprotective

    Directory of Open Access Journals (Sweden)

    S. N. Suresh

    2018-04-01

    Full Text Available Mechanistic insights into aggrephagy, a selective basal autophagy process to clear misfolded protein aggregates, are lacking. Here, we report and describe the role of Estrogen Related Receptor α (ERRα, HUGO Gene Nomenclature ESRRA, new molecular player of aggrephagy, in keeping autophagy flux in check by inhibiting autophagosome formation. A screen for small molecule modulators for aggrephagy identified ERRα inverse agonist XCT 790, that cleared α-synuclein aggregates in an autophagy dependent, but mammalian target of rapamycin (MTOR independent manner. XCT 790 modulates autophagosome formation in an ERRα dependent manner as validated by siRNA mediated knockdown and over expression approaches. We show that, in a basal state, ERRα is localized on to the autophagosomes and upon autophagy induction by XCT 790, this localization is lost and is accompanied with an increase in autophagosome biogenesis. In a preclinical mouse model of Parkinson’s disease (PD, XCT 790 exerted neuroprotective effects in the dopaminergic neurons of nigra by inducing autophagy to clear toxic protein aggregates and, in addition, ameliorated motor co-ordination deficits. Using a chemical biology approach, we unrevealed the role of ERRα in regulating autophagy and can be therapeutic target for neurodegeneration.

  16. The non-biphenyl-tetrazole angiotensin AT1 receptor antagonist eprosartan is a unique and robust inverse agonist of the active state of the AT1 receptor.

    Science.gov (United States)

    Takezako, Takanobu; Unal, Hamiyet; Karnik, Sadashiva S; Node, Koichi

    2018-03-23

    Conditions such as hypertension and renal allograft rejection are accompanied by chronic, agonist-independent, signalling by angiotensin II AT 1 receptors. The current treatment paradigm for these diseases entails the preferred use of inverse agonist AT 1 receptor blockers (ARBs). However, variability in the inverse agonist activities of common biphenyl-tetrazole ARBs for the active state of AT 1 receptors often leads to treatment failure. Therefore, characterization of robust inverse agonist ARBs for the active state of AT 1 receptors is necessary. To identify the robust inverse agonist for active state of AT 1 receptors and its molecular mechanism, we performed site-directed mutagenesis, competition binding assay, inositol phosphate production assay and molecular modelling for both ground-state wild-type AT 1 receptors and active-state N111G mutant AT 1 receptors. Although candesartan and telmisartan exhibited weaker inverse agonist activity for N111G- compared with WT-AT 1 receptors, only eprosartan exhibited robust inverse agonist activity for both N111G- and WT- AT 1 receptors. Specific ligand-receptor contacts for candesartan and telmisartan are altered in the active-state N111G- AT 1 receptors compared with the ground-state WT-AT 1 receptors, suggesting an explanation of their attenuated inverse agonist activity for the active state of AT 1 receptors. In contrast, interactions between eprosartan and N111G-AT 1 receptors were not significantly altered, and the inverse agonist activity of eprosartan was robust. Eprosartan may be a better therapeutic option than other ARBs. Comparative studies investigating eprosartan and other ARBs for the treatment of diseases caused by chronic, agonist-independent, AT 1 receptor activation are warranted. © 2018 The British Pharmacological Society.

  17. Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis.

    Science.gov (United States)

    Ouvry, Gilles; Atrux-Tallau, Nicolas; Bihl, Franck; Bondu, Aline; Bouix-Peter, Claire; Carlavan, Isabelle; Christin, Olivier; Cuadrado, Marie-Josée; Defoin-Platel, Claire; Deret, Sophie; Duvert, Denis; Feret, Christophe; Forissier, Mathieu; Fournier, Jean-François; Froude, David; Hacini-Rachinel, Fériel; Harris, Craig Steven; Hervouet, Catherine; Huguet, Hélène; Lafitte, Guillaume; Luzy, Anne-Pascale; Musicki, Branislav; Orfila, Danielle; Ozello, Benjamin; Pascau, Coralie; Pascau, Jonathan; Parnet, Véronique; Peluchon, Guillaume; Pierre, Romain; Piwnica, David; Raffin, Catherine; Rossio, Patricia; Spiesse, Delphine; Taquet, Nathalie; Thoreau, Etienne; Vatinel, Rodolphe; Vial, Emmanuel; Hennequin, Laurent François

    2018-02-20

    With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28.

    Science.gov (United States)

    Hulshof, Janneke W; Vischer, Henry F; Verheij, Mark H P; Fratantoni, Silvina A; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

    2006-11-01

    G-protein coupled receptors encoded by viruses represent an unexplored class of potential drug targets. In this study, we describe the synthesis and pharmacological characterization of the first class of inverse agonists acting on the HCMV-encoded receptor US28. It is shown that replacement of the 4-hydroxy group of lead compound 1 with a methylamine group results in a significant 6-fold increase in affinity. Interestingly, increasing the rigidity of the spacer by the introduction of a double bond also leads to a significant increase in binding affinity compared to 1. These novel inverse agonists serve as valuable tools to elucidate the role of constitutive signaling in the pathogenesis of viral infection and may have therapeutic potential as leads for new antiviral drugs.

  19. Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28.

    Science.gov (United States)

    Hulshof, Janneke W; Casarosa, Paola; Menge, Wiro M P B; Kuusisto, Leena M S; van der Goot, Henk; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

    2005-10-06

    US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in a constitutively active manner. Recently, we identified 1 [5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile] as the first reported nonpeptidergic inverse agonist for a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibit the viral entry of HIV-1. In this study we describe the synthesis of 1 and several of its analogues and unique structure-activity relationships for this first class of small-molecule ligands for the chemokine receptor US28. Moreover, the compounds have been pharmacologically characterized as inverse agonists on US28. By modification of lead structure 1, it is shown that a 4-phenylpiperidine moiety is essential for affinity and activity. Other structural features of 1 are shown to be of less importance. These compounds define the first SAR of ligands on a viral GPCR (US28) and may therefore serve as important tools to investigate the significance of US28-mediated constitutive activity during viral infection.

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

    Science.gov (United States)

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

    2018-02-01

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

  1. Reduction in lipophilicity improved the solubility, plasma–protein binding, and permeability of tertiary sulfonamide RORc inverse agonists

    Energy Technology Data Exchange (ETDEWEB)

    Fauber, Benjamin P.; René, Olivier; de Leon Boenig, Gladys; Burton, Brenda; Deng, Yuzhong; Eidenschenk, Céline; Everett, Christine; Gobbi, Alberto; Hymowitz, Sarah G.; Johnson, Adam R.; La, Hank; Liimatta, Marya; Lockey, Peter; Norman, Maxine; Ouyang, Wenjun; Wang, Weiru; Wong, Harvey (Genentech); (Argenta)

    2014-08-01

    Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma–protein unbound fraction and improvements in cellular permeability and aqueous solubility.

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  3. Reconstruction Methods for Inverse Problems with Partial Data

    DEFF Research Database (Denmark)

    Hoffmann, Kristoffer

    This thesis presents a theoretical and numerical analysis of a general mathematical formulation of hybrid inverse problems in impedance tomography. This includes problems from several existing hybrid imaging modalities such as Current Density Impedance Imaging, Magnetic Resonance Electrical...... Impedance Tomography, and Ultrasound Modulated Electrical Impedance Tomography. After giving an introduction to hybrid inverse problems in impedance tomography and the mathematical tools that facilitate the related analysis, we explain in detail the stability properties associated with the classification...... of a linearised hybrid inverse problem. This is done using pseudo-differential calculus and theory for overdetermined boundary value problem. Using microlocal analysis we then present novel results on the propagation of singularities, which give a precise description of the distinct features of solutions...

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

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  5. Identification of PPARgamma partial agonists of natural origin (II: in silico prediction in natural extracts with known antidiabetic activity.

    Directory of Open Access Journals (Sweden)

    Laura Guasch

    Full Text Available BACKGROUND: Natural extracts have played an important role in the prevention and treatment of diseases and are important sources for drug discovery. However, to be effectively used in these processes, natural extracts must be characterized through the identification of their active compounds and their modes of action. METHODOLOGY/PRINCIPAL FINDINGS: From an initial set of 29,779 natural products that are annotated with their natural source and using a previously developed virtual screening procedure (carefully validated experimentally, we have predicted as potential peroxisome proliferators-activated receptor gamma (PPARγ partial agonists 12 molecules from 11 extracts known to have antidiabetic activity. Six of these molecules are similar to molecules with described antidiabetic activity but whose mechanism of action is unknown. Therefore, it is plausible that these 12 molecules could be the bioactive molecules responsible, at least in part, for the antidiabetic activity of the extracts containing them. In addition, we have also identified as potential PPARγ partial agonists 10 molecules from 16 plants with undescribed antidiabetic activity but that are related (i.e., they are from the same genus to plants with known antidiabetic properties. None of the 22 molecules that we predict as PPARγ partial agonists show chemical similarity with a group of 211 known PPARγ partial agonists obtained from the literature. CONCLUSIONS/SIGNIFICANCE: Our results provide a new hypothesis about the active molecules of natural extracts with antidiabetic properties and their mode of action. We also suggest plants with undescribed antidiabetic activity that may contain PPARγ partial agonists. These plants represent a new source of potential antidiabetic extracts. Consequently, our work opens the door to the discovery of new antidiabetic extracts and molecules that can be of use, for instance, in the design of new antidiabetic drugs or functional foods focused

  6. Progress in the development of histamine H3 receptor antagonists/inverse agonists: a patent review (2013-2017).

    Science.gov (United States)

    Łażewska, Dorota; Kieć-Kononowicz, Katarzyna

    2018-03-01

    Since years, ligands blocking histamine H 3 receptor (H 3 R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H 3 R antagonists/inverse agonists. Some of them have reached to clinical trials. Areas covered: Patent applications from January 2013 to September 2017 and the most important topics connected with H 3 R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials. Expert opinion: The research interest in histamine H 3 R field is still high although the number of patent applications has decreased during the past 4 years (around 20 publications). Complexity of histamine H 3 R biology e.g. many isoforms, constitutive activity, heteromerization with other receptors (dopamine D 2 , D 1 , adenosine A 2A ) and pharmacology make not easy realization and evaluation of therapeutic potential of anti-H 3 R ligands. First results from clinical trials have verified potential utility of histamine H 3 R antagonist/inverse agonists in some diseases. However, more studies are necessary for better understanding of an involvement of the histaminergic system in CNS-related disorders and helping more ligands approach to clinical trials and the market. Lists of abbreviations: hAChEI - human acetylcholinesterase inhibitor; hBuChEI - human butyrylcholinesterase inhibitor; hMAO - human monoamine oxidase; MAO - monoamine oxidase.

  7. Preliminary effects of pagoclone, a partial GABAA agonist, on neuropsychological performance

    Directory of Open Access Journals (Sweden)

    Angela F Caveney

    2008-03-01

    Full Text Available Angela F Caveney1, Bruno Giordani1, George M Haig21Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; 2Neurosciences Development, Abbott Laboratories, Abbott Park, IL, USAAbstract: Pagoclone is a novel cyclopyrrolone that acts as a partial GABAA receptor agonist. Preclinical studies suggest that pagoclone may have clinical utility as an anxiolytic agent, as well as a reduced incidence of side-effects. The present study was conducted to determine whether pagoclone would affect healthy individuals’ performances on neuropsychological measures as a function of dose within the projected therapeutic range. Twelve healthy adult subjects were randomly assigned to dosage groups in a 3-way crossover study. Participants were administered neuropsychological measures six hours following dosing on Day 1 and Day 6 of administration of the drug. Dose effects were noted on measures of alertness, learning, and memory and movement time. Significant effects were also noted on measures of alertness, learning and memory, information processing and psychomotor speed. Overall, the results of this small, preliminary study do not support a finding of behavioral toxicity for these doses of pagoclone. Rather, a pattern was found of transient and mild negative effects on learning and memory scores at the highest dose administered, though these changes were small and no longer evident by the sixth day of use.Keywords: pagoclone, cyclopyrrolone, neuropsychological, memory, generalized anxiety disorder

  8. The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of analgesia and toxicity.

    Science.gov (United States)

    Sirohi, Sunil; Dighe, Shveta V; Madia, Priyanka A; Yoburn, Byron C

    2009-08-01

    Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was examined. First, the potency of two opioid inverse agonists (naltrexone and naloxone) and a neutral antagonist (6beta-naltrexol) to antagonize fentanyl-induced analgesia and lethality was determined. The order of potency to block analgesia was naltrexone > naloxone > 6beta-naltrexol (17, 4, 1), which was similar to that to block lethality (13, 2, 1). Next, the antagonists were compared using withdrawal jumping in fentanyl-dependent mice. The order of potency to precipitate withdrawal jumping was naltrexone > naloxone 6beta-naltrexol (1107, 415, 1). The relative potencies to precipitate withdrawal for the inverse agonists compared with the neutral antagonist were dramatically different from that for antagonism of analgesia and lethality. Finally, the effect of 6beta-naltrexol pretreatment on naloxone-precipitated jumping was determined in morphine and fentanyl-dependent mice. 6beta-Naltrexol pretreatment decreased naloxone precipitated withdrawal, indicating that 6beta-naltrexol is a neutral antagonist. These data demonstrate that inverse agonists and neutral antagonists have generally comparable potencies to block opioid analgesia and lethality, whereas the neutral opioid antagonist is substantially less potent in precipitating opioid withdrawal. These results support suggestions that neutral antagonists may have advantages over inverse agonists in the management of opioid overdose.

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

    Science.gov (United States)

    Lam, Sum; Patel, Priti N

    2007-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Marcelo Vizoná Liberato

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

  11. Collage-based approaches for elliptic partial differential equations inverse problems

    Science.gov (United States)

    Yodzis, Michael; Kunze, Herb

    2017-01-01

    The collage method for inverse problems has become well-established in the literature in recent years. Initial work developed a collage theorem, based upon Banach's fixed point theorem, for treating inverse problems for ordinary differential equations (ODEs). Amongst the subsequent work was a generalized collage theorem, based upon the Lax-Milgram representation theorem, useful for treating inverse problems for elliptic partial differential equations (PDEs). Each of these two different approaches can be applied to elliptic PDEs in one space dimension. In this paper, we explore and compare how the two different approaches perform for the estimation of the diffusivity for a steady-state heat equation.

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

    Science.gov (United States)

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

    2017-04-01

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

  13. Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28

    NARCIS (Netherlands)

    Hulshof, Janneke W; Casarosa, Paola; Menge, Wiro M P B; Kuusisto, Leena M S; van der Goot, Henk; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

    2005-01-01

    US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in a constitutively active manner. Recently, we identified 1 [5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile] as the first reported nonpeptidergic inverse agonist for a viral-encoded

  14. A model reduction approach to numerical inversion for a parabolic partial differential equation

    International Nuclear Information System (INIS)

    Borcea, Liliana; Druskin, Vladimir; Zaslavsky, Mikhail; Mamonov, Alexander V

    2014-01-01

    We propose a novel numerical inversion algorithm for the coefficients of parabolic partial differential equations, based on model reduction. The study is motivated by the application of controlled source electromagnetic exploration, where the unknown is the subsurface electrical resistivity and the data are time resolved surface measurements of the magnetic field. The algorithm presented in this paper considers inversion in one and two dimensions. The reduced model is obtained with rational interpolation in the frequency (Laplace) domain and a rational Krylov subspace projection method. It amounts to a nonlinear mapping from the function space of the unknown resistivity to the small dimensional space of the parameters of the reduced model. We use this mapping as a nonlinear preconditioner for the Gauss–Newton iterative solution of the inverse problem. The advantage of the inversion algorithm is twofold. First, the nonlinear preconditioner resolves most of the nonlinearity of the problem. Thus the iterations are less likely to get stuck in local minima and the convergence is fast. Second, the inversion is computationally efficient because it avoids repeated accurate simulations of the time-domain response. We study the stability of the inversion algorithm for various rational Krylov subspaces, and assess its performance with numerical experiments. (paper)

  15. A model reduction approach to numerical inversion for a parabolic partial differential equation

    Science.gov (United States)

    Borcea, Liliana; Druskin, Vladimir; Mamonov, Alexander V.; Zaslavsky, Mikhail

    2014-12-01

    We propose a novel numerical inversion algorithm for the coefficients of parabolic partial differential equations, based on model reduction. The study is motivated by the application of controlled source electromagnetic exploration, where the unknown is the subsurface electrical resistivity and the data are time resolved surface measurements of the magnetic field. The algorithm presented in this paper considers inversion in one and two dimensions. The reduced model is obtained with rational interpolation in the frequency (Laplace) domain and a rational Krylov subspace projection method. It amounts to a nonlinear mapping from the function space of the unknown resistivity to the small dimensional space of the parameters of the reduced model. We use this mapping as a nonlinear preconditioner for the Gauss-Newton iterative solution of the inverse problem. The advantage of the inversion algorithm is twofold. First, the nonlinear preconditioner resolves most of the nonlinearity of the problem. Thus the iterations are less likely to get stuck in local minima and the convergence is fast. Second, the inversion is computationally efficient because it avoids repeated accurate simulations of the time-domain response. We study the stability of the inversion algorithm for various rational Krylov subspaces, and assess its performance with numerical experiments.

  16. Differential effects of beta-adrenoceptor partial agonists in patients with postural hypotension

    DEFF Research Database (Denmark)

    Mehlsen, J; Stadeager, C; Trap-Jensen, J

    1993-01-01

    patients with postural hypotension of different aetiologies. Blood pressure, heart rate and stroke volume were measured in the supine and head-up tilted positions. Left ventricular ejection fraction (LVEF) was measured in the supine position, and vascular resistance, left ventricular volume, and left.......min-1 and LVEF from 0.57 to 0.52, and reduced mean arterial blood pressure from 103 mm Hg to 93 mm Hg. Xamoterol showed beta-adrenoceptor agonistic effects in the supine position through increments in heart rate from 72 to 90 beats.min-1 and LVEF from 0.58 to 0.66, and raised mean arterial blood...... pressure from 108 to 123 mm Hg. It is concluded that the degree of agonist activity of a beta-adrenergic agent is of importance if it is given to a patient with postural hypotension....

  17. HISTAMINE H3 RECEPTOR INVERSE AGONISTS ON COGNITIVE AND MOTOR PROCESSES: RELEVANCE TO ALZHEIMER’S DISEASE, ADHD, SCHIZOPHRENIA AND DRUG ABUSE

    Directory of Open Access Journals (Sweden)

    Divya eVohora

    2012-10-01

    Full Text Available Histamine H3 receptor antagonists/ inverse agonists possess potential to treat diverse disease states of the central nervous system (CNS. Cognitive dysfunction and motor impairments are the hallmark of multifarious neurodegenerative and/or psychiatric disorders. This review presents the various neurobiological/ neurochemical evidences available so far following H3 receptor inverse agonists/ antagonists in the pathophysiology of Alzheimer’s disease (AD, attention-deficit hyperactivity disorder (ADHD, schizophrenia and drug abuse each of which is accompanied by deficits of some aspects of cognitive and/or motor functions. Whether the H3 receptor inverse agonism modulates the neurochemical basis underlying the disease condition or affects only the cognitive/motor component of the disease process is discussed with the aim to provide a rationale for their use in diverse disease states that are interlinked and are accompanied by some common motor, cognitive and attentional deficits.

  18. Inverse agonist-like action of cadmium on G-protein-gated inward-rectifier K+ channels

    International Nuclear Information System (INIS)

    Inanobe, Atsushi; Matsuura, Takanori; Nakagawa, Atsushi; Kurachi, Yoshihisa

    2011-01-01

    Highlights: → We examined allosteric control of K + channel gating. → We identified a high-affinity site for Cd 2+ to inhibit Kir3.2 activity. → The 6-coordination geometry supports the binding. → Cd 2+ inhibits Kir3.2 by trapping the conformation in the closed state. -- Abstract: The gate at the pore-forming domain of potassium channels is allosterically controlled by a stimulus-sensing domain. Using Cd 2+ as a probe, we examined the structural elements responsible for gating in an inward-rectifier K + channel (Kir3.2). One of four endogenous cysteines facing the cytoplasm contributes to a high-affinity site for inhibition by internal Cd 2+ . Crystal structure of its cytoplasmic domain in complex with Cd 2+ reveals that octahedral coordination geometry supports the high-affinity binding. This mode of action causes the tethering of the N-terminus to CD loop in the stimulus-sensing domain, suggesting that their conformational changes participate in gating and Cd 2+ inhibits Kir3.2 by trapping the conformation in the closed state like 'inverse agonist'.

  19. Inverse agonist-like action of cadmium on G-protein-gated inward-rectifier K{sup +} channels

    Energy Technology Data Exchange (ETDEWEB)

    Inanobe, Atsushi, E-mail: inanobe@pharma2.med.osaka-u.ac.jp [Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka (Japan); Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka (Japan); Matsuura, Takanori [Laboratory of Protein Informatics, Institute for Protein Research, Osaka University, Osaka (Japan); Nakagawa, Atsushi [Laboratory of Supramolecular Crystallography, Institute for Protein Research, Osaka University, Osaka (Japan); Kurachi, Yoshihisa, E-mail: ykurachi@pharma2.med.osaka-u.ac.jp [Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka (Japan); Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka (Japan)

    2011-04-08

    Highlights: {yields} We examined allosteric control of K{sup +} channel gating. {yields} We identified a high-affinity site for Cd{sup 2+} to inhibit Kir3.2 activity. {yields} The 6-coordination geometry supports the binding. {yields} Cd{sup 2+} inhibits Kir3.2 by trapping the conformation in the closed state. -- Abstract: The gate at the pore-forming domain of potassium channels is allosterically controlled by a stimulus-sensing domain. Using Cd{sup 2+} as a probe, we examined the structural elements responsible for gating in an inward-rectifier K{sup +} channel (Kir3.2). One of four endogenous cysteines facing the cytoplasm contributes to a high-affinity site for inhibition by internal Cd{sup 2+}. Crystal structure of its cytoplasmic domain in complex with Cd{sup 2+} reveals that octahedral coordination geometry supports the high-affinity binding. This mode of action causes the tethering of the N-terminus to CD loop in the stimulus-sensing domain, suggesting that their conformational changes participate in gating and Cd{sup 2+} inhibits Kir3.2 by trapping the conformation in the closed state like 'inverse agonist'.

  20. Structural, electronic and magnetic properties of partially inverse spinel CoFe2O4: a first-principles study

    International Nuclear Information System (INIS)

    Hou, Y H; Liu, Z W; Yu, H Y; Zhong, X C; Qiu, W Q; Zeng, D C; Wen, L S; Zhao, Y J

    2010-01-01

    Partially inverse spinel CoFe 2 O 4 , which may be prepared through various heat treatments, differs remarkably from the ideal inverse spinel in many properties. The structure of partially inverse spinel CoFe 2 O 4 as well as its electronic and magnetic properties through a systemic theoretical calculation of (Co 1-x Fe x ) Tet (Co x Fe 2-x ) Oct O 4 (x = 0, 0.25, 0.5, 0.75 and 1.0) have been investigated by the generalized gradient approximation (GGA) + U approach. It is found that the Co and Fe ions prefer their high spin configurations with higher spin moments at octahedral sites in all the studied cases, in line with experimental observations. The Co ions at the octahedral sites favour being far away from each other in the partial inverse spinels, which also show half metallicity at certain inversion degrees.

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

    Directory of Open Access Journals (Sweden)

    Linda J Bristow

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

  2. Molecular interactions of agonist and inverse agonist ligands at serotonin 5-HT2C G protein-coupled receptors: computational ligand docking and molecular dynamics studies validated by experimental mutagenesis results

    Science.gov (United States)

    Córdova-Sintjago, Tania C.; Liu, Yue; Booth, Raymond G.

    2015-02-01

    To understand molecular determinants for ligand activation of the serotonin 5-HT2C G protein-coupled receptor (GPCR), a drug target for obesity and neuropsychiatric disorders, a 5-HT2C homology model was built according to an adrenergic β2 GPCR (β2AR) structure and validated using a 5-HT2B GPCR crystal structure. The models were equilibrated in a simulated phosphatidyl choline membrane for ligand docking and molecular dynamics studies. Ligands included (2S, 4R)-(-)-trans-4-(3'-bromo- and trifluoro-phenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalene-2-amine (3'-Br-PAT and 3'-CF3-PAT), a 5-HT2C agonist and inverse agonist, respectively. Distinct interactions of 3'-Br-PAT and 3'-CF3-PAT at the wild-type (WT) 5-HT2C receptor model were observed and experimental 5-HT2C receptor mutagenesis studies were undertaken to validate the modelling results. For example, the inverse agonist 3'-CF3-PAT docked deeper in the WT 5-HT2C binding pocket and altered the orientation of transmembrane helices (TM) 6 in comparison to the agonist 3'-Br-PAT, suggesting that changes in TM orientation that result from ligand binding impact function. For both PATs, mutation of 5-HT2C residues S3.36, T3.37, and F5.47 to alanine resulted in significantly decreased affinity, as predicted from modelling results. It was concluded that upon PAT binding, 5-HT2C residues T3.37 and F5.47 in TMs 3 and 5, respectively, engage in inter-helical interactions with TMs 4 and 6, respectively. The movement of TMs 5 and 6 upon agonist and inverse agonist ligand binding observed in the 5-HT2C receptor modelling studies was similar to movements reported for the activation and deactivation of the β2AR, suggesting common mechanisms among aminergic neurotransmitter GPCRs.

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

    DEFF Research Database (Denmark)

    Tonstad, Serena; Holme, Ingar; Tønnesen, Philip

    2011-01-01

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

  4. Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189.

    Science.gov (United States)

    Reiner, Anton; Heldt, Scott A; Presley, Chaela S; Guley, Natalie H; Elberger, Andrea J; Deng, Yunping; D'Surney, Lauren; Rogers, Joshua T; Ferrell, Jessica; Bu, Wei; Del Mar, Nobel; Honig, Marcia G; Gurley, Steven N; Moore, Bob M

    2014-12-31

    We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50-60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50-60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI.

  5. Motor, Visual and Emotional Deficits in Mice after Closed-Head Mild Traumatic Brain Injury Are Alleviated by the Novel CB2 Inverse Agonist SMM-189

    Directory of Open Access Journals (Sweden)

    Anton Reiner

    2014-12-01

    Full Text Available We have developed a focal blast model of closed-head mild traumatic brain injury (TBI in mice. As true for individuals that have experienced mild TBI, mice subjected to 50–60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2, we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50–60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI.

  6. (11)C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists.

    Science.gov (United States)

    Van Laere, Koenraad J; Sanabria-Bohórquez, Sandra M; Mozley, David P; Burns, Donald H; Hamill, Terence G; Van Hecken, Anne; De Lepeleire, Inge; Koole, Michel; Bormans, Guy; de Hoon, Jan; Depré, Marleen; Cerchio, Kristine; Plalcza, John; Han, Lingling; Renger, John; Hargreaves, Richard J; Iannone, Robert

    2014-01-01

    The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. Using PET and a novel high-affinity and selective radioligand (11)C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. The mean effective dose for (11)C-MK-8278 was 5.4 ± 1.1 μSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses. (11)C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules.

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

    Science.gov (United States)

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

    2015-03-06

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

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  9. Analysis of pumping tests of partially penetrating wells in an unconfined aquifer using inverse numerical optimization

    Science.gov (United States)

    Hvilshøj, S.; Jensen, K. H.; Barlebo, H. C.; Madsen, B.

    1999-08-01

    Inverse numerical modeling was applied to analyze pumping tests of partially penetrating wells carried out in three wells established in an unconfined aquifer in Vejen, Denmark, where extensive field investigations had previously been carried out, including tracer tests, mini-slug tests, and other hydraulic tests. Drawdown data from multiple piezometers located at various horizontal and vertical distances from the pumping well were included in the optimization. Horizontal and vertical hydraulic conductivities, specific storage, and specific yield were estimated, assuming that the aquifer was either a homogeneous system with vertical anisotropy or composed of two or three layers of different hydraulic properties. In two out of three cases, a more accurate interpretation was obtained for a multi-layer model defined on the basis of lithostratigraphic information obtained from geological descriptions of sediment samples, gammalogs, and flow-meter tests. Analysis of the pumping tests resulted in values for horizontal hydraulic conductivities that are in good accordance with those obtained from slug tests and mini-slug tests. Besides the horizontal hydraulic conductivity, it is possible to determine the vertical hydraulic conductivity, specific yield, and specific storage based on a pumping test of a partially penetrating well. The study demonstrates that pumping tests of partially penetrating wells can be analyzed using inverse numerical models. The model used in the study was a finite-element flow model combined with a non-linear regression model. Such a model can accommodate more geological information and complex boundary conditions, and the parameter-estimation procedure can be formalized to obtain optimum estimates of hydraulic parameters and their standard deviations.

  10. Ciproxifan, a histamine H{sub 3} receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Cheng-Wei; Lin, Tzu-Yu [Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan (China); Department of Mechanical Engineering, Yuan Ze University, Taoyuan 320, Taiwan (China); Chang, Chia-Ying [Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan (China); Department of Chemistry, Fu Jen Catholic University, No. 510, Chung-Cheng Road, Hsin-Chuang District, New Taipei City 24205, Taiwan (China); Huang, Shu-Kuei [Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan (China); Wang, Su-Jane, E-mail: med0003@mail.fju.edu.tw [School of Medicine, Fu Jen Catholic University, No. 510, Chung-Cheng Rd., Hsin-Chuang, New Taipei 24205, Taiwan (China); Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan City, Taiwan (China)

    2017-03-15

    Ciproxifan is an H{sub 3} receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca{sup 2+}-dependent glutamate release and cytosolic Ca{sup 2+} concentration elevation but did not affect the membrane potential. The inhibitory effect of ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Ca{sub v}2.2 (N-type) and Ca{sub v}2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was not affected by the intracellular Ca{sup 2+}-release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A{sub 2} (PLA{sub 2}) inhibitor OBAA, prostaglandin E{sub 2} (PGE{sub 2}), PGE2 subtype 2 (EP{sub 2}) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that ciproxifan, acting through the blockade of Gi/Go protein-coupled H{sub 3} receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca{sup 2+} entry by diminishing PLA{sub 2}/PGE{sub 2}/EP{sub 2} receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release. - Highlights: • Ciproxifan presynaptically reduces glutamate release in the hippocampus in vitro. • Decrease in voltage-dependent Ca{sup 2+} influx is involved. • A role for the PLA{sub 2}/PGE{sub 2}/EP{sub 2} pathway in the action of

  11. A dynamical regularization algorithm for solving inverse source problems of elliptic partial differential equations

    Science.gov (United States)

    Zhang, Ye; Gong, Rongfang; Cheng, Xiaoliang; Gulliksson, Mårten

    2018-06-01

    This study considers the inverse source problem for elliptic partial differential equations with both Dirichlet and Neumann boundary data. The unknown source term is to be determined by additional boundary conditions. Unlike the existing methods found in the literature, which usually employ the first-order in time gradient-like system (such as the steepest descent methods) for numerically solving the regularized optimization problem with a fixed regularization parameter, we propose a novel method with a second-order in time dissipative gradient-like system and a dynamical selected regularization parameter. A damped symplectic scheme is proposed for the numerical solution. Theoretical analysis is given for both the continuous model and the numerical algorithm. Several numerical examples are provided to show the robustness of the proposed algorithm.

  12. ImprimatinC1, a novel plant immune-priming compound, functions as a partial agonist of salicylic acid.

    Science.gov (United States)

    Noutoshi, Yoshiteru; Jikumaru, Yusuke; Kamiya, Yuji; Shirasu, Ken

    2012-01-01

    Plant activators are agrochemicals that protect crops from pathogens. They confer durable resistance to a broad range of diseases by activating intrinsic immune mechanisms in plants. To obtain leads regarding useful compounds, we have screened a chemical library using an established method that allows selective identification of immune-priming compounds. Here, we report the characterisation of one of the isolated chemicals, imprimatinC1, and its structural derivative imprimatinC2. ImprimatinC1 functions as a weak analogue of salicylic acid (SA) and activates the expression of defence-related genes. However, it lacks antagonistic activity toward jasmonic acid. Structure-activity relationship analysis suggests that imprimatinC1 and C2 can be metabolised to 4-chlorobenzoic acid and 3,4-chlorobenzoic acid, respectively, to function in Arabidopsis. We also found that imprimatinC1 and C2 and their potential functional metabolites acted as partial agonists of SA. Thus, imprimatinC compounds could be useful tools for dissecting SA-dependent signal transduction pathways.

  13. In vitro phototoxic potential and photochemical properties of imidazopyridine derivative: a novel 5-HT4 partial agonist.

    Science.gov (United States)

    Onoue, Satomi; Igarashi, Naoko; Yamauchi, Yukinori; Kojima, Takashi; Murase, Noriaki; Zhou, Yu; Yamada, Shizuo; Tsuda, Yoshiko

    2008-10-01

    Drug-induced phototoxic skin responses have been recognized as undesirable side effects, and as we previously proposed the determination of reactive oxygen species (ROS) from photo-irradiated compounds can be effective for the prediction of phototoxic potential. In this investigation, we evaluated the photosensitizing properties of imidazopyridine derivative, a novel 5-HT(4) partial agonist, using ROS assay and several analytical/biochemical techniques. Exposure of the compound to simulated sunlight resulted in the significant production of singlet oxygen, which is indicative of its phototoxic potential. In practice, an imidazopyridine derivative under UVA/B light exposure also showed significant photodegradation and even photobiochemical events; peroxidation of fatty acid and genetic damage after DNA-binding, which are considered as causative agents for phototoxic dermatitis. Interestingly, both photodegradation and lipoperoxidation were dramatically attenuated by the addition of radical scavengers, especially singlet oxygen quenchers, suggesting the possible involvement of ROS generation in the phototoxic pathways. In the 3T3 neutral red uptake phototoxicity test, imidazopyridine derivative also showed the phototoxic effect on 3T3 mouse fibroblast cells. These results suggest the phototoxic risk of newly synthesized imidazopyridine derivative and also verify the usefulness of ROS assay for phototoxicity prediction. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association

  14. Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys.

    Science.gov (United States)

    Banks, Matthew L

    2016-08-01

    Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. Behavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10mg/kg/day, intramuscular) treatment periods. Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights

  15. Inversions

    Science.gov (United States)

    Brown, Malcolm

    2009-01-01

    Inversions are fascinating phenomena. They are reversals of the normal or expected order. They occur across a wide variety of contexts. What do inversions have to do with learning spaces? The author suggests that they are a useful metaphor for the process that is unfolding in higher education with respect to education. On the basis of…

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

    Science.gov (United States)

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

    2007-03-01

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

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

    Science.gov (United States)

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

    2003-01-01

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

  18. Development of a novel severe triple allergen asthma model in mice which is resistant to dexamethasone and partially resistant to TLR7 and TLR9 agonist treatment.

    Directory of Open Access Journals (Sweden)

    Matthias J Duechs

    Full Text Available Severe asthma is characterised by persistent inflammation, hyperreactivity and remodeling of the airways. No efficient treatment is available, this is particularly the case for steroid resistant phenotypes. Our aim therefore was to develop a preclinical model showing characteristics of severe human asthma including steroid insensitivity. Mice were first sensitized with ovalbumin, extracts of cockroach or house dust mite followed by a challenge period of seven weeks. Further to this, an additional group of mice was sensitized with all three allergens and then challenged with allergen alternating weekly between allergens. All three allergens applied separately to the mice induced comparably strong Th2-type airway inflammation, airway hyperreactivity and airway remodeling, which was characterised by fibrosis and increased smooth muscle thickness. In contrast, application of all three allergens together resulted in a greater Th2 response and increased airway hyperreactivity and a stronger albeit not significant remodeling phenotype compared to using HDM or CRA. In this triple allergen model dexamethasone application, during the last 4 weeks of challenge, showed no suppressive effects on any of these parameters in this model. In contrast, both TLR7 agonist resiquimod and TLR9 agonist CpG-ODN reduced allergen-specific IgE, eosinophils, and collagen I in the lungs. The TLR9 agonist also reduced IL-4 and IL-5 whilst increasing IFN-γ and strongly IL-10 levels in the lungs, effects not seen with the TLR7 agonist. However, neither TLR agonist had any effect on airway hyperreactivity and airway smooth muscle mass. In conclusion we have developed a severe asthma model, which is steroid resistant and only partially sensitive to TLR7 and TLR9 agonist treatment. This model may be particular useful to test new potential therapeutics aiming at treating steroid resistant asthma in humans and investigating the underlying mechanisms responsible for steroid

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

    Directory of Open Access Journals (Sweden)

    Michael Gabl

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

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

    Science.gov (United States)

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

    2002-01-15

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

  1. The scattering potential of partial derivative wavefields in 3-D elastic orthorhombic media: an inversion prospective

    KAUST Repository

    Oh, Ju-Won

    2016-07-04

    Multiparameter full waveform inversion (FWI) applied to an elastic orthorhombic model description of the subsurface requires in theory a nine-parameter representation of each pixel of the model. Even with optimal acquisition on the Earth surface that includes large offsets, full azimuth, and multicomponent sensors, the potential for trade-off between the elastic orthorhombic parameters are large. The first step to understanding such trade-off is analysing the scattering potential of each parameter, and specifically, its scattering radiation patterns. We investigate such radiation patterns for diffraction and for scattering from a horizontal reflector considering a background isotropic model. The radiation patterns show considerable potential for trade-off between the parameters and the potentially limited resolution in their recovery. The radiation patterns of C11, C22, and C33 are well separated so that we expect to recover these parameters with limited trade-offs. However, the resolution of their recovery represented by recovered range of model wavenumbers varies between these parameters. We can only invert for the short wavelength components (reflection) of C33 while we can mainly invert for the long wavelength components (transmission) of the elastic coefficients C11 and C22 if we have large enough offsets. The elastic coefficients C13, C23, and C12 suffer from strong trade-offs with C55, C44, and C66, respectively. The trade-offs between C13 and C55, as well as C23 and C44, can be partially mitigated if we acquire P–SV and SV–SV waves. However, to reduce the trade-offs between C12 and C66, we require credible SH–SH waves. The analytical radiation patterns of the elastic constants are supported by numerical gradients of these parameters.

  2. Short-term memory impairment after isoflurane in mice is prevented by the α5 γ-aminobutyric acid type A receptor inverse agonist L-655,708.

    Science.gov (United States)

    Saab, Bechara J; Maclean, Ashley J B; Kanisek, Marijana; Zurek, Agnieszka A; Martin, Loren J; Roder, John C; Orser, Beverley A

    2010-11-01

    Memory blockade is an essential component of the anesthetic state. However, postanesthesia memory deficits represent an undesirable and poorly understood adverse effect. Inhibitory α5 subunit-containing γ-aminobutyric acid subtype A receptors (α5GABAA) are known to play a critical role in memory processes and are highly sensitive to positive modulation by anesthetics. We postulated that inhibiting the activity of α5GABAA receptors during isoflurane anesthesia would prevent memory deficits in the early postanesthesia period. Mice were pretreated with L-655,708, an α5GABAA receptor-selective inverse agonist, or vehicle. They were then exposed to isoflurane for 1 h (1.3%, or 1 minimum alveolar concentration, or air-oxygen control). Then, either 1 or 24 h later, mice were conditioned in fear-associated contextual and cued learning paradigms. In addition, the effect of L-655,708 on the immobilizing dose of isoflurane was studied. Motor coordination, sedation, anxiety, and the concentration of isoflurane in the brain at 5 min, 1 h, and 24 h after isoflurane were also examined. Motor and sensory function recovered within minutes after termination of isoflurane administration. In contrast, a robust deficit in contextual fear memory persisted for at least 24 h. The α5GABAA receptor inverse agonist, L-655,708, completely prevented memory deficits without changing the immobilizing dose of isoflurane. Trace concentrations of isoflurane were measured in the brain 24 h after treatment. Memory deficits occurred long after the sedative, analgesic, and anxiolytic effects of isoflurane subsided. L-655,708 prevented memory deficit, suggesting that an isoflurane interaction at α5GABAA receptors contributes to memory impairment during the early postanesthesia period.

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

    Science.gov (United States)

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

    2011-10-27

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

  4. Synthesis of [{sup 11}C]-S21007 a novel 5HT{sub 3} partial agonist as a potential tracer for PET studies

    Energy Technology Data Exchange (ETDEWEB)

    Guillouet, S.; Barre, L.; Gourand, F. [CEA Centre de Cyceron, 14 -Caen (France); Lasne, M.C. [Centre National de la Recherche Scientifique, 14 - Caen (France); Rault, S. [Caen Univ., 14 (France). Faculte de Pharmacie

    1996-04-01

    5HT{sub 3} receptors have been the focus of much research during the last decade. The presence of these receptors has been demonstrated in many neuronal tissues, both in periphery and in the CNS. The identification of selective agonists and antagonists for this receptor subtype has allowed the discovery of several important new therapeutic applications as the inhibition of pain, migraine, cytotoxic and radiation-induced emesis and treatment of psychoses and anxiety. The first 5HT{sub 3} antagonist labelled with a {beta}+ emitter atom was [{sup 11}C]MDL72222. The PET studies which have been performed with it in the brain of baboon (distribution, kinetics and binding) have established that it was not a good radioligand to detect a specific binding, due to its high lipophilicity. Other radioligands have been developed since, but their affinities for 5HT{sub 3} receptors PET studies have not been demonstrated. Among a series of of tricyclic piperazine derivatives synthesized, S21007 has been described as a novel selective and partial agonist which possesses a good affinity for 5HT{sub 3} receptors (IC{sub 50} = 1nM) versus other 5HT subtypes studied where IC{sub 50} > 1{mu}M. We report here the radiosynthesis of [{sup 11}C]S21007. (author).

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

    Science.gov (United States)

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

    2017-07-15

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

  6. Inverse Boundary Value Problem for Non-linear Hyperbolic Partial Differential Equations

    OpenAIRE

    Nakamura, Gen; Vashisth, Manmohan

    2017-01-01

    In this article we are concerned with an inverse boundary value problem for a non-linear wave equation of divergence form with space dimension $n\\geq 3$. This non-linear wave equation has a trivial solution, i.e. zero solution. By linearizing this equation at the trivial solution, we have the usual linear isotropic wave equation with the speed $\\sqrt{\\gamma(x)}$ at each point $x$ in a given spacial domain. For any small solution $u=u(t,x)$ of this non-linear equation, we have the linear isotr...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1996-09-01

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

  8. Scale-Up Synthesis and Identification of GLYX-13, a NMDAR Glycine-Site Partial Agonist for the Treatment of Major Depressive Disorder.

    Science.gov (United States)

    Li, Wenchao; Liu, Jingjian; Fan, Minghua; Li, Zhongtang; Chen, Yin; Zhang, Guisen; Huang, Zhuo; Zhang, Liangren

    2018-04-24

    GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique.

  9. Discovery of a novel selective PPARγ ligand with partial agonist binding properties by integrated in silico / in vitro work flow

    DEFF Research Database (Denmark)

    Kouskoumvekaki, Irene; Petersen, Rasmus K.; Fratev, Filip Filipov

    2013-01-01

    that control glucose and lipid metabolism and is an important target for drugs against type 2 diabetes, dyslipidemia, atherosclerosis, and cardiovascular disease. In an effort to identify novel PPARγ ligands with an improved pharmacological profile, emphasis has shifted to selective ligands with partial...

  10. Dielectric response of fully and partially depleted ferroelectric thin films and inversion of the thickness effect

    International Nuclear Information System (INIS)

    Misirlioglu, I B; Yildiz, M

    2013-01-01

    We study the effect of full and partial depletion on the dielectric response characteristics of ferroelectric thin films with impurities via a computational approach. Using a thermodynamic approach along with the fundamental equations for semiconductors, we show that films with partial depletion display unique features and an enhanced dielectric response compared with those fully depleted. We find that the capacitance peak at switching can be significantly suppressed in the case of high impurity densities (>10 25 m −3 ) with relatively low ionization energy, of the order of 0.5 eV. For conserved number of species in films, electromigration of ionized impurities at room temperature is negligible and has nearly no effect on the dielectric response. In films with high impurity density, the dielectric response at zero bias is enhanced with respect to charge-free films or those with relatively low impurity density ( 24 m −3 ). We demonstrate that partially depleted films should be expected to exhibit peculiar capacitance–voltage characteristics at low and high bias and that the thickness effect probed in experiments in ferroelectric thin films could be entirely inverted in thin films with depletion charges where a higher dielectric response can be measured in thicker films. Therefore, depletion charge densities in ferroelectric thin films should be estimated before size-effect-related studies. Finally, we noted that these findings are in good qualitative agreement with dielectric measurements carried out on PbZr x Ti 1−x O 3 . (paper)

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

    Science.gov (United States)

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

    2012-02-01

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

  12. Partial inversion of elliptic operator to speed up computation of likelihood in Bayesian inference

    KAUST Repository

    Litvinenko, Alexander

    2017-08-09

    In this paper, we speed up the solution of inverse problems in Bayesian settings. By computing the likelihood, the most expensive part of the Bayesian formula, one compares the available measurement data with the simulated data. To get simulated data, repeated solution of the forward problem is required. This could be a great challenge. Often, the available measurement is a functional $F(u)$ of the solution $u$ or a small part of $u$. Typical examples of $F(u)$ are the solution in a point, solution on a coarser grid, in a small subdomain, the mean value in a subdomain. It is a waste of computational resources to evaluate, first, the whole solution and then compute a part of it. In this work, we compute the functional $F(u)$ direct, without computing the full inverse operator and without computing the whole solution $u$. The main ingredients of the developed approach are the hierarchical domain decomposition technique, the finite element method and the Schur complements. To speed up computations and to reduce the storage cost, we approximate the forward operator and the Schur complement in the hierarchical matrix format. Applying the hierarchical matrix technique, we reduced the computing cost to $\\\\mathcal{O}(k^2n \\\\log^2 n)$, where $k\\\\ll n$ and $n$ is the number of degrees of freedom. Up to the $\\\\H$-matrix accuracy, the computation of the functional $F(u)$ is exact. To reduce the computational resources further, we can approximate $F(u)$ on, for instance, multiple coarse meshes. The offered method is well suited for solving multiscale problems. A disadvantage of this method is the assumption that one has to have access to the discretisation and to the procedure of assembling the Galerkin matrix.

  13. Partially satisfied to fully satisfied transitions in co-evolving inverse voter model and possible scaling behavior

    International Nuclear Information System (INIS)

    Choi, C.W.; Xu, C.; Hui, P.M.

    2015-01-01

    Understanding co-evolving networks characterized by the mutual influence of agents' actions and network structure remains a challenge. We study a co-evolving inverse voter model in which agents adapt to achieve a preferred environment with more opposite-opinion neighbors by rewiring their connections and switching opinion. Numerical studies reveal a transition from a dynamic partially satisfied phase to a frozen fully satisfied phase as the rewiring probability is varied. A simple mean field theory is shown to capture the behavior only qualitatively. An improved mean field theory carrying a longer spatial correlation gives better results. Motivated by numerical results in networks of different degrees and mean field results, we propose a scaling variable that combines the rewiring probability and mean degree in a special form. The scaling variable is shown to work well in analyzing data corresponding to different networks and different rewiring probabilities. An application is to predict the results for networks of different degrees based solely on results obtained from networks of one degree. Studying scaling behavior provides an alternative path for understanding co-evolving agent-based dynamical systems, especially in light of the trade-off between complexity of a theory and its accuracy. - Highlights: • Identified key features and phase transitions in coevolving inverse voter model. • Constructed a better theory incorporating longer spatial correlation. • Proposed scaling variable and illustrated possible scaling behavior. • Used scaling behavior to predict results of IVM in a different network.

  14. The Ghrelin agonist TZP-101 for management of postoperative ileus after partial colectomy: a randomized, dose-ranging, placebo-controlled clinical trial.

    Science.gov (United States)

    Popescu, Irinel; Fleshner, Phillip R; Pezzullo, John C; Charlton, Philippa A; Kosutic, Gordana; Senagore, Anthony J

    2010-02-01

    Ghrelin agonist TZP-101 is a potent prokinetic. This phase 2b study evaluated TZP-101 safety and efficacy in postoperative ileus management. Adults undergoing open partial colectomy were adaptively randomized to receive 20, 40, 80, 160, 320, 480 or 600 microg/kg TZP-101 (n = 168) or the placebo (n = 68) by 30-minute IV infusion within 1 hour of surgical closure and then daily for up to 7 days. The primary efficacy end point was the time to first bowel movement. Secondary end points included the percentage of patients with return of gastrointestinal function within 72 hours, and the time to readiness for discharge. TZP-101 accelerated the time to first bowel movement in all groups, with Cox proportional hazard ratios of 1.57 (P = .056) for the low-efficacious dose (80 microg/kg) and 1.67 (P = .03) for the most efficacious dose (480 microg/kg). Using Kaplan-Meier analysis, the median time to first bowel movement was reduced in all TZP-101 groups by 10 to 22 hours vs. the placebo. A greater number of patients who received TZP-101 achieved recovery (P readiness for hospital discharge was significantly accelerated by 20.4 hours at the 480 microg/kg TZP-101 dose compared with the placebo (hazard ratio = 1.69; P = .03). The most common treatment-emergent adverse events were nausea and vomiting, which were reduced in the TZP-101 group compared with the placebo group. In patients undergoing major abdominal surgery, the first-in-class ghrelin agonist TZP-101 was well-tolerated and accelerated recovery of the upper and lower gastrointestinal tract, with a large proportion of subjects recovering within 72 hours compared with the placebo.

  15. Partial Least Square Discriminant Analysis Discovered a Dietary Pattern Inversely Associated with Nasopharyngeal Carcinoma Risk.

    Science.gov (United States)

    Lo, Yen-Li; Pan, Wen-Harn; Hsu, Wan-Lun; Chien, Yin-Chu; Chen, Jen-Yang; Hsu, Mow-Ming; Lou, Pei-Jen; Chen, I-How; Hildesheim, Allan; Chen, Chien-Jen

    2016-01-01

    Evidence on the association between dietary component, dietary pattern and nasopharyngeal carcinoma (NPC) is scarce. A major challenge is the high degree of correlation among dietary constituents. We aimed to identify dietary pattern associated with NPC and to illustrate the dose-response relationship between the identified dietary pattern scores and the risk of NPC. Taking advantage of a matched NPC case-control study, data from a total of 319 incident cases and 319 matched controls were analyzed. Dietary pattern was derived employing partial least square discriminant analysis (PLS-DA) performed on energy-adjusted food frequencies derived from a 66-item food-frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with multiple conditional logistic regression models, linking pattern scores and NPC risk. A high score of the PLS-DA derived pattern was characterized by high intakes of fruits, milk, fresh fish, vegetables, tea, and eggs ordered by loading values. We observed that one unit increase in the scores was associated with a significantly lower risk of NPC (ORadj = 0.73, 95% CI = 0.60-0.88) after controlling for potential confounders. Similar results were observed among Epstein-Barr virus seropositive subjects. An NPC protective diet is indicated with more phytonutrient-rich plant foods (fruits, vegetables), milk, other protein-rich foods (in particular fresh fish and eggs), and tea. This information may be used to design potential dietary regimen for NPC prevention.

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

    International Nuclear Information System (INIS)

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

    2003-01-01

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

  17. Enhanced down regulation of cortical ±-propranolol sensitive [3H]-DHA binding sites by co-administration of DMI and 5-HT1A partial agonist gepirone

    International Nuclear Information System (INIS)

    Geissler, M.A.; Yocca, F.D.

    1990-01-01

    The putative interrelationship between the noradrenergic and serotonergic systems has been supported by numerous studies. Recently, Dudley et al. (1989) demonstrated significant down regulation of cortical β-adrenergic receptors by co-administration of desipramine (DMI), a norepinephrine uptake inhibitor, and the full 5-HT 1A agonist 8-OH-DPAT. To this end, the effects of acute and chronic (4 and 14 day) administration of DMI, gepirone, a selective 5-HT 1A post-synaptic partial agonist, as well as a combination of the two, on cortical (±)-propranolol sensitive [ 3 H]-DHA binding sites were examined in rats. Down regulation was apparent after 4 and 14 day treatment with DMI. However, this was not the case with gepirone. Of particular importance is the demonstration of a greater magnitude of down regulation with co-administration of a greater magnitude of down regulation with co-administration of DMI and gepirone. These results suggests that alteration in rat cortical (±)-propranolol sensitive [ 3 H]-DHA binding sites by noradrenergic uptake inhibitors can be further modulated by selective partial agonist activity at central 5-HT 1A postsynaptic receptors. Further data on the co-administration of DMI and BMY 7378 (7,9-dioxo-8-[2-(4-o-methoxyphenylpiperazinyl)ethyl]-8-azaspiro[4,5]decane dihydrochloride), a weak partial agonist at postsynaptic 5-HT 1A receptors, are also presented

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

    Science.gov (United States)

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

    2014-09-01

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

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

    Science.gov (United States)

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

    2014-02-01

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

  20. BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology.

    Science.gov (United States)

    Ligneau, X; Perrin, D; Landais, L; Camelin, J-C; Calmels, T P G; Berrebi-Bertrand, I; Lecomte, J-M; Parmentier, R; Anaclet, C; Lin, J-S; Bertaina-Anglade, V; la Rochelle, C Drieu; d'Aniello, F; Rouleau, A; Gbahou, F; Arrang, J-M; Ganellin, C R; Stark, H; Schunack, W; Schwartz, J-C

    2007-01-01

    Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H3 receptor. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.

  1. Adsorption isotherms of some alkyl aromatic hydrocarbons and surface energies on partially dealuminated Y faujasite zeolite by inverse gas chromatography.

    Science.gov (United States)

    Kondor, Anett; Dallos, András

    2014-10-03

    Adsorption isotherm data of some alkyl aromatic hydrocarbons (benzene, toluene, ethylbenzene, o-xylene, m-xylene and p-xylene) measured in the temperature range of 423-523K on a partially dealuminated faujasite type DAY F20 zeolite by inverse gas chromatography are presented in this work. The temperature dependent form of Tóth's equation has been fitted to the multiple temperature adsorption isotherms of benzene, toluene, ethylbenzene, o-xylene, m-xylene and p-xylene with standard deviations of 4.6, 5.0, 5.9, 4.3, 5.1 and 6.3mmolkg(-1) and coefficients of determinations (r(2)) of 0.977, 0.971, 0.974, 0.975, 0.991 and 0.991, respectively. The gas-solid equilibria and modeling were interpreted on the basis of the interfacial properties of the zeolite, by dispersive, specific and total surface energy heterogeneity profiles and distributions of the adsorbent measured by surface energy analysis. Copyright © 2014 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2010-02-01

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

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

    Science.gov (United States)

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

    2013-04-01

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

  4. Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial {alpha}7 nicotinic cholinergic agonist drug

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Won [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States) and Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States)]. E-mail: swkim@bnl.gov; Ding Yushin [Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Department of Radiology, Yale University School of Medicine, New Haven, CT 06520-8048 (United States); Alexoff, David [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Patel, Vinal [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Logan, Jean [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Lin, K.-S. [Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Shea, Colleen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Muench, Lisa [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Xu Youwen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Carter, Pauline [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); King, Payton [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Constanzo, Jasmine R. [Department of Chemistry, Fordham University, Bronx, NY 10458 (United States); Ciaccio, James A. [Department of Chemistry, Fordham University, Bronx, NY 10458 (United States); Fowler, Joanna S. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029 (United States)

    2007-07-15

    Introduction: (3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6-tetrahydro-2,3'-bipyridine (GTS-21), a partial {alpha}7 nicotinic acetylcholine receptor agonist drug, has recently been shown to improve cognition in schizophrenia and Alzheimer's disease. One of its two major demethylated metabolites, 4-OH-GTS-21, has been suggested to contribute to its therapeutic effects. Methods: We labeled GTS-21 in two different positions with carbon-11 ([2-methoxy-{sup 11}C]GTS-21 and [4-{sup 11}C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy-{sup 11}C]4-OH-GTS-21 and [4-methoxy-{sup 11}C]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET). Results: Both [2-{sup 11}C]GTS-21 and [4-methoxy-{sup 11}C]GTS-21 showed similar initial high rapid uptake in baboon brain, peaking from 1 to 3.5 min (0.027-0.038%ID/cc) followed by rapid clearance (t {sub 1/2}<15 min), resulting in low brain retention by 30 min. However, after 30 min, [2-methoxy-{sup 11}C]GTS-21 continued to clear while [4-methoxy-{sup 11}C]GTS-21 plateaued, suggesting the entry of a labeled metabolite into the brain. Comparison of the pharmacokinetics of the two labeled metabolites confirmed expected higher brain uptake and retention of [4-methoxy-{sup 11}C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy-{sup 11}C]GTS-21) relative to [2-methoxy-{sup 11}C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy-{sup 11}C]GTS-21), which had negligible brain uptake. Ex vivo studies in mice showed that GTS-21 is the major chemical form in the mouse brain. Whole-body dynamic PET imaging in baboon and mouse showed that the major route of excretion of C-11 is through the gallbladder. Conclusions: The major findings are as follows: (a) extremely rapid uptake and clearance of [2-methoxy-{sup 11}C]GTS-21 from the brain, which may need to be considered in developing optimal dosing of GTS-21 for patients, and (b) significant brain uptake of 2-OH-GTS-21

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

    Science.gov (United States)

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

    2018-04-01

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

  6. Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial α7 nicotinic cholinergic agonist drug

    International Nuclear Information System (INIS)

    Kim, Sung Won; Ding Yushin; Alexoff, David; Patel, Vinal; Logan, Jean; Lin, K.-S.; Shea, Colleen; Muench, Lisa; Xu Youwen; Carter, Pauline; King, Payton; Constanzo, Jasmine R.; Ciaccio, James A.; Fowler, Joanna S.

    2007-01-01

    Introduction: (3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6-tetrahydro-2,3'-bipyridine (GTS-21), a partial α7 nicotinic acetylcholine receptor agonist drug, has recently been shown to improve cognition in schizophrenia and Alzheimer's disease. One of its two major demethylated metabolites, 4-OH-GTS-21, has been suggested to contribute to its therapeutic effects. Methods: We labeled GTS-21 in two different positions with carbon-11 ([2-methoxy- 11 C]GTS-21 and [4- 11 C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy- 11 C]4-OH-GTS-21 and [4-methoxy- 11 C]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET). Results: Both [2- 11 C]GTS-21 and [4-methoxy- 11 C]GTS-21 showed similar initial high rapid uptake in baboon brain, peaking from 1 to 3.5 min (0.027-0.038%ID/cc) followed by rapid clearance (t 1/2 11 C]GTS-21 continued to clear while [4-methoxy- 11 C]GTS-21 plateaued, suggesting the entry of a labeled metabolite into the brain. Comparison of the pharmacokinetics of the two labeled metabolites confirmed expected higher brain uptake and retention of [4-methoxy- 11 C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy- 11 C]GTS-21) relative to [2-methoxy- 11 C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy- 11 C]GTS-21), which had negligible brain uptake. Ex vivo studies in mice showed that GTS-21 is the major chemical form in the mouse brain. Whole-body dynamic PET imaging in baboon and mouse showed that the major route of excretion of C-11 is through the gallbladder. Conclusions: The major findings are as follows: (a) extremely rapid uptake and clearance of [2-methoxy- 11 C]GTS-21 from the brain, which may need to be considered in developing optimal dosing of GTS-21 for patients, and (b) significant brain uptake of 2-OH-GTS-21, suggesting that it might contribute to the therapeutic effects of GTS-21. This study illustrates the value of comparing different label positions and labeled

  7. Comparative Evaluation of Partial α2 -Adrenoceptor Agonist and Pure α2 -Adrenoceptor Antagonist on the Behavioural Symptoms of Withdrawal after Chronic Alcohol Administration in Mice.

    Science.gov (United States)

    Arora, Shivani; Vohora, Divya

    2016-08-01

    As an addictive drug, alcohol produces withdrawal symptoms if discontinued abruptly after chronic use. Clonidine (CLN), a partial α2 -adrenergic agonist, and mirtazapine (MRT), an antagonist of α2 -adrenoceptor, both clinically aid alcohol withdrawal. Considering different mechanisms of action of the two drugs, this study was designed to see how far these two mechanistically different drugs differ in their ability to decrease the severity of ethanol withdrawal syndrome. The effect of CLN and MRT on ethanol withdrawal-induced anxiety, depression and memory impairment was analysed using EPM, FST and PAR tests, respectively. Animals received distilled water, ethanol and/or either of the drugs (CLN and MRT) in different doses. Relapse to alcohol use was analysed by CPP test. Animals received ethanol as a conditioning drug and distilled water, CLN or MRT as test drug. CLN and MRT both alleviated anxiety in a dose-dependent manner. MRT (4 mg/kg) was more effective than CLN (0.1 mg/kg) in ameliorating the anxiogenic effect of alcohol withdrawal. However, CLN treatment increased depression. It significantly decreased swimming time and increased immobility time, whereas MRT treatment decreased immobility time and increased climbing and swimming time during abstinence. The effect was dose dependent for both drugs. The results of PAR test show that CLN treatment worsens working memory. Significant increase in SDE and TSZ and decrease in SDL were observed in CLN-treated animals. MRT treatment, on the other hand, improved working memory at both doses. Further, both CLN and MRT alleviated craving. A significant decrease in time spent in the ethanol-paired chamber was seen. MRT treatment at both doses showed better effect than CLN in preventing the development of preference in CPP test. These findings indicate a potential therapeutic use and better profile of mirtazapine over clonidine in improving memory, as well as in alleviating depression, anxiety and craving associated

  8. Efficacy and safety of the partial PPARγ agonist balaglitazone compared with pioglitazone and placebo: A phase III, randomised, parallel-group study in patients with type 2 diabetes on stable insulin therapy

    DEFF Research Database (Denmark)

    Henriksen, Kim; Byrjalsen, Inger; Qvist, Per

    2011-01-01

    Treatment of patients with full PPARγ agonists is associated with weight gain, heart failure, peripheral oedema and bone loss. However, the safety of partial PPARγ agonists has not been established in a clinical trial. The BALLET trial aimed to establish the glucose-lowering effects and safety...... in all treatment arms. DXA analyses showed balaglitazone 10mg led to less fat and fluid accumulation and no change in bone mineral density, when compared to pioglitazone. In the balaglitazone 10mg treated group clinically relevant reductions in HbA(1c) and glucose levels were observed, although...... it appeared to be a little less potent that pioglitazone 45mg. On the other hand significantly less fluid and fat accumulation were observed, highlighting this treatment regimen for further studies....

  9. Inverse spectral results for Schroedinger operators on the unit interval with partial information given on the potentials

    International Nuclear Information System (INIS)

    Amour, L.; Raoux, T.; Faupin, J.

    2009-01-01

    We pursue the analysis of the Schroedinger operator on the unit interval in inverse spectral theory initiated in the work of Amour and Raoux [''Inverse spectral results for Schroedinger operators on the unit interval with potentials in Lp spaces,'' Inverse Probl. 23, 2367 (2007)]. While the potentials in the work of Amour and Raoux belong to L 1 with their difference in L p (1≤p k,1 spaces having their difference in W k,p , where 1≤p≤+∞, k(set-membership sign)(0,1,2). It is proved that two potentials in W k,1 ([0,1]) being equal on [a,1] are also equal on [0,1] if their difference belongs to W k,p ([0,a]) and if the number of their common eigenvalues is sufficiently high. Naturally, this number decreases as the parameter a decreases and as the parameters k and p increase

  10. Inverse spectral results for Schrödinger operators on the unit interval with partial information given on the potentials

    Science.gov (United States)

    Amour, L.; Faupin, J.; Raoux, T.

    2009-03-01

    We pursue the analysis of the Schrödinger operator on the unit interval in inverse spectral theory initiated in the work of Amour and Raoux ["Inverse spectral results for Schrödinger operators on the unit interval with potentials in Lp spaces," Inverse Probl. 23, 2367 (2007)]. While the potentials in the work of Amour and Raoux belong to L1 with their difference in Lp (1≤p<∞), we consider here potentials in Wk,1 spaces having their difference in Wk,p, where 1≤p≤+∞, k ɛ{0,1,2}. It is proved that two potentials in Wk,1([0,1]) being equal on [a,1] are also equal on [0,1] if their difference belongs to Wk,p([0,a]) and if the number of their common eigenvalues is sufficiently high. Naturally, this number decreases as the parameter a decreases and as the parameters k and p increase.

  11. Changes of seizure susceptibility during benzodiazepine withdrawal in immature rats: comparison of clonazepam and partial benzodiazepine agonist Ro 19-8022

    Czech Academy of Sciences Publication Activity Database

    Kubová, Hana

    2006-01-01

    Roč. 47, č. S4 (2006), s. 221-221 ISSN 0013-9580. [Annual Meeting of the American Epilepsy Society and Canadian League against Epilepsy. 01.12.2006-05.12.2006, San Diego, CA] R&D Projects: GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : PTZ-induced seizures * clonazepam * agonist Ro 19-8022 Subject RIV: ED - Physiology

  12. [Recombinant chromosome 4 with partial 4p deletion and 4q duplication inherited from paternal pericentric inversion].

    Science.gov (United States)

    Mun, Se Jin; Cho, Eun Hae; Chey, Myoung-Jae; Shim, Gyu-Hong; Shin, Bo-Moon; Lee, Rae-Kyung; Ko, Ji-Kyung; Yoo, Soo Jin

    2010-02-01

    Pericentric inversion of chromosome 4 can give rise to 2 alternate recombinant (rec) chromosomesby duplication or deletion of 4p. The deletion of distal 4p manifests as Wolf-Hirschhorn syndrome (WHS). Here, we report the molecular cytogenetic findings and clinical manifestations observed in an infant with 46,XX,rec(4)dup(4q)inv(4)(p16q31.3)pat. The infant was delivered by Cesarean section at the 33rd week of gestation because pleural effusion and polyhydramnios were detected on ultrasonography. At birth, the infant showed no malformation or dysfunction, except for a preauricular skin tag. Array comparative genomic hybridization analysis of neonatal peripheral blood samples showed a gain of 38 Mb on 4q31.3-qter and a loss of 3 Mb on 4p16.3, and these results were consistent with WHS. At the last follow-up at 8 months of age (corrected age, 6 months), the infant had not achieved complete head control.

  13. Safety, Tolerability, and Antihypertensive Effect of SER100, an Opiate Receptor-Like 1 (ORL-1) Partial Agonist, in Patients With Isolated Systolic Hypertension.

    Science.gov (United States)

    Kantola, Ilkka; Scheinin, Mika; Gulbrandsen, Trygve; Meland, Nils; Smerud, Knut T

    2017-11-01

    The purpose of the present trial was to evaluate safety, tolerability, and effect on systolic blood pressure (SBP) of SER100 in a small group of patients with isolated systolic hypertension (ISH) in treatment with at least 1 antihypertensive drug. Eligible patients were randomized to either SER100 (10 mg) or placebo in a crossover design, and 2 doses were given subcutaneously (SC), 8 hours apart, on 2 consecutive days. On all treatment days patients were monitored with an ambulatory blood pressure measurement device for 12 daytime hours. Seventeen patients completed treatment. There were no serious or severe adverse events. Relative to placebo SER100 induced an average reduction of SBP during the 2 treatment days of 7.0 mm Hg (P = 0.0032), whereas the average reduction of diastolic blood pressure (DBP) over the same period was 3.8 mm Hg (P = 0.0011). For patients with ISH, this short-term cross-over study of SC SER100 demonstrated an acceptable safety profile and consistent, significant lowering of SBP and DBP. As initial clinical proof of concept for a new class of drugs, a nociceptin agonist peptide, the results were encouraging and warrant further research. © 2016, The American College of Clinical Pharmacology.

  14. Identification and characterization of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a novel, orally bioavailable C5a receptor inverse agonist.

    Science.gov (United States)

    Brodbeck, Robbin M; Cortright, Daniel N; Kieltyka, Andrzej P; Yu, Jianying; Baltazar, Carolyn O; Buck, Marianne E; Meade, Robin; Maynard, George D; Thurkauf, Andrew; Chien, Du-Shieng; Hutchison, Alan J; Krause, James E

    2008-12-01

    The complement system represents an innate immune mechanism of host defense that has three effector arms, the C3a receptor, the C5a receptor (C5aR), and the membrane attack complex. Because of its inflammatory and immune-enhancing properties, the biological activity of C5a and its classical receptor have been widely studied. Because specific antagonism of the C5aR could have therapeutic benefit without affecting the protective immune response, the C5aR continues to be a promising target for pharmaceutical research. The lack of specific, potent and orally bioavailable small-molecule antagonists has limited the clinical investigation of the C5aR. We report the discovery of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a small-molecule, orally bioavailable, selective, and potent inverse agonist of the human C5aR. NDT 9513727 was discovered based on the integrated use of in vitro affinity and functional assays in conjunction with medicinal chemistry. NDT 9513727 inhibited C5a-stimulated responses, including guanosine 5'-3-O-(thio)triphosphate binding, Ca(2+) mobilization, oxidative burst, degranulation, cell surface CD11b expression and chemotaxis in various cell types with IC(50)s from 1.1 to 9.2 nM, respectively. In C5a competition radioligand binding experiments, NDT 9513727 exhibited an IC(50) of 11.6 nM. NDT 9513727 effectively inhibited C5a-induced neutropenia in gerbil and cynomolgus macaque in vivo. The findings suggest that NDT 9513727 may be a promising new entity for the treatment of human inflammatory diseases.

  15. Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy.

    Science.gov (United States)

    Jakubík, J; Janíčková, H; El-Fakahany, E E; Doležal, V

    2011-03-01

    Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5'-γ-thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M₂ muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [³⁵S]GTPγS and [³H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M₂ muscarinic acetylcholine receptor. Agonists displayed biphasic competition curves with the antagonist [³H]-N-methylscopolamine. GTPγS (1 µM) changed the competition curves to monophasic with low affinity and 50 µM GDP produced a similar effect. Depletion of membrane-bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [³H]GDP from membranes. The inverse agonist N-methylscopolamine slowed GDP dissociation and GTPγS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from G(i/o) G-proteins but only its dissociation from G(s/olf) G-proteins. These findings suggest the existence of a low-affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G-protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of G(i/o) versus G(s/olf) G-proteins that are not identified by conventional GTPγS binding. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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

    Directory of Open Access Journals (Sweden)

    Takashi eUehara

    2014-09-01

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

  17. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

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

    2015-01-01

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

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

    DEFF Research Database (Denmark)

    Campiani, G; Morelli, E; Nacci, V

    2001-01-01

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

  19. Glutamate receptor agonists

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Greenwood, Jeremy R; Bunch, Lennart

    2011-01-01

    The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally a-amino acids with one or more...... stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses...... mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist...

  20. Comparison of three IMRT inverse planning techniques that allow for partial esophagus sparing in patients receiving thoracic radiation therapy for lung cancer

    International Nuclear Information System (INIS)

    Xiao Ying; Werner-Wasik, Maria; Michalski, D.; Houser, C.; Bednarz, G.; Curran, W.; Galvin, James

    2004-01-01

    The purpose of this study is to compare 3 intensity-modulated radiation therapy (IMRT) inverse treatment planning techniques as applied to locally-advanced lung cancer. This study evaluates whether sufficient radiotherapy (RT) dose is given for durable control of tumors while sparing a portion of the esophagus, and whether large number of segments and monitor units are required. We selected 5 cases of locally-advanced lung cancer with large central tumor, abutting the esophagus. To ensure that no more than half of the esophagus circumference at any level received the specified dose limit, it was divided into disk-like sections and dose limits were imposed on each. Two sets of dose objectives were specified for tumor and other critical structures for standard dose RT and for dose escalation RT. Plans were generated using an aperture-based inverse planning (ABIP) technique with the Cimmino algorithm for optimization. Beamlet-based inverse treatment planning was carried out with a commercial simulated annealing package (CORVUS) and with an in-house system that used the Cimmino projection algorithm (CIMM). For 3 of the 5 cases, results met all of the constraints from the 3 techniques for the 2 sets of dose objectives. The CORVUS system without delivery efficiency consideration required the most segments and monitor units. The CIMM system reduced the number while the ABIP techniques showed a further reduction, although for one of the cases, a solution was not readily obtained using the ABIP technique for dose escalation objectives

  1. Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study.

    Science.gov (United States)

    Newman-Tancredi, A; Gavaudan, S; Conte, C; Chaput, C; Touzard, M; Verrièle, L; Audinot, V; Millan, M J

    1998-08-21

    Recombinant human (h) 5-HT1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS binding). The potency and efficacy of 21 5-HT receptor agonists and antagonists was determined. The agonists, 5-CT (carboxamidotryptamine) and flesinoxan displayed high affinity (subnanomolar Ki values) and high efficacy (Emax > 90%, relative to 5-HT = 100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC50s for agonist stimulation of [35S]GTPgammaS binding correlated well with Ki values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and (+)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [35S]GTPgammaS binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychotic agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Likewise the 'typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and 'neutral' antagonist activity at h5-HT1A receptors with Ki values which correlated with their respective Kb values. The present data show that (i) [35S]GTPgammaS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'atypical' antipsychotic drugs display balanced serotonin h5-HT1A/dopamine hD2 receptor affinity and partial agonist activity at h5-HT1A receptors. (iii) Several 'typical' and some putatively 'atypical

  2. Toxicological Evaluation of a Potential Immunosensitizer for Use as a Mucosal Adjuvant—Bacillus thuringiensis Cry1Ac Spore-Crystals: A Possible Inverse Agonist that Deserves Further Investigation

    Directory of Open Access Journals (Sweden)

    Bélin Poletto Mezzomo

    2015-12-01

    Full Text Available In addition to their applicability as biopesticides, Bacillus thuringiensis (Bt Cry1Ac spore-crystals are being researched in the immunology field for their potential as adjuvants in mucosal and parenteral immunizations. We aimed to investigate the hematotoxicity and genotoxicity of Bt spore-crystals genetically modified to express Cry1Ac individually, administered orally (p.o. or with a single intraperitoneal (i.p. injection 24 h before euthanasia, to simulate the routes of mucosal and parenteral immunizations in Swiss mice. Blood samples were used to perform hemogram, and bone marrow was used for the micronucleus test. Cry1Ac presented cytotoxic effects on erythroid lineage in both routes, being more severe in the i.p. route, which also showed genotoxic effects. The greater severity noted in this route, mainly at 6.75 mg/kg, as well as the intermediate effects at 13.5 mg/kg, and the very low hematotoxicity at 27 mg/kg, suggested a possible inverse agonism. The higher immunogenicity for the p.o. route, particularly at 27 mg/kg, suggested that at this dose, Cry 1Ac could potentially be used as a mucosal adjuvant (but not in parenteral immunizations, due to the genotoxic effects observed. This potential should be investigated further, including making an evaluation of the proposed inverse agonism and carrying out cytokine profiling.

  3. Inverse photoemission

    International Nuclear Information System (INIS)

    Namatame, Hirofumi; Taniguchi, Masaki

    1994-01-01

    Photoelectron spectroscopy is regarded as the most powerful means since it can measure almost perfectly the occupied electron state. On the other hand, inverse photoelectron spectroscopy is the technique for measuring unoccupied electron state by using the inverse process of photoelectron spectroscopy, and in principle, the similar experiment to photoelectron spectroscopy becomes feasible. The development of the experimental technology for inverse photoelectron spectroscopy has been carried out energetically by many research groups so far. At present, the heightening of resolution of inverse photoelectron spectroscopy, the development of inverse photoelectron spectroscope in which light energy is variable and so on are carried out. But the inverse photoelectron spectroscope for vacuum ultraviolet region is not on the market. In this report, the principle of inverse photoelectron spectroscopy and the present state of the spectroscope are described, and the direction of the development hereafter is groped. As the experimental equipment, electron guns, light detectors and so on are explained. As the examples of the experiment, the inverse photoelectron spectroscopy of semimagnetic semiconductors and resonance inverse photoelectron spectroscopy are reported. (K.I.)

  4. Application of hierarchical matrices for partial inverse

    KAUST Repository

    Litvinenko, Alexander

    2013-11-26

    In this work we combine hierarchical matrix techniques (Hackbusch, 1999) and domain decomposition methods to obtain fast and efficient algorithms for the solution of multiscale problems. This combination results in the hierarchical domain decomposition (HDD) method, which can be applied for solution multi-scale problems. Multiscale problems are problems that require the use of different length scales. Using only the finest scale is very expensive, if not impossible, in computational time and memory. Domain decomposition methods decompose the complete problem into smaller systems of equations corresponding to boundary value problems in subdomains. Then fast solvers can be applied to each subdomain. Subproblems in subdomains are independent, much smaller and require less computational resources as the initial problem.

  5. Application of hierarchical matrices for partial inverse

    KAUST Repository

    Litvinenko, Alexander

    2013-01-01

    Multiscale problems are problems that require the use of different length scales. Using only the finest scale is very expensive, if not impossible, in computational time and memory. Domain decomposition methods decompose the complete problem into smaller systems of equations corresponding to boundary value problems in subdomains. Then fast solvers can be applied to each subdomain. Subproblems in subdomains are independent, much smaller and require less computational resources as the initial problem.

  6. Inverse scale space decomposition

    DEFF Research Database (Denmark)

    Schmidt, Marie Foged; Benning, Martin; Schönlieb, Carola-Bibiane

    2018-01-01

    We investigate the inverse scale space flow as a decomposition method for decomposing data into generalised singular vectors. We show that the inverse scale space flow, based on convex and even and positively one-homogeneous regularisation functionals, can decompose data represented...... by the application of a forward operator to a linear combination of generalised singular vectors into its individual singular vectors. We verify that for this decomposition to hold true, two additional conditions on the singular vectors are sufficient: orthogonality in the data space and inclusion of partial sums...... of the subgradients of the singular vectors in the subdifferential of the regularisation functional at zero. We also address the converse question of when the inverse scale space flow returns a generalised singular vector given that the initial data is arbitrary (and therefore not necessarily in the range...

  7. Inverse Limits

    CERN Document Server

    Ingram, WT

    2012-01-01

    Inverse limits provide a powerful tool for constructing complicated spaces from simple ones. They also turn the study of a dynamical system consisting of a space and a self-map into a study of a (likely more complicated) space and a self-homeomorphism. In four chapters along with an appendix containing background material the authors develop the theory of inverse limits. The book begins with an introduction through inverse limits on [0,1] before moving to a general treatment of the subject. Special topics in continuum theory complete the book. Although it is not a book on dynamics, the influen

  8. Dopaminergic agonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with an impairment of the dopaminergic neurotransmission. Dopaminergic agonists may therefore have a beneficial effect on patients with hepatic encephalopathy....

  9. Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

    International Nuclear Information System (INIS)

    Molenaar, P.; Malta, E.

    1986-01-01

    In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-[ 125 I]iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants

  10. Unique interaction pattern for a functionally biased ghrelin receptor agonist

    DEFF Research Database (Denmark)

    Sivertsen, Bjørn Behrens; Lang, Manja; Frimurer, Thomas M.

    2011-01-01

    Based on the conformationally constrained D-Trp-Phe-D-Trp (wFw) core of the prototype inverse agonist [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]substance P, a series of novel, small, peptide-mimetic agonists for the ghrelin receptor were generated. By using various simple, ring-constrained spacers...... connecting the D-Trp-Phe-D-Trp motif with the important C-terminal carboxyamide group, 40 nm agonism potency was obtained and also in one case (wFw-Isn-NH(2), where Isn is isonipecotic acid) ~80% efficacy. However, in contrast to all previously reported ghrelin receptor agonists, the piperidine-constrained w......Fw-Isn-NH(2) was found to be a functionally biased agonist. Thus, wFw-Isn-NH(2) mediated potent and efficacious signaling through the Ga(q) and ERK1/2 signaling pathways, but in contrast to all previous ghrelin receptor agonists it did not signal through the serum response element, conceivably the Ga(12...

  11. Inverse Kinematics

    Directory of Open Access Journals (Sweden)

    Joel Sereno

    2010-01-01

    Full Text Available Inverse kinematics is the process of converting a Cartesian point in space into a set of joint angles to more efficiently move the end effector of a robot to a desired orientation. This project investigates the inverse kinematics of a robotic hand with fingers under various scenarios. Assuming the parameters of a provided robot, a general equation for the end effector point was calculated and used to plot the region of space that it can reach. Further, the benefits obtained from the addition of a prismatic joint versus an extra variable angle joint were considered. The results confirmed that having more movable parts, such as prismatic points and changing angles, increases the effective reach of a robotic hand.

  12. Multidimensional inversion

    International Nuclear Information System (INIS)

    Desesquelles, P.

    1997-01-01

    Computer Monte Carlo simulations occupy an increasingly important place between theory and experiment. This paper introduces a global protocol for the comparison of model simulations with experimental results. The correlated distributions of the model parameters are determined using an original recursive inversion procedure. Multivariate analysis techniques are used in order to optimally synthesize the experimental information with a minimum number of variables. This protocol is relevant in all fields if physics dealing with event generators and multi-parametric experiments. (authors)

  13. Partial agonists and subunit selectivity at NMDA receptors

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  14. An inverse problem for evolution inclusions

    OpenAIRE

    Ton, Bui An

    2002-01-01

    An inverse problem, the determination of the shape and a convective coefficient on a part of the boundary from partial measurements of the solution, is studied using 2-person optimal control techniques.

  15. Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act?

    DEFF Research Database (Denmark)

    Schwartz, Thue W; Holst, Birgitte

    2007-01-01

    Many small-molecule agonists also display allosteric properties. Such ago-allosteric modulators act as co-agonists, providing additive efficacy--instead of partial antagonism--and they can affect--and often improve--the potency of the endogenous agonist. Surprisingly, the apparent binding sites...... different binding modes. In another, dimeric, receptor scenario, the endogenous agonist binds to one protomer while the ago-allosteric modulator binds to the other, 'allosteric' protomer. It is suggested that testing for ago-allosteric properties should be an integral part of the agonist drug discovery...... process because a compound that acts with--rather than against--the endogenous agonist could be an optimal agonist drug....

  16. Intersections, ideals, and inversion

    International Nuclear Information System (INIS)

    Vasco, D.W.

    1998-01-01

    Techniques from computational algebra provide a framework for treating large classes of inverse problems. In particular, the discretization of many types of integral equations and of partial differential equations with undetermined coefficients lead to systems of polynomial equations. The structure of the solution set of such equations may be examined using algebraic techniques.. For example, the existence and dimensionality of the solution set may be determined. Furthermore, it is possible to bound the total number of solutions. The approach is illustrated by a numerical application to the inverse problem associated with the Helmholtz equation. The algebraic methods are used in the inversion of a set of transverse electric (TE) mode magnetotelluric data from Antarctica. The existence of solutions is demonstrated and the number of solutions is found to be finite, bounded from above at 50. The best fitting structure is dominantly one dimensional with a low crustal resistivity of about 2 ohm-m. Such a low value is compatible with studies suggesting lower surface wave velocities than found in typical stable cratons

  17. Intersections, ideals, and inversion

    Energy Technology Data Exchange (ETDEWEB)

    Vasco, D.W.

    1998-10-01

    Techniques from computational algebra provide a framework for treating large classes of inverse problems. In particular, the discretization of many types of integral equations and of partial differential equations with undetermined coefficients lead to systems of polynomial equations. The structure of the solution set of such equations may be examined using algebraic techniques.. For example, the existence and dimensionality of the solution set may be determined. Furthermore, it is possible to bound the total number of solutions. The approach is illustrated by a numerical application to the inverse problem associated with the Helmholtz equation. The algebraic methods are used in the inversion of a set of transverse electric (TE) mode magnetotelluric data from Antarctica. The existence of solutions is demonstrated and the number of solutions is found to be finite, bounded from above at 50. The best fitting structure is dominantly onedimensional with a low crustal resistivity of about 2 ohm-m. Such a low value is compatible with studies suggesting lower surface wave velocities than found in typical stable cratons.

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

    DEFF Research Database (Denmark)

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

    2005-01-01

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

  19. Hormones and β-Agonists

    NARCIS (Netherlands)

    Ginkel, van L.A.; Bovee, T.F.H.; Blokland, M.H.; Sterk, S.S.; Smits, N.G.E.; Pleadin, Jelka; Vulić, Ana

    2016-01-01

    This chapter provides some updated information on contemporary methods for hormone and β-agonist analyses. It deals with the classical approaches for the effective detection and identification of exogenous hormones. The chapter examines specific problems related to control strategies for natural

  20. Inverse source problems in elastodynamics

    Science.gov (United States)

    Bao, Gang; Hu, Guanghui; Kian, Yavar; Yin, Tao

    2018-04-01

    We are concerned with time-dependent inverse source problems in elastodynamics. The source term is supposed to be the product of a spatial function and a temporal function with compact support. We present frequency-domain and time-domain approaches to show uniqueness in determining the spatial function from wave fields on a large sphere over a finite time interval. The stability estimate of the temporal function from the data of one receiver and the uniqueness result using partial boundary data are proved. Our arguments rely heavily on the use of the Fourier transform, which motivates inversion schemes that can be easily implemented. A Landweber iterative algorithm for recovering the spatial function and a non-iterative inversion scheme based on the uniqueness proof for recovering the temporal function are proposed. Numerical examples are demonstrated in both two and three dimensions.

  1. Inverse problems of geophysics

    International Nuclear Information System (INIS)

    Yanovskaya, T.B.

    2003-07-01

    This report gives an overview and the mathematical formulation of geophysical inverse problems. General principles of statistical estimation are explained. The maximum likelihood and least square fit methods, the Backus-Gilbert method and general approaches for solving inverse problems are discussed. General formulations of linearized inverse problems, singular value decomposition and properties of pseudo-inverse solutions are given

  2. Partial volume effect in MRI

    International Nuclear Information System (INIS)

    Maeda, Munehiro; Yoshiya, Kazuhiko; Suzuki, Eiji

    1989-01-01

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

  3. Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

    DEFF Research Database (Denmark)

    Goncalves de Azavedo, Carlos M. B. P.; Watterson, Kenneth R; Wargent, Ed T

    2016-01-01

    The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure......-activity relationship studies of a previously disclosed non-acidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although...... a significant fraction of these non-carboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice...

  4. X-ray induced pericentric inversions in Anopheles albimanus

    International Nuclear Information System (INIS)

    Rabbani, M.G.; Seawright, J.A.; Kitzmiller, J.B.

    1977-01-01

    Sixteen different pericentric inversions, ten on chromosome 2 and six on chromosome 3, have been isolated and characterized. The partial sterility in the inversion heterozygotes ranged from about 28 to 50%. Contrary to theoretical considerations, a curvilinear relationship exists between inversion length and partial sterility, whereby a reduction in sterility was noted for progressively longer inversions. The break-points are distributed randomly over the autosomes, but are observed more frequently in the areas of the salivary gland chromosomes where diffuse and broken bands of variable stainability are located. (author)

  5. Structural differences in the two agonist binding sites of the Torpedo nicotinic acetylcholine receptor revealed by time-resolved fluorescence spectroscopy

    DEFF Research Database (Denmark)

    Martinez, K. L.; Corringer, P. J.; Edelstein, S. J.

    2000-01-01

    The nicotinic acetylcholine receptor (nAChR) from Torpedo marmorata carries two nonequivalent agonist binding sites at the αδ and αγ subunit interfaces. These sites have been characterized by time-resolved fluorescence with the partial nicotinic agonist dansyl-C6-choline (Dnscho). When bound...

  6. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

    Full Text Available A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes. Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

  7. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...... development may improve the effects of GLP-1 even further with optimized pharmacokinetic profiles resulting in fewer side effects. Meta-analyses have shown promising effects on cardiovascular disease and data from ongoing multicenter trials with cardiovascular endpoints are expected in 2015....

  8. The epileptogenic spectrum of opiate agonists.

    Science.gov (United States)

    Snead, O C; Bearden, L J

    1982-11-01

    The present authors gave mu, delta, kappa, epsilon and sigma opiate receptor agonists intracerebroventricularly to rats both singly and in combination while monitoring the electroencephalogram from cortical and depth electrodes. Dose-response curves were plotted with naloxone against the changes produced by each agonist, and the effect of a number of anticonvulsant drugs on agonist-induced seizures was ascertained. Each opiate agonist produced a different seizure pattern with a different naloxone dose-response curve and anticonvulsant profile. The order of convulsive potency was epsilon greater than delta greater than mu greater than sigma much greater than kappa. Petit mal-like seizure activity was unique to the delta agonist, leucine-enkephalin, while only the mu agonist, morphine produced generalized convulsive seizures. These experiments raise the possibility that opiate systems in the brain may be involved in the pathogenesis of a wide spectrum of seizure disorders.

  9. Inhibition by TRPA1 agonists of compound action potentials in the frog sciatic nerve

    Energy Technology Data Exchange (ETDEWEB)

    Matsushita, Akitomo; Ohtsubo, Sena; Fujita, Tsugumi; Kumamoto, Eiichi, E-mail: kumamote@cc.saga-u.ac.jp

    2013-04-26

    Highlights: •TRPA1 agonists inhibited compound action potentials in frog sciatic nerves. •This inhibition was not mediated by TRPA1 channels. •This efficacy was comparable to those of lidocaine and cocaine. •We found for the first time an ability of TRPA1 agonists to inhibit nerve conduction. -- Abstract: Although TRPV1 and TRPM8 agonists (vanilloid capsaicin and menthol, respectively) at high concentrations inhibit action potential conduction, it remains to be unknown whether TRPA1 agonists have a similar action. The present study examined the actions of TRPA1 agonists, cinnamaldehyde (CA) and allyl isothiocyanate (AITC), which differ in chemical structure from each other, on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. CA and AITC concentration-dependently reduced the peak amplitude of the CAP with the IC{sub 50} values of 1.2 and 1.5 mM, respectively; these activities were resistant to a non-selective TRP antagonist ruthenium red or a selective TRPA1 antagonist HC-030031. The CA and AITC actions were distinct in property; the latter but not former action was delayed in onset and partially reversible, and CA but not AITC increased thresholds to elicit CAPs. A CAP inhibition was seen by hydroxy-α-sanshool (by 60% at 0.05 mM), which activates both TRPA1 and TRPV1 channels, a non-vanilloid TRPV1 agonist piperine (by 20% at 0.07 mM) and tetrahydrolavandulol (where the six-membered ring of menthol is opened; IC{sub 50} = 0.38 mM). It is suggested that TRPA1 agonists as well as TRPV1 and TRPM8 agonists have an ability to inhibit nerve conduction without TRP activation, although their agonists are quite different in chemical structure from each other.

  10. Partial Cancellation

    Indian Academy of Sciences (India)

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

  11. AGONISTIC BEHAVIOR OF LABORATORY MICE

    Directory of Open Access Journals (Sweden)

    D. Cinghiţă

    2005-01-01

    Full Text Available In this work we study agonistic behavior of laboratory white mice when they are kept in captivity. For all this experimental work we used direct observation of mice, in small lists, because we need a reduced space to emphasize characteristics of agonistic behavior. Relations between members of the same species that live in organized groups are based in most cases on hierarchical structure. Relations between leader and subservient, decided by fighting, involve a thorough observation between individuals. Each member of a group has its own place on the ierarchical scale depending on resultes of fhights – it can be leader or it can be subsurvient, depending on if it wines or looses the fight. Once hierarchical scale made, every animal will adjust its behavior. After analyzing the obtained data we have enough reasons to believe that after fights the winner, usually, is the massive mouse, but it is also very important the sexual ripeness, so the immature male will be beaten. The leader male had a big exploring area and it checks up all territory.The females can be more aggressive, its fights are more brutal, than male fights are, when they fight for supremacy, but in this case fights are not as frequent as in the case of males. Always the superior female, on hierarchical scale, shows males its own statute, so the strongest genes will be perpetuated.

  12. Molecular mechanism of agonism and inverse agonism in the melanocortin receptors: Zn(2+) as a structural and functional probe

    DEFF Research Database (Denmark)

    Holst, Birgitte; Schwartz, Thue W

    2003-01-01

    Among the rhodopsin-like 7TM receptors, the MC receptors are functionally unique because their high constitutive signaling activity is regulated not only by endogenous peptide agonists-MSH peptides-but also by endogenous inverse agonists, namely, the proteins agouti and AGRP. Moreover, the metal......-ion Zn(2+) increases the signaling activity of at least the MC1 and MC4 receptors in three distinct ways: (1). by directly functioning as an agonist; (2). by potentiating the action of the endogenous agonist; and (3). by inhibiting the binding of the endogenous inverse agonist. Structurally the MC...... extracellular loop 2 is ultrashort because TM-IV basically connects directly into TM-V, whereas extracellular loop 3 appears to be held in a particular, constrained conformation by a putative, internal disulfide bridge. The interaction mode for the small and well-defined zinc-ion between a third, free Cys...

  13. Partial processing

    International Nuclear Information System (INIS)

    1978-11-01

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

  14. Partial gigantism

    Directory of Open Access Journals (Sweden)

    М.М. Karimova

    2017-05-01

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

  15. Translation of Novel Serotonin 5-HT7 Agonist Drug Candidates in Rodent Models of Fragile X Syndrome

    Science.gov (United States)

    2016-09-01

    HT1A partial agonist for autism . 6th Cisbio HTRF symposium (Brewster, MA), September 14-17, 2015. Acknowledged DOD funding. Teaching Lectures . 10...grant is to synthesize 5-PAT-type 5HT7 receptor agonists and assess their effectiveness to correct FXS phenotypes in Fmr1-KO mice and other mouse models...President of DELSIA (Delivering Science Innovation for Autism ) and Vice President, Innovative Technologies at Autism Speaks, Daniel Smith, who

  16. Multiscale Seismic Inversion in the Data and Image Domains

    KAUST Repository

    Zhang, Sanzong

    2015-01-01

    I present a general methodology for inverting seismic data in either the data or image domains. It partially overcomes one of the most serious problems with current waveform inversion methods, which is the tendency to converge to models far from

  17. Beta-agonists and animal welfare

    Science.gov (United States)

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

  18. Small molecule fluoride toxicity agonists.

    Science.gov (United States)

    Nelson, James W; Plummer, Mark S; Blount, Kenneth F; Ames, Tyler D; Breaker, Ronald R

    2015-04-23

    Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here, we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. The seismic reflection inverse problem

    International Nuclear Information System (INIS)

    Symes, W W

    2009-01-01

    The seismic reflection method seeks to extract maps of the Earth's sedimentary crust from transient near-surface recording of echoes, stimulated by explosions or other controlled sound sources positioned near the surface. Reasonably accurate models of seismic energy propagation take the form of hyperbolic systems of partial differential equations, in which the coefficients represent the spatial distribution of various mechanical characteristics of rock (density, stiffness, etc). Thus the fundamental problem of reflection seismology is an inverse problem in partial differential equations: to find the coefficients (or at least some of their properties) of a linear hyperbolic system, given the values of a family of solutions in some part of their domains. The exploration geophysics community has developed various methods for estimating the Earth's structure from seismic data and is also well aware of the inverse point of view. This article reviews mathematical developments in this subject over the last 25 years, to show how the mathematics has both illuminated innovations of practitioners and led to new directions in practice. Two themes naturally emerge: the importance of single scattering dominance and compensation for spectral incompleteness by spatial redundancy. (topical review)

  20. Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Bräuner-Osborne, Hans

    1999-01-01

    A number of CXC chemokines competed with similar, nanomolar affinity against 125I-interleukin-8 (IL-8) binding to ORF-74, a constitutively active seven-transmembrane receptor encoded by human herpesvirus 8. However, in competition against 125I-labeled growth-related oncogene (GRO)-alpha, the ORF-74...

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

    Science.gov (United States)

    Nutt, David J

    2010-02-01

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

  2. Convex blind image deconvolution with inverse filtering

    Science.gov (United States)

    Lv, Xiao-Guang; Li, Fang; Zeng, Tieyong

    2018-03-01

    Blind image deconvolution is the process of estimating both the original image and the blur kernel from the degraded image with only partial or no information about degradation and the imaging system. It is a bilinear ill-posed inverse problem corresponding to the direct problem of convolution. Regularization methods are used to handle the ill-posedness of blind deconvolution and get meaningful solutions. In this paper, we investigate a convex regularized inverse filtering method for blind deconvolution of images. We assume that the support region of the blur object is known, as has been done in a few existing works. By studying the inverse filters of signal and image restoration problems, we observe the oscillation structure of the inverse filters. Inspired by the oscillation structure of the inverse filters, we propose to use the star norm to regularize the inverse filter. Meanwhile, we use the total variation to regularize the resulting image obtained by convolving the inverse filter with the degraded image. The proposed minimization model is shown to be convex. We employ the first-order primal-dual method for the solution of the proposed minimization model. Numerical examples for blind image restoration are given to show that the proposed method outperforms some existing methods in terms of peak signal-to-noise ratio (PSNR), structural similarity (SSIM), visual quality and time consumption.

  3. Dopamine Agonists and Pathologic Behaviors

    Directory of Open Access Journals (Sweden)

    Brendan J. Kelley

    2012-01-01

    Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

  4. Endogenous Receptor Agonists: Resolving Inflammation

    Directory of Open Access Journals (Sweden)

    Gerhard Bannenberg

    2007-01-01

    Full Text Available Controlled resolution or the physiologic resolution of a well-orchestrated inflammatory response at the tissue level is essential to return to homeostasis. A comprehensive understanding of the cellular and molecular events that control the termination of acute inflammation is needed in molecular terms given the widely held view that aberrant inflammation underlies many common diseases. This review focuses on recent advances in the understanding of the role of arachidonic acid and ω-3 polyunsaturated fatty acids (PUFA–derived lipid mediators in regulating the resolution of inflammation. Using a functional lipidomic approach employing LC-MS-MS–based informatics, recent studies, reviewed herein, uncovered new families of local-acting chemical mediators actively biosynthesized during the resolution phase from the essential fatty acids eicosapentaenoic acid (EPA and docosahexaenoic acid (DHA. These new families of local chemical mediators are generated endogenously in exudates collected during the resolution phase, and were coined resolvins and protectins because specific members of these novel chemical families control both the duration and magnitude of inflammation in animal models of complex diseases. Recent advances on the biosynthesis, receptors, and actions of these novel anti-inflammatory and proresolving lipid mediators are reviewed with the aim to bring to attention the important role of specific lipid mediators as endogenous agonists in inflammation resolution.

  5. Acute puerperal uterine inversion

    International Nuclear Information System (INIS)

    Hussain, M.; Liaquat, N.; Noorani, K.; Bhutta, S.Z; Jabeen, T.

    2004-01-01

    Objective: To determine the frequency, causes, clinical presentations, management and maternal mortality associated with acute puerperal inversion of the uterus. Materials and Methods: All the patients who developed acute puerperal inversion of the uterus either in or outside the JPMC were included in the study. Patients of chronic uterine inversion were not included in the present study. Abdominal and vaginal examination was done to confirm and classify inversion into first, second or third degrees. Results: 57036 deliveries and 36 acute uterine inversions occurred during the study period, so the frequency of uterine inversion was 1 in 1584 deliveries. Mismanagement of third stage of labour was responsible for uterine inversion in 75% of patients. Majority of the patients presented with shock, either hypovolemic (69%) or neurogenic (13%) in origin. Manual replacement of the uterus under general anaesthesia with 2% halothane was successfully done in 35 patients (97.5%). Abdominal hysterectomy was done in only one patient. There were three maternal deaths due to inversion. Conclusion: Proper education and training regarding placental delivery, diagnosis and management of uterine inversion must be imparted to the maternity care providers especially to traditional birth attendants and family physicians to prevent this potentially life-threatening condition. (author)

  6. Classical limit of the quantum inverse scattering problem

    International Nuclear Information System (INIS)

    Bogdanov, I.V.

    1986-01-01

    This paper studies the passage to the limit of classical mechanics which is realized in the formalism of Marchenko's method for a spherically symmetric inverse problem of quantum scattering for fixed angular momentum. The limit is considered for the general case of partial waves with arbitrary values of the orbital number 1>0 in the lowest order of perturbation theory. It is shown how in the limit h→0 in the quantum inverse problem the integral Able transformation characteristic of classical inverse problems arises. The classical inversion formula with delay time is derived from the Marchenko equation

  7. Inverse logarithmic potential problem

    CERN Document Server

    Cherednichenko, V G

    1996-01-01

    The Inverse and Ill-Posed Problems Series is a series of monographs publishing postgraduate level information on inverse and ill-posed problems for an international readership of professional scientists and researchers. The series aims to publish works which involve both theory and applications in, e.g., physics, medicine, geophysics, acoustics, electrodynamics, tomography, and ecology.

  8. Inverse Kinematics using Quaternions

    DEFF Research Database (Denmark)

    Henriksen, Knud; Erleben, Kenny; Engell-Nørregård, Morten

    In this project I describe the status of inverse kinematics research, with the focus firmly on the methods that solve the core problem. An overview of the different methods are presented Three common methods used in inverse kinematics computation have been chosen as subject for closer inspection....

  9. Identification of novel selective V2 receptor non-peptide agonists.

    Science.gov (United States)

    Del Tredici, Andria L; Vanover, Kim E; Knapp, Anne E; Bertozzi, Sine M; Nash, Norman R; Burstein, Ethan S; Lameh, Jelveh; Currier, Erika A; Davis, Robert E; Brann, Mark R; Mohell, Nina; Olsson, Roger; Piu, Fabrice

    2008-10-30

    Peptides with agonist activity at the vasopressin V(2) receptor are used clinically to treat fluid homeostasis disorders such as polyuria and central diabetes insipidus. Of these peptides, the most commonly used is desmopressin, which displays poor bioavailability as well as potent activity at the V(1b) receptor, with possible stress-related adverse effects. Thus, there is a strong need for the development of small molecule chemistries with selective V(2) receptor agonist activity. Using the functional cell-based assay Receptor Selection and Amplification Technology (R-SAT((R))), a screening effort identified three small molecule chemotypes (AC-94544, AC-88324, and AC-110484) with selective agonist activity at the V(2) receptor. One of these compounds, AC-94544, displayed over 180-fold selectivity at the V(2) receptor compared to related vasopressin and oxytocin receptors and no activity at 28 other G protein-coupled receptors (GPCRs). All three compounds also showed partial agonist activity at the V(2) receptor in a cAMP accumulation assay. In addition, in a rat model of central diabetes insipidus, AC-94544 was able to significantly reduce urine output in a dose-dependent manner. Thus, AC-94544, AC-88324, and AC-110484 represent novel opportunities for the treatment of disorders associated with V(2) receptor agonist deficiency.

  10. Cold suppresses agonist-induced activation of TRPV1.

    Science.gov (United States)

    Chung, M-K; Wang, S

    2011-09-01

    Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

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

    Science.gov (United States)

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

    2016-01-01

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

  12. Gravity inversion code

    International Nuclear Information System (INIS)

    Burkhard, N.R.

    1979-01-01

    The gravity inversion code applies stabilized linear inverse theory to determine the topography of a subsurface density anomaly from Bouguer gravity data. The gravity inversion program consists of four source codes: SEARCH, TREND, INVERT, and AVERAGE. TREND and INVERT are used iteratively to converge on a solution. SEARCH forms the input gravity data files for Nevada Test Site data. AVERAGE performs a covariance analysis on the solution. This document describes the necessary input files and the proper operation of the code. 2 figures, 2 tables

  13. Instrument developments for inverse photoemission

    International Nuclear Information System (INIS)

    Brenac, A.

    1987-02-01

    Experimental developments principally concerning electron sources for inverse photoemission are presented. The specifications of the electron beam are derived from experiment requirements, taking into account the limitations encountered (space charge divergence). For a wave vector resolution of 0.2 A -1 , the maximum current is 25 microA at 20 eV. The design of a gun providing such a beam in the range 5 to 50 eV is presented. Angle-resolved inverse photoemission experiments show angular effects at 30 eV. For an energy of 10 eV, angular effects should be stronger, but the low efficiency of the spectrometer in this range makes the experiments difficult. The total energy resolution of 0.3 eV is the result mainly of electron energy spread, as expected. The electron sources are based on field effect electron emission from a cathode consisting of a large number of microtips. The emission arises from a few atomic cells for each tip. The ultimate theoretical energy spread is 0.1 eV. This value is not attained because of an interface resistance problem. A partial solution of this problem allows measurement of an energy spread of 0.9 eV for a current of 100 microA emitted at 60 eV. These cathodes have a further advantage in that emission can occur at a low temperature [fr

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

    Directory of Open Access Journals (Sweden)

    S. Stevens Negus

    2012-01-01

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

  15. Sharp spatially constrained inversion

    DEFF Research Database (Denmark)

    Vignoli, Giulio G.; Fiandaca, Gianluca G.; Christiansen, Anders Vest C A.V.C.

    2013-01-01

    We present sharp reconstruction of multi-layer models using a spatially constrained inversion with minimum gradient support regularization. In particular, its application to airborne electromagnetic data is discussed. Airborne surveys produce extremely large datasets, traditionally inverted...... by using smoothly varying 1D models. Smoothness is a result of the regularization constraints applied to address the inversion ill-posedness. The standard Occam-type regularized multi-layer inversion produces results where boundaries between layers are smeared. The sharp regularization overcomes...... inversions are compared against classical smooth results and available boreholes. With the focusing approach, the obtained blocky results agree with the underlying geology and allow for easier interpretation by the end-user....

  16. Inverse planning IMRT

    International Nuclear Information System (INIS)

    Rosenwald, J.-C.

    2008-01-01

    The lecture addressed the following topics: Optimizing radiotherapy dose distribution; IMRT contributes to optimization of energy deposition; Inverse vs direct planning; Main steps of IMRT; Background of inverse planning; General principle of inverse planning; The 3 main components of IMRT inverse planning; The simplest cost function (deviation from prescribed dose); The driving variable : the beamlet intensity; Minimizing a 'cost function' (or 'objective function') - the walker (or skier) analogy; Application to IMRT optimization (the gradient method); The gradient method - discussion; The simulated annealing method; The optimization criteria - discussion; Hard and soft constraints; Dose volume constraints; Typical user interface for definition of optimization criteria; Biological constraints (Equivalent Uniform Dose); The result of the optimization process; Semi-automatic solutions for IMRT; Generalisation of the optimization problem; Driving and driven variables used in RT optimization; Towards multi-criteria optimization; and Conclusions for the optimization phase. (P.A.)

  17. Partial differential equations an introduction

    CERN Document Server

    Colton, David

    2004-01-01

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

  18. Small-molecule AT2 receptor agonists

    DEFF Research Database (Denmark)

    Hallberg, Mathias; Sumners, Colin; Steckelings, U Muscha

    2018-01-01

    The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist...... with the highest affinity for the AT2R reported to date (Ki = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8......, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also...

  19. Switch from antagonist to agonist after addition of a DOTA chelator to a somatostatin analog

    International Nuclear Information System (INIS)

    Reubi, Jean Claude; Cescato, Renzo; Waser, Beatrice; Erchegyi, Judit; Rivier, Jean E.

    2010-01-01

    Peptide receptor targeting has become an increasingly attractive method to target tumors diagnostically and radiotherapeutically. Peptides linked to a variety of chelators have been developed for this purpose. They have, however, rarely been tested for their agonistic or antagonistic properties. We report here on a somatostatin antagonist that switched to an agonist upon coupling to a DOTA chelator. Two novel somatostatin analogs, 406-040-15 and its DOTA-coupled counterpart 406-051-20, with and without cold Indium labeling, were tested for their somatostatin receptor subtypes 1-5 (sst 1 -sst 5 ) binding affinity using receptor autoradiography. Moreover, they were tested functionally for their ability to affect sst 2 and sst 3 internalization in vitro in HEK293 cells stably expressing the human sst 2 or sst 3 receptor, using an immunofluorescence microscopy-based internalization assay. All three compounds were characterized as pan-somatostatin analogs having a high affinity for all five sst. In the sst 2 internalization assay, all three compounds showed an identical behavior, namely, a weak agonistic effect complemented by a weak antagonistic effect, compatible with the behavior of a partial agonist. Conversely, in the sst 3 internalization assay, 406-040-15 was a full antagonist whereas its DOTA-coupled counterpart, 406-051-20, with and without Indium labeling, switched to a full agonist. Adding the DOTA chelator to the somatostatin analog 406-040-15 triggers a switch at sst 3 receptor from an antagonist to an agonist. This indicates that potential radioligands for tumor targeting should always be tested functionally before further development, in particular if a chelator is added. (orig.)

  20. Limits to Nonlinear Inversion

    DEFF Research Database (Denmark)

    Mosegaard, Klaus

    2012-01-01

    For non-linear inverse problems, the mathematical structure of the mapping from model parameters to data is usually unknown or partly unknown. Absence of information about the mathematical structure of this function prevents us from presenting an analytical solution, so our solution depends on our......-heuristics are inefficient for large-scale, non-linear inverse problems, and that the 'no-free-lunch' theorem holds. We discuss typical objections to the relevance of this theorem. A consequence of the no-free-lunch theorem is that algorithms adapted to the mathematical structure of the problem perform more efficiently than...... pure meta-heuristics. We study problem-adapted inversion algorithms that exploit the knowledge of the smoothness of the misfit function of the problem. Optimal sampling strategies exist for such problems, but many of these problems remain hard. © 2012 Springer-Verlag....

  1. Reciprocity of agonistic support in ravens.

    Science.gov (United States)

    Fraser, Orlaith N; Bugnyar, Thomas

    2012-01-01

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

  2. FXR agonist activity of conformationally constrained analogs of GW 4064.

    Science.gov (United States)

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y; Caldwell, Richard D; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Navas, Frank; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Bruce Wisely, G

    2009-08-15

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  3. Generalized inverses theory and computations

    CERN Document Server

    Wang, Guorong; Qiao, Sanzheng

    2018-01-01

    This book begins with the fundamentals of the generalized inverses, then moves to more advanced topics. It presents a theoretical study of the generalization of Cramer's rule, determinant representations of the generalized inverses, reverse order law of the generalized inverses of a matrix product, structures of the generalized inverses of structured matrices, parallel computation of the generalized inverses, perturbation analysis of the generalized inverses, an algorithmic study of the computational methods for the full-rank factorization of a generalized inverse, generalized singular value decomposition, imbedding method, finite method, generalized inverses of polynomial matrices, and generalized inverses of linear operators. This book is intended for researchers, postdocs, and graduate students in the area of the generalized inverses with an undergraduate-level understanding of linear algebra.

  4. Some results on inverse scattering

    International Nuclear Information System (INIS)

    Ramm, A.G.

    2008-01-01

    A review of some of the author's results in the area of inverse scattering is given. The following topics are discussed: (1) Property C and applications, (2) Stable inversion of fixed-energy 3D scattering data and its error estimate, (3) Inverse scattering with 'incomplete' data, (4) Inverse scattering for inhomogeneous Schroedinger equation, (5) Krein's inverse scattering method, (6) Invertibility of the steps in Gel'fand-Levitan, Marchenko, and Krein inversion methods, (7) The Newton-Sabatier and Cox-Thompson procedures are not inversion methods, (8) Resonances: existence, location, perturbation theory, (9) Born inversion as an ill-posed problem, (10) Inverse obstacle scattering with fixed-frequency data, (11) Inverse scattering with data at a fixed energy and a fixed incident direction, (12) Creating materials with a desired refraction coefficient and wave-focusing properties. (author)

  5. Gonadotropin releasing hormone agonists: Expanding vistas

    Directory of Open Access Journals (Sweden)

    Navneet Magon

    2011-01-01

    Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

  6. Children's strategies to solving additive inverse problems: a preliminary analysis

    Science.gov (United States)

    Ding, Meixia; Auxter, Abbey E.

    2017-03-01

    Prior studies show that elementary school children generally "lack" formal understanding of inverse relations. This study goes beyond lack to explore what children might "have" in their existing conception. A total of 281 students, kindergarten to third grade, were recruited to respond to a questionnaire that involved both contextual and non-contextual tasks on inverse relations, requiring both computational and explanatory skills. Results showed that children demonstrated better performance in computation than explanation. However, many students' explanations indicated that they did not necessarily utilize inverse relations for computation. Rather, they appeared to possess partial understanding, as evidenced by their use of part-whole structure, which is a key to understanding inverse relations. A close inspection of children's solution strategies further revealed that the sophistication of children's conception of part-whole structure varied in representation use and unknown quantity recognition, which suggests rich opportunities to develop students' understanding of inverse relations in lower elementary classrooms.

  7. Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs.

    Science.gov (United States)

    Moore, Thomas J; Glenmullen, Joseph; Mattison, Donald R

    2014-12-01

    Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia. To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs. We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System. Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs. We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001). Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present

  8. Sports doping: Emerging designer and therapeutic B2-agonists

    NARCIS (Netherlands)

    Fragkaki, A.G.; Georgakopoulos, C.; Sterk, S.S.; Nielen, M.W.F.

    2013-01-01

    Beta2-adrenergic agonists, or ß2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of ß2-agonists is prohibited in sports by the World Anti-Doping

  9. Modification of kindled amygdaloid seizures by opiate agonists and antagonists.

    Science.gov (United States)

    Albertson, T E; Joy, R M; Stark, L G

    1984-03-01

    The effects of 19 opiate agonists and antagonists on kindled amygdaloid seizures in the rat were studied. The mu agonists tended to reduce the length of elicited afterdischarges and behavioral ranks, while markedly increasing postictal electroencephalogram spikes and behavioral arrest time. These effects were reversed by naloxone. The kappa agonists reduced behavioral rank and variably reduced afterdischarge length with a concomitant lengthening of postictal behavioral arrest time and number of electroencephalogram spikes. The putative sigma agonist, SKF 10,047, reduced afterdischarge durations only at the higher doses tested. The decreases found after the sigma agonists in postictal electroencephalogram spiking and time of behavioral arrest were not reversed by naloxone. Only the lower doses of normeperidine were found to decrease seizure thresholds. The mixed agonist/antagonists (MAA) cyclazocine and cyclorphan markedly increased seizure threshold and reduced afterdischarge duration and behavioral rank. Only the MAA pentazocine tended to increase threshold but not suprathreshold afterdischarge durations. The order of ability to modify the ictal events was MAA (selected) greater than kappa agonists greater than mu agonists greater than sigma agonists. The increase in postictal events (behavior arrest and spikes) was caused most effectively by pretreatment with mu agonist greater than kappa agonist greater than selected MAA greater than sigma agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Inversion assuming weak scattering

    DEFF Research Database (Denmark)

    Xenaki, Angeliki; Gerstoft, Peter; Mosegaard, Klaus

    2013-01-01

    due to the complex nature of the field. A method based on linear inversion is employed to infer information about the statistical properties of the scattering field from the obtained cross-spectral matrix. A synthetic example based on an active high-frequency sonar demonstrates that the proposed...

  11. Bayesian seismic AVO inversion

    Energy Technology Data Exchange (ETDEWEB)

    Buland, Arild

    2002-07-01

    A new linearized AVO inversion technique is developed in a Bayesian framework. The objective is to obtain posterior distributions for P-wave velocity, S-wave velocity and density. Distributions for other elastic parameters can also be assessed, for example acoustic impedance, shear impedance and P-wave to S-wave velocity ratio. The inversion algorithm is based on the convolutional model and a linearized weak contrast approximation of the Zoeppritz equation. The solution is represented by a Gaussian posterior distribution with explicit expressions for the posterior expectation and covariance, hence exact prediction intervals for the inverted parameters can be computed under the specified model. The explicit analytical form of the posterior distribution provides a computationally fast inversion method. Tests on synthetic data show that all inverted parameters were almost perfectly retrieved when the noise approached zero. With realistic noise levels, acoustic impedance was the best determined parameter, while the inversion provided practically no information about the density. The inversion algorithm has also been tested on a real 3-D dataset from the Sleipner Field. The results show good agreement with well logs but the uncertainty is high. The stochastic model includes uncertainties of both the elastic parameters, the wavelet and the seismic and well log data. The posterior distribution is explored by Markov chain Monte Carlo simulation using the Gibbs sampler algorithm. The inversion algorithm has been tested on a seismic line from the Heidrun Field with two wells located on the line. The uncertainty of the estimated wavelet is low. In the Heidrun examples the effect of including uncertainty of the wavelet and the noise level was marginal with respect to the AVO inversion results. We have developed a 3-D linearized AVO inversion method with spatially coupled model parameters where the objective is to obtain posterior distributions for P-wave velocity, S

  12. Calculation of the inverse data space via sparse inversion

    KAUST Repository

    Saragiotis, Christos

    2011-01-01

    The inverse data space provides a natural separation of primaries and surface-related multiples, as the surface multiples map onto the area around the origin while the primaries map elsewhere. However, the calculation of the inverse data is far from trivial as theory requires infinite time and offset recording. Furthermore regularization issues arise during inversion. We perform the inversion by minimizing the least-squares norm of the misfit function by constraining the $ell_1$ norm of the solution, being the inverse data space. In this way a sparse inversion approach is obtained. We show results on field data with an application to surface multiple removal.

  13. Introduction to inverse problems for differential equations

    CERN Document Server

    Hasanov Hasanoğlu, Alemdar

    2017-01-01

    This book presents a systematic exposition of the main ideas and methods in treating inverse problems for PDEs arising in basic mathematical models, though it makes no claim to being exhaustive. Mathematical models of most physical phenomena are governed by initial and boundary value problems for PDEs, and inverse problems governed by these equations arise naturally in nearly all branches of science and engineering. The book’s content, especially in the Introduction and Part I, is self-contained and is intended to also be accessible for beginning graduate students, whose mathematical background includes only basic courses in advanced calculus, PDEs and functional analysis. Further, the book can be used as the backbone for a lecture course on inverse and ill-posed problems for partial differential equations. In turn, the second part of the book consists of six nearly-independent chapters. The choice of these chapters was motivated by the fact that the inverse coefficient and source problems considered here a...

  14. Direct and Inverse Problems in Statistical Wavefields

    International Nuclear Information System (INIS)

    Wolf, Emil

    2002-01-01

    In this report account is presented of research carried out during the period September 1, 1999-August 31, 2002 under the sponsorship of the Department of Energy, grant DE-FG02-90ER14119. The research covered several areas of modern optical physics, particularly propagation of partially coherent light and its interaction with deterministic and with random media, spectroscopy with partially coherent light, polarization properties of statistical wave fields, effects of moving diffusers on coherence and on the spectra of light transmitted and scattered by them, reciprocity inequalities involving spatial and angular correlations of partially coherent beams, spreading of partially coherent beams in-random media, inverse source problems, computed and diffraction tomography and partially coherent solitons. We have discovered a new phenomenon in an emerging field of physical optics, known as singular optics; specifically we found that the spectrum of light changes drastically in the neighborhood of points where the intensity has zero value and where, consequently, the phase becomes singular, We noted some potential applications of this phenomenon. The results of our investigations were reported in 39 publications. They are listed on pages 3 to 5. Summaries of these publications are given on pages 6-13. Scientists who have participated in this research are listed on page 14

  15. Subtype selective kainic acid receptor agonists

    DEFF Research Database (Denmark)

    Bunch, Lennart; Krogsgaard-Larsen, Povl

    2009-01-01

    (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (m......GluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists...

  16. Partial mGlu₅ Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects.

    Science.gov (United States)

    Gould, Robert W; Amato, Russell J; Bubser, Michael; Joffe, Max E; Nedelcovych, Michael T; Thompson, Analisa D; Nickols, Hilary H; Yuh, Johannes P; Zhan, Xiaoyan; Felts, Andrew S; Rodriguez, Alice L; Morrison, Ryan D; Byers, Frank W; Rook, Jerri M; Daniels, John S; Niswender, Colleen M; Conn, P Jeffrey; Emmitte, Kyle A; Lindsley, Craig W; Jones, Carrie K

    2016-03-01

    Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant- and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu5 NAMs in these assays corresponded with increasing in vivo mGlu5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu5 NAMs, but with a broader therapeutic index.

  17. Electrochemically driven emulsion inversion

    Science.gov (United States)

    Johans, Christoffer; Kontturi, Kyösti

    2007-09-01

    It is shown that emulsions stabilized by ionic surfactants can be inverted by controlling the electrical potential across the oil-water interface. The potential dependent partitioning of sodium dodecyl sulfate (SDS) was studied by cyclic voltammetry at the 1,2-dichlorobenzene|water interface. In the emulsion the potential control was achieved by using a potential-determining salt. The inversion of a 1,2-dichlorobenzene-in-water (O/W) emulsion stabilized by SDS was followed by conductometry as a function of added tetrapropylammonium chloride. A sudden drop in conductivity was observed, indicating the change of the continuous phase from water to 1,2-dichlorobenzene, i.e. a water-in-1,2-dichlorobenzene emulsion was formed. The inversion potential is well in accordance with that predicted by the hydrophilic-lipophilic deviation if the interfacial potential is appropriately accounted for.

  18. Channelling versus inversion

    DEFF Research Database (Denmark)

    Gale, A.S.; Surlyk, Finn; Anderskouv, Kresten

    2013-01-01

    Evidence from regional stratigraphical patterns in Santonian−Campanian chalk is used to infer the presence of a very broad channel system (5 km across) with a depth of at least 50 m, running NNW−SSE across the eastern Isle of Wight; only the western part of the channel wall and fill is exposed. W......−Campanian chalks in the eastern Isle of Wight, involving penecontemporaneous tectonic inversion of the underlying basement structure, are rejected....

  19. Reactivity in inverse micelles

    International Nuclear Information System (INIS)

    Brochette, Pascal

    1987-01-01

    This research thesis reports the study of the use of micro-emulsions of water in oil as reaction support. Only the 'inverse micelles' domain of the ternary mixing (water/AOT/isooctane) has been studied. The main addressed issues have been: the micro-emulsion disturbance in presence of reactants, the determination of reactant distribution and the resulting kinetic theory, the effect of the interface on electron transfer reactions, and finally protein solubilization [fr

  20. Inverse transition radiation

    International Nuclear Information System (INIS)

    Steinhauer, L.C.; Romea, R.D.; Kimura, W.D.

    1997-01-01

    A new method for laser acceleration is proposed based upon the inverse process of transition radiation. The laser beam intersects an electron-beam traveling between two thin foils. The principle of this acceleration method is explored in terms of its classical and quantum bases and its inverse process. A closely related concept based on the inverse of diffraction radiation is also presented: this concept has the significant advantage that apertures are used to allow free passage of the electron beam. These concepts can produce net acceleration because they do not satisfy the conditions in which the Lawson-Woodward theorem applies (no net acceleration in an unbounded vacuum). Finally, practical aspects such as damage limits at optics are employed to find an optimized set of parameters. For reasonable assumptions an acceleration gradient of 200 MeV/m requiring a laser power of less than 1 GW is projected. An interesting approach to multi-staging the acceleration sections is also presented. copyright 1997 American Institute of Physics

  1. Testing earthquake source inversion methodologies

    KAUST Repository

    Page, Morgan T.; Mai, Paul Martin; Schorlemmer, Danijel

    2011-01-01

    Source Inversion Validation Workshop; Palm Springs, California, 11-12 September 2010; Nowadays earthquake source inversions are routinely performed after large earthquakes and represent a key connection between recorded seismic and geodetic data

  2. Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells.

    Directory of Open Access Journals (Sweden)

    Lanlan Liu

    Full Text Available Emerging evidence suggests that tumor-initiating cells (TICs are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPARγ agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC cells. Reactive oxygen species (ROS initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPARγ agonists. However, PPARγ agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPARγ agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPARγ agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPARγ agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPARγ agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.

  3. Effects of agonist efficacy on desensitization of phosphoinositide hydrolysis mediated by m1 and m3 muscarinic receptors expressed in Chinese hamster ovary cells

    International Nuclear Information System (INIS)

    Hu, J.; Wang, S.Z.; el-Fakahany, E.E.

    1991-01-01

    Muscarinic receptor agonist-induced desensitization of phosphoinositide (PI) hydrolysis and loss of receptors were studied in Chinese hamster ovary (CHO) cells transfected with the m1 and m3 muscarinic receptor genes. Long-term exposure to the full agonist carbamylcholine (CBC) resulted in a time-dependent attenuation of the maximal PI response and a decrease in agonist potency. This desensitization was accompanied by a parallel loss of maximal ligand binding without an alteration of the binding affinity. The time course of both receptor desensitization and down-regulation was similar in m1 and m3 CHO cells. The PI response to the partial agonist McN-A-343 (McN) in m1 cells was more sensitive to desensitization by CBC than the response to the latter agonist, and this desensitization was faster than receptor down-regulation. Desensitization of the PI response to McN was reflected as a decrease in the maximal response without a marked change in potency. McN induced slow desensitization of the PI response to CBC but a much faster desensitization of its own response. Our data provide evidence that although muscarinic agonist-induced desensitization of PI hydrolysis in CHO cells is due mainly to loss of receptors, there are other important factors which play a role in this process, e.g., receptor-effector uncoupling. The relative contribution of these different mechanisms depends on the efficacy of the agonists used for the receptor desensitization and activation steps

  4. A mathematical framework for inverse wave problems in heterogeneous media

    NARCIS (Netherlands)

    Blazek, K.D.; Stolk, C.; Symes, W.W.

    2013-01-01

    This paper provides a theoretical foundation for some common formulations of inverse problems in wave propagation, based on hyperbolic systems of linear integro-differential equations with bounded and measurable coefficients. The coefficients of these time-dependent partial differential equations

  5. Sphingosine-1-Phosphate Receptor-1 Selective Agonist Enhances Collateral Growth and Protects against Subsequent Stroke.

    Directory of Open Access Journals (Sweden)

    Masahiko Ichijo

    Full Text Available Collateral growth after acute occlusion of an intracranial artery is triggered by increasing shear stress in preexisting collateral pathways. Recently, sphingosine-1-phosphate receptor-1 (S1PR1 on endothelial cells was reported to be essential in sensing fluid shear stress. Here, we evaluated the expression of S1PR1 in the hypoperfused mouse brain and investigated the effect of a selective S1PR1 agonist on leptomeningeal collateral growth and subsequent ischemic damage after focal ischemia.In C57Bl/6 mice (n = 133 subjected to unilateral common carotid occlusion (CCAO and sham surgery. The first series examined the time course of collateral growth, cell proliferation, and S1PR1 expression in the leptomeningeal arteries after CCAO. The second series examined the relationship between pharmacological regulation of S1PR1 and collateral growth of leptomeningeal anastomoses. Animals were randomly assigned to one of the following groups: LtCCAO and daily intraperitoneal (i.p. injection for 7 days of an S1PR1 selective agonist (SEW2871, 5 mg/kg/day; sham surgery and daily i.p. injection for 7 days of SEW2871 after surgery; LtCCAO and daily i.p. injection for 7 days of SEW2871 and an S1PR1 inverse agonist (VPC23019, 0.5 mg/kg; LtCCAO and daily i.p. injection of DMSO for 7 days after surgery; and sham surgery and daily i.p. injection of DMSO for 7 days. Leptomeningeal anastomoses were visualized 14 days after LtCCAO by latex perfusion method, and a set of animals underwent subsequent permanent middle cerebral artery occlusion (pMCAO 7 days after the treatment termination. Neurological functions 1 hour, 1, 4, and 7 days and infarction volume 7 days after pMCAO were evaluated.In parallel with the increase in S1PR1 mRNA levels, S1PR1 expression colocalized with endothelial cell markers in the leptomeningeal arteries, increased markedly on the side of the CCAO, and peaked 7 days after CCAO. Mitotic cell numbers in the leptomeningeal arteries increased after

  6. Essential oils of culinary herbs and spices display agonist and antagonist activities at human aryl hydrocarbon receptor AhR.

    Science.gov (United States)

    Bartoňková, Iveta; Dvořák, Zdeněk

    2018-01-01

    Essential oils (EOs) of culinary herbs and spices are used to flavor, color and preserve foods and drinks. Dietary intake of EOs is significant, deserving an attention of toxicologists. We examined the effects of 31 EOs of culinary herbs and spices on the transcriptional activity of human aryl hydrocarbon receptor (AhR), which is a pivotal xenobiotic sensor, having also multiple roles in human physiology. Tested EOs were sorted out into AhR-inactive ones (14 EOs) and AhR-active ones, including full agonists (cumin, jasmine, vanilla, bay leaf), partial agonists (cloves, dill, thyme, nutmeg, oregano) and antagonists (tarragon, caraway, turmeric, lovage, fennel, spearmint, star anise, anise). Major constituents (>10%) of AhR-active EOs were studied in more detail. We identified AhR partial agonists (carvacrol, ligustilide, eugenol, eugenyl acetate, thymol, ar-turmerone) and antagonists (trans-anethole, butylidine phtalide, R/S-carvones, p-cymene), which account for AhR-mediated activities of EOs of fennel, anise, star anise, caraway, spearmint, tarragon, cloves, dill, turmeric, lovage, thyme and oregano. We also show that AhR-mediated effects of some individual constituents of EOs differ from those manifested in mixtures. In conclusion, EOs of culinary herbs and spices are agonists and antagonists of human AhR, implying a potential for food-drug interactions and interference with endocrine pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Partial tooth gear bearings

    Science.gov (United States)

    Vranish, John M. (Inventor)

    2010-01-01

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

  8. Introduction to Schroedinger inverse scattering

    International Nuclear Information System (INIS)

    Roberts, T.M.

    1991-01-01

    Schroedinger inverse scattering uses scattering coefficients and bound state data to compute underlying potentials. Inverse scattering has been studied extensively for isolated potentials q(x), which tend to zero as vertical strokexvertical stroke→∞. Inverse scattering for isolated impurities in backgrounds p(x) that are periodic, are Heaviside steps, are constant for x>0 and periodic for x<0, or that tend to zero as x→∞ and tend to ∞ as x→-∞, have also been studied. This paper identifies literature for the five inverse problems just mentioned, and for four other inverse problems. Heaviside-step backgrounds are discussed at length. (orig.)

  9. Essays on partial retirement

    NARCIS (Netherlands)

    Kantarci, T.

    2012-01-01

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

  10. GLP-1 agonists for type 2 diabetes

    DEFF Research Database (Denmark)

    Jespersen, Maria J; Knop, Filip K; Christensen, Mikkel

    2013-01-01

    and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration. EXPERT OPINION: GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes......Within recent years, glucagon-like peptide 1 receptor agonists (GLP-1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles. AREAS COVERED: This review describes the pharmacokinetics...

  11. Sports doping: emerging designer and therapeutic β2-agonists.

    Science.gov (United States)

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future. © 2013.

  12. Inverse Faraday Effect Revisited

    Science.gov (United States)

    Mendonça, J. T.; Ali, S.; Davies, J. R.

    2010-11-01

    The inverse Faraday effect is usually associated with circularly polarized laser beams. However, it was recently shown that it can also occur for linearly polarized radiation [1]. The quasi-static axial magnetic field by a laser beam propagating in plasma can be calculated by considering both the spin and the orbital angular momenta of the laser pulse. A net spin is present when the radiation is circularly polarized and a net orbital angular momentum is present if there is any deviation from perfect rotational symmetry. This orbital angular momentum has recently been discussed in the plasma context [2], and can give an additional contribution to the axial magnetic field, thus enhancing or reducing the inverse Faraday effect. As a result, this effect that is usually attributed to circular polarization can also be excited by linearly polarized radiation, if the incident laser propagates in a Laguerre-Gauss mode carrying a finite amount of orbital angular momentum.[4pt] [1] S. ALi, J.R. Davies and J.T. Mendonca, Phys. Rev. Lett., 105, 035001 (2010).[0pt] [2] J. T. Mendonca, B. Thidé, and H. Then, Phys. Rev. Lett. 102, 185005 (2009).

  13. Pharmacological Characterization of 30 Human Melanocortin-4 Receptor Polymorphisms with the Endogenous Proopiomelanocortin Derived Agonists, Synthetic Agonists, and the Endogenous Agouti-Related Protein (AGRP) Antagonist

    Science.gov (United States)

    Xiang, Zhimin; Proneth, Bettina; Dirain, Marvin L.; Litherland, Sally A.; Haskell-Luevano, Carrie

    2010-01-01

    cytometry. The F51L, I69T, and A219V hMC4Rs possessed full agonist activity and significantly decreased endogenous agonist ligand potency. At the E61K, D90N, Y157S, and C271R hMC4Rs, all agonist ligands examined were only partially efficacious in generating a maximal signaling response (partial agonists) and possessed significantly decreased endogenous agonist ligand potency. Only the A219V, G238D, and S295P hMC4Rs possessed significantly decreased AGRP(87-132) antagonist potency. These data provide new information for use in GPCR computational development as well as insights into MC4R structure ad function. PMID:20462274

  14. Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist.

    Science.gov (United States)

    Xiang, Zhimin; Proneth, Bettina; Dirain, Marvin L; Litherland, Sally A; Haskell-Luevano, Carrie

    2010-06-08

    expression by flow cytometry. The F51L, I69T, and A219V hMC4Rs possessed full agonist activity and significantly decreased endogenous agonist ligand potency. At the E61K, D90N, Y157S, and C271R hMC4Rs, all agonist ligands examined were only partially efficacious in generating a maximal signaling response (partial agonists) and possessed significantly decreased endogenous agonist ligand potency. Only the A219V, G238D, and S295P hMC4Rs possessed significantly decreased AGRP(87-132) antagonist potency. These data provide new information for use in GPCR computational development as well as insights into MC4R structure ad function.

  15. Conformational variability of the glycine receptor M2 domain in response to activation by different agonists

    DEFF Research Database (Denmark)

    Pless, Stephan Alexander; Dibas, Mohammed I; Lester, Henry A

    2007-01-01

    change. Although taurine and beta-alanine were weak partial agonists at the alpha1R19'C glycine receptor, they induced large fluorescence changes. Propofol, which drastically enhanced these currents, did not induce a glycine-like blue shift in the spectral emission peak. The inhibitors strychnine...... and picrotoxin elicited fluorescence and current changes as expected for a competitive antagonist and an open channel blocker, respectively. Glycine and taurine (or beta-alanine) also produced an increase and a decrease, respectively, in the fluorescence of a label attached to the nearby L22'C residue. Thus...

  16. Recurrent Partial Words

    Directory of Open Access Journals (Sweden)

    Francine Blanchet-Sadri

    2011-08-01

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

  17. Complex partial seizures: cerebellar metabolism

    Energy Technology Data Exchange (ETDEWEB)

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

    1987-07-01

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

  18. LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone

    Energy Technology Data Exchange (ETDEWEB)

    Bian, Xuting; Zhong, Hongyu; Li, Fen; Cai, Yulong; Li, Xin; Wang, Lian; Fan, Xiaotang, E-mail: fanxiaotang2005@163.com

    2016-09-02

    Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects.

  19. LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone

    International Nuclear Information System (INIS)

    Bian, Xuting; Zhong, Hongyu; Li, Fen; Cai, Yulong; Li, Xin; Wang, Lian; Fan, Xiaotang

    2016-01-01

    Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects.

  20. Molecular pharmacology of the AMPA agonist, (S)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(S)-APPA] and the AMPA antagonist, (R)-APPA

    DEFF Research Database (Denmark)

    Ebert, B; Madsen, U; Lund, Trine Meldgaard

    1994-01-01

    )-APPA, whereas (R)-APPA is a non-N-methyl-D-aspartic acid (non-NMDA) receptor antagonist showing preferential AMPA blocking effects. In agreement with classical theories for competitive interaction between agonists and antagonists, the efficacy of depolarizations produced by (S)-APPA in the rat cortical wedge......The heterocyclic analogue of (S)-glutamic acid, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [(S)-AMPA] is a potent and selective AMPA receptor agonist, whereas the enantiomeric compound, (R)-AMPA, is virtually inactive. We have previously characterized (RS)-2-amino-3-(3-hydroxy-5......-phenyl-4-isoxazolyl)propionic acid [(RS)-APPA] as a partial AMPA receptor agonist showing about 60% of the efficacy of (RS)-AMPA. This partial agonism produced by (RS)-APPA is, however, only apparent, since resolution of (RS)-APPA has now been shown to provide the full AMPA receptor agonist, (S...

  1. Inverse fusion PCR cloning.

    Directory of Open Access Journals (Sweden)

    Markus Spiliotis

    Full Text Available Inverse fusion PCR cloning (IFPC is an easy, PCR based three-step cloning method that allows the seamless and directional insertion of PCR products into virtually all plasmids, this with a free choice of the insertion site. The PCR-derived inserts contain a vector-complementary 5'-end that allows a fusion with the vector by an overlap extension PCR, and the resulting amplified insert-vector fusions are then circularized by ligation prior transformation. A minimal amount of starting material is needed and experimental steps are reduced. Untreated circular plasmid, or alternatively bacteria containing the plasmid, can be used as templates for the insertion, and clean-up of the insert fragment is not urgently required. The whole cloning procedure can be performed within a minimal hands-on time and results in the generation of hundreds to ten-thousands of positive colonies, with a minimal background.

  2. Inverse plasma equilibria

    International Nuclear Information System (INIS)

    Hicks, H.R.; Dory, R.A.; Holmes, J.A.

    1983-01-01

    We illustrate in some detail a 2D inverse-equilibrium solver that was constructed to analyze tokamak configurations and stellarators (the latter in the context of the average method). To ensure that the method is suitable not only to determine equilibria, but also to provide appropriately represented data for existing stability codes, it is important to be able to control the Jacobian, tilde J is identical to delta(R,Z)/delta(rho, theta). The form chosen is tilde J = J 0 (rho)R/sup l/rho where rho is a flux surface label, and l is an integer. The initial implementation is for a fixed conducting-wall boundary, but the technique can be extended to a free-boundary model

  3. Binding Mode of Insulin Receptor and Agonist Peptide

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue, as well as the production and storage of hepatic glycogen. The insulin receptor is a transmembrane glycoprotein in which two α subunits with a molecular weight of 135 kD and twoβ subunits with a molecular weight of 95 kD are joined by a disulfide bond to form a β-α-α-β structure. The extracellular α subunit, especially, its three domains near the N-terminal are partially responsible for signal transduction or ligand-binding, as indicated by the experiments. The extracellular α subunits are involved in binding the ligands. The experimental results indicate that the three domains of the N-terminal of the α subunits are the main determinative parts of the insulin receptor to bind the insulin or mimetic peptide.We employed the extracellular domain (PDBID: 1IGR) of the insulin-like growth factor-1 receptor (IGF-1 R ) as the template to simulate and optimize the spatial structures of the three domains in the extracellular domain of the insulin receptor, which includes 468 residues. The work was accomplished by making use of the homology program in the Insight Ⅱ package on an Origin3800 server. The docking calculations of the insulin receptor obtained by homology with hexapeptides were carried out by means of the program Affinity. The analysis indicated that there were hydrogen bonding, and electrostatic and hydrophobic effects in the docking complex of the insulin receptor with hexapeptides.Moreover, we described the spatial orientation of a mimetic peptide with agonist activity in the docking complex. We obtained a rough model of binding of DLAPSQ or STIVYS with the insulin receptor, which provides the powerful theoretical support for designing the minimal insulin mimetic peptide with agonist activity, making it possible to develop oral small

  4. Incomplete inversion of the hippocampus - a common developmental anomaly

    Energy Technology Data Exchange (ETDEWEB)

    Bajic, Dragan; Wang, Chen; Raininko, Raili [Uppsala University Hospital, Department of Radiology, Uppsala (Sweden); Kumlien, Eva; Mattsson, Peter [Uppsala University Hospital, Department of Neurology, Uppsala (Sweden); Lundberg, Staffan; Eeg-Olofsson, Orvar [Uppsala University Hospital, Department of Child Neurology, Uppsala (Sweden)

    2008-01-15

    Incomplete inversion of the hippocampus, an imperfect fetal development, has been described in patients with epilepsy or severe midline malformations. We studied this condition in a nonepileptic population without obvious developmental anomalies. We analyzed the coronal MR images of 50 women and 50 men who did not have epilepsy. Twenty of them were healthy volunteers and 80 were patients without obvious intracranial developmental anomalies, intracranial masses, hydrocephalus or any condition affecting the temporal lobes. If the entire hippocampus (the head could not be evaluated) were affected, the incomplete inversion was classified as total, otherwise as partial. Incomplete inversion of the hippocampus was found in 19/100 subjects (9 women, 10 men). It was unilateral, always on the left side, in 13 subjects (4 women, 9 men): 9 were of the total type, 4 were partial. It was bilateral in six subjects (five women, one man): four subjects had total types bilaterally, two had a combination of total and partial types. The collateral sulcus was vertically oriented in all subjects with a deviating hippocampal shape. We conclude that incomplete inversion of the hippocampus is not an unusual morphologic variety in a nonepileptic population without other obvious intracranial developmental anomalies. (orig.)

  5. Transmuted Generalized Inverse Weibull Distribution

    OpenAIRE

    Merovci, Faton; Elbatal, Ibrahim; Ahmed, Alaa

    2013-01-01

    A generalization of the generalized inverse Weibull distribution so-called transmuted generalized inverse Weibull dis- tribution is proposed and studied. We will use the quadratic rank transmutation map (QRTM) in order to generate a flexible family of probability distributions taking generalized inverse Weibull distribution as the base value distribution by introducing a new parameter that would offer more distributional flexibility. Various structural properties including explicit expression...

  6. Solution of some types of differential equations: operational calculus and inverse differential operators.

    Science.gov (United States)

    Zhukovsky, K

    2014-01-01

    We present a general method of operational nature to analyze and obtain solutions for a variety of equations of mathematical physics and related mathematical problems. We construct inverse differential operators and produce operational identities, involving inverse derivatives and families of generalised orthogonal polynomials, such as Hermite and Laguerre polynomial families. We develop the methodology of inverse and exponential operators, employing them for the study of partial differential equations. Advantages of the operational technique, combined with the use of integral transforms, generating functions with exponentials and their integrals, for solving a wide class of partial derivative equations, related to heat, wave, and transport problems, are demonstrated.

  7. Structural basis for constitutive activity and agonist-induced activation of the enteroendocrine fat sensor GPR119

    DEFF Research Database (Denmark)

    Engelstoft, Maja Storm; Norn, C; Pedersen, Maria Hauge

    2014-01-01

    BACKGROUND AND PURPOSE: GPR119 is a Gαs-coupled 7TM receptor activated by endogenous lipids such as oleoylethanolamide (OEA) and by the dietary triglyceride metabolite 2-monoacylglycerol. GPR119 stimulates enteroendocrine hormone and insulin secretion. But despite massive drug discovery efforts...... activation (AR231453 and OEA). Novel Rosetta-based receptor modelling was applied, using a composite template approach with segments from different X-ray structures and fully flexible ligand docking. KEY RESULTS: The increased signalling induced by increasing the cell surface expression of GPR119...... in the absence of agonist and the inhibitory effect of two synthetic inverse agonists demonstrated that GRP119 signals with a high degree of constitutive activity through the Gαs pathway. The mutational maps for AR231453 and OEA were very similar and, surprisingly, also similar to the mutational map for residues...

  8. Calculation of the inverse data space via sparse inversion

    KAUST Repository

    Saragiotis, Christos; Doulgeris, Panagiotis C.; Verschuur, Dirk Jacob Eric

    2011-01-01

    The inverse data space provides a natural separation of primaries and surface-related multiples, as the surface multiples map onto the area around the origin while the primaries map elsewhere. However, the calculation of the inverse data is far from

  9. Inverse feasibility problems of the inverse maximum flow problems

    Indian Academy of Sciences (India)

    199–209. c Indian Academy of Sciences. Inverse feasibility problems of the inverse maximum flow problems. ADRIAN DEACONU. ∗ and ELEONOR CIUREA. Department of Mathematics and Computer Science, Faculty of Mathematics and Informatics, Transilvania University of Brasov, Brasov, Iuliu Maniu st. 50,. Romania.

  10. Differential activation of G-proteins by μ-opioid receptor agonists

    Science.gov (United States)

    Saidak, Zuzana; Blake-Palmer, Katherine; Hay, Debbie L; Northup, John K; Glass, Michelle

    2006-01-01

    We investigated the ability of the activated μ-opioid receptor (MOR) to differentiate between myristoylated Gαi1 and GαoA type Gα proteins, and the maximal activity of a range of synthetic and endogenous agonists to activate each Gα protein. Membranes from HEK293 cells stably expressing transfected MOR were chaotrope extracted to denature endogenous G-proteins and reconstituted with specific purified G-proteins. The Gα subunits were generated in bacteria and were demonstrated to be recognised equivalently to bovine brain purified Gα protein by CB1 cannabinoid receptors. The ability of agonists to catalyse the MOR-dependent GDP/[35S]GTPγS exchange was then compared for Gαi1 and GαoA. Activation of MOR by DAMGO produced a high-affinity saturable interaction for GαoA (Km=20±1 nM) but a low-affinity interaction with Gαi1 (Km=116±12 nM). DAMGO, met-enkephalin and leucine-enkephalin displayed maximal Gα activation among the agonists evaluated. Endomorphins 1 and 2, methadone and β-endorphin activated both Gα to more than 75% of the maximal response, whereas fentanyl partially activated both G-proteins. Buprenorphine and morphine demonstrated a statistically significant difference between the maximal activities between Gαi1 and GαoA. Interestingly, DAMGO, morphine, endomorphins 1 and 2, displayed significant differences in the potencies for the activation of the two Gα. Differences in maximal activity and potency, for Gαi1 versus GαoA, are both indicative of agonist selective activation of G-proteins in response to MOR activation. These findings may provide a starting point for the design of drugs that demonstrate greater selectivity between these two G-proteins and therefore produce a more limited range of effects. PMID:16415903

  11. Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging.

    Science.gov (United States)

    Smith, Roy G; Sun, Yuxiang; Jiang, Hong; Albarran-Zeckler, Rosie; Timchenko, Nikolai

    2007-11-01

    Administration of an orally active agonist (MK-0677) of the growth hormone secretagogue receptor (GHS-R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS-R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase-2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS-R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS-R1a and dopamine receptor subtype-1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS-R and D1R form heterodimers, which modified G-protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS-R1a agonists to improve quality of life and maintain independence.

  12. Principles of agonist recognition in Cys-loop receptors

    DEFF Research Database (Denmark)

    Lynagh, Timothy Peter; Pless, Stephan Alexander

    2014-01-01

    , functional studies, and X-ray crystallography experiments identified the extracellular interface of adjacent subunits as the principal site of agonist binding. The question of how subtle differences at and around agonist-binding sites of different Cys-loop receptors can accommodate transmitters as chemically...

  13. Combining GLP-1 receptor agonists with insulin

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Vilsbøll, T

    2013-01-01

    Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among...... physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose......, compared with insulin, the antihyperglycaemic efficacy of GLP-1RAs is limited. The combination of a GLP-1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic...

  14. Face inversion increases attractiveness.

    Science.gov (United States)

    Leder, Helmut; Goller, Juergen; Forster, Michael; Schlageter, Lena; Paul, Matthew A

    2017-07-01

    Assessing facial attractiveness is a ubiquitous, inherent, and hard-wired phenomenon in everyday interactions. As such, it has highly adapted to the default way that faces are typically processed: viewing faces in upright orientation. By inverting faces, we can disrupt this default mode, and study how facial attractiveness is assessed. Faces, rotated at 90 (tilting to either side) and 180°, were rated on attractiveness and distinctiveness scales. For both orientations, we found that faces were rated more attractive and less distinctive than upright faces. Importantly, these effects were more pronounced for faces rated low in upright orientation, and smaller for highly attractive faces. In other words, the less attractive a face was, the more it gained in attractiveness by inversion or rotation. Based on these findings, we argue that facial attractiveness assessments might not rely on the presence of attractive facial characteristics, but on the absence of distinctive, unattractive characteristics. These unattractive characteristics are potentially weighed against an individual, attractive prototype in assessing facial attractiveness. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  15. Inverse problem in hydrogeology

    Science.gov (United States)

    Carrera, Jesús; Alcolea, Andrés; Medina, Agustín; Hidalgo, Juan; Slooten, Luit J.

    2005-03-01

    The state of the groundwater inverse problem is synthesized. Emphasis is placed on aquifer characterization, where modelers have to deal with conceptual model uncertainty (notably spatial and temporal variability), scale dependence, many types of unknown parameters (transmissivity, recharge, boundary conditions, etc.), nonlinearity, and often low sensitivity of state variables (typically heads and concentrations) to aquifer properties. Because of these difficulties, calibration cannot be separated from the modeling process, as it is sometimes done in other fields. Instead, it should be viewed as one step in the process of understanding aquifer behavior. In fact, it is shown that actual parameter estimation methods do not differ from each other in the essence, though they may differ in the computational details. It is argued that there is ample room for improvement in groundwater inversion: development of user-friendly codes, accommodation of variability through geostatistics, incorporation of geological information and different types of data (temperature, occurrence and concentration of isotopes, age, etc.), proper accounting of uncertainty, etc. Despite this, even with existing codes, automatic calibration facilitates enormously the task of modeling. Therefore, it is contended that its use should become standard practice. L'état du problème inverse des eaux souterraines est synthétisé. L'accent est placé sur la caractérisation de l'aquifère, où les modélisateurs doivent jouer avec l'incertitude des modèles conceptuels (notamment la variabilité spatiale et temporelle), les facteurs d'échelle, plusieurs inconnues sur différents paramètres (transmissivité, recharge, conditions aux limites, etc.), la non linéarité, et souvent la sensibilité de plusieurs variables d'état (charges hydrauliques, concentrations) des propriétés de l'aquifère. A cause de ces difficultés, le calibrage ne peut êtreséparé du processus de modélisation, comme c'est le

  16. Multiples waveform inversion

    KAUST Repository

    Zhang, Dongliang

    2013-01-01

    To increase the illumination of the subsurface and to eliminate the dependency of FWI on the source wavelet, we propose multiples waveform inversion (MWI) that transforms each hydrophone into a virtual point source with a time history equal to that of the recorded data. These virtual sources are used to numerically generate downgoing wavefields that are correlated with the backprojected surface-related multiples to give the migration image. Since the recorded data are treated as the virtual sources, knowledge of the source wavelet is not required, and the subsurface illumination is greatly enhanced because the entire free surface acts as an extended source compared to the radiation pattern of a traditional point source. Numerical tests on the Marmousi2 model show that the convergence rate and the spatial resolution of MWI is, respectively, faster and more accurate then FWI. The potential pitfall with this method is that the multiples undergo more than one roundtrip to the surface, which increases attenuation and reduces spatial resolution. This can lead to less resolved tomograms compared to conventional FWI. The possible solution is to combine both FWI and MWI in inverting for the subsurface velocity distribution.

  17. Fast downscaled inverses for images compressed with M-channel lapped transforms.

    Science.gov (United States)

    de Queiroz, R L; Eschbach, R

    1997-01-01

    Compressed images may be decompressed and displayed or printed using different devices at different resolutions. Full decompression and rescaling in space domain is a very expensive method. We studied downscaled inverses where the image is decompressed partially, and a reduced inverse transform is used to recover the image. In this fashion, fewer transform coefficients are used and the synthesis process is simplified. We studied the design of fast inverses, for a given forward transform. General solutions are presented for M-channel finite impulse response (FIR) filterbanks, of which block and lapped transforms are a subset. Designs of faster inverses are presented for popular block and lapped transforms.

  18. An interpretation of signature inversion

    International Nuclear Information System (INIS)

    Onishi, Naoki; Tajima, Naoki

    1988-01-01

    An interpretation in terms of the cranking model is presented to explain why signature inversion occurs for positive γ of the axially asymmetric deformation parameter and emerges into specific orbitals. By introducing a continuous variable, the eigenvalue equation can be reduced to a one dimensional Schroedinger equation by means of which one can easily understand the cause of signature inversion. (author)

  19. Inverse problems for Maxwell's equations

    CERN Document Server

    Romanov, V G

    1994-01-01

    The Inverse and Ill-Posed Problems Series is a series of monographs publishing postgraduate level information on inverse and ill-posed problems for an international readership of professional scientists and researchers. The series aims to publish works which involve both theory and applications in, e.g., physics, medicine, geophysics, acoustics, electrodynamics, tomography, and ecology.

  20. Algebraic properties of generalized inverses

    CERN Document Server

    Cvetković‐Ilić, Dragana S

    2017-01-01

    This book addresses selected topics in the theory of generalized inverses. Following a discussion of the “reverse order law” problem and certain problems involving completions of operator matrices, it subsequently presents a specific approach to solving the problem of the reverse order law for {1} -generalized inverses. Particular emphasis is placed on the existence of Drazin invertible completions of an upper triangular operator matrix; on the invertibility and different types of generalized invertibility of a linear combination of operators on Hilbert spaces and Banach algebra elements; on the problem of finding representations of the Drazin inverse of a 2x2 block matrix; and on selected additive results and algebraic properties for the Drazin inverse. In addition to the clarity of its content, the book discusses the relevant open problems for each topic discussed. Comments on the latest references on generalized inverses are also included. Accordingly, the book will be useful for graduate students, Ph...

  1. Blocky inversion of multichannel elastic impedance for elastic parameters

    Science.gov (United States)

    Mozayan, Davoud Karami; Gholami, Ali; Siahkoohi, Hamid Reza

    2018-04-01

    Petrophysical description of reservoirs requires proper knowledge of elastic parameters like P- and S-wave velocities (Vp and Vs) and density (ρ), which can be retrieved from pre-stack seismic data using the concept of elastic impedance (EI). We propose an inversion algorithm which recovers elastic parameters from pre-stack seismic data in two sequential steps. In the first step, using the multichannel blind seismic inversion method (exploited recently for recovering acoustic impedance from post-stack seismic data), high-resolution blocky EI models are obtained directly from partial angle-stacks. Using an efficient total-variation (TV) regularization, each angle-stack is inverted independently in a multichannel form without prior knowledge of the corresponding wavelet. The second step involves inversion of the resulting EI models for elastic parameters. Mathematically, under some assumptions, the EI's are linearly described by the elastic parameters in the logarithm domain. Thus a linear weighted least squares inversion is employed to perform this step. Accuracy of the concept of elastic impedance in predicting reflection coefficients at low and high angles of incidence is compared with that of exact Zoeppritz elastic impedance and the role of low frequency content in the problem is discussed. The performance of the proposed inversion method is tested using synthetic 2D data sets obtained from the Marmousi model and also 2D field data sets. The results confirm the efficiency and accuracy of the proposed method for inversion of pre-stack seismic data.

  2. Inverse Cerenkov experiment

    International Nuclear Information System (INIS)

    Kimura, W.D.

    1993-01-01

    The final report describes work performed to investigate inverse Cherenkov acceleration (ICA) as a promising method for laser particle acceleration. In particular, an improved configuration of ICA is being tested in a experiment presently underway on the Accelerator Test Facility (ATF). In the experiment, the high peak power (∼ 10 GW) linearly polarized ATF CO 2 laser beam is converted to a radially polarized beam. This is beam is focused with an axicon at the Cherenkov angle onto the ATF 50-MeV e-beam inside a hydrogen gas cell, where the gas acts as the phase matching medium of the interaction. An energy gain of ∼12 MeV is predicted assuming a delivered laser peak power of 5 GW. The experiment is divided into two phases. The Phase I experiments, which were completed in the spring of 1992, were conducted before the ATF e-beam was available and involved several successful tests of the optical systems. Phase II experiments are with the e-beam and laser beam, and are still in progress. The ATF demonstrated delivery of the e-beam to the experiment in Dec. 1992. A preliminary ''debugging'' run with the e-beam and laser beam occurred in May 1993. This revealed the need for some experimental modifications, which have been implemented. The second run is tentatively scheduled for October or November 1993. In parallel to the experimental efforts has been ongoing theoretical work to support the experiment and investigate improvement and/or offshoots. One exciting offshoot has been theoretical work showing that free-space laser acceleration of electrons is possible using a radially-polarized, axicon-focused laser beam, but without any phase-matching gas. The Monte Carlo code used to model the ICA process has been upgraded and expanded to handle different types of laser beam input profiles

  3. A Generalization of the Spherical Inversion

    Science.gov (United States)

    Ramírez, José L.; Rubiano, Gustavo N.

    2017-01-01

    In the present article, we introduce a generalization of the spherical inversion. In particular, we define an inversion with respect to an ellipsoid, and prove several properties of this new transformation. The inversion in an ellipsoid is the generalization of the elliptic inversion to the three-dimensional space. We also study the inverse images…

  4. Hyperbolic partial differential equations

    CERN Document Server

    Witten, Matthew

    1986-01-01

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

  5. Successful removable partial dentures.

    Science.gov (United States)

    Lynch, Christopher D

    2012-03-01

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

  6. Beginning partial differential equations

    CERN Document Server

    O'Neil, Peter V

    2011-01-01

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

  7. Inverse Diffusion Curves Using Shape Optimization.

    Science.gov (United States)

    Zhao, Shuang; Durand, Fredo; Zheng, Changxi

    2018-07-01

    The inverse diffusion curve problem focuses on automatic creation of diffusion curve images that resemble user provided color fields. This problem is challenging since the 1D curves have a nonlinear and global impact on resulting color fields via a partial differential equation (PDE). We introduce a new approach complementary to previous methods by optimizing curve geometry. In particular, we propose a novel iterative algorithm based on the theory of shape derivatives. The resulting diffusion curves are clean and well-shaped, and the final image closely approximates the input. Our method provides a user-controlled parameter to regularize curve complexity, and generalizes to handle input color fields represented in a variety of formats.

  8. Inverse problems in ordinary differential equations and applications

    CERN Document Server

    Llibre, Jaume

    2016-01-01

    This book is dedicated to study the inverse problem of ordinary differential equations, that is it focuses in finding all ordinary differential equations that satisfy a given set of properties. The Nambu bracket is the central tool in developing this approach. The authors start characterizing the ordinary differential equations in R^N which have a given set of partial integrals or first integrals. The results obtained are applied first to planar polynomial differential systems with a given set of such integrals, second to solve the 16th Hilbert problem restricted to generic algebraic limit cycles, third for solving the inverse problem for constrained Lagrangian and Hamiltonian mechanical systems, fourth for studying the integrability of a constrained rigid body. Finally the authors conclude with an analysis on nonholonomic mechanics, a generalization of the Hamiltonian principle, and the statement an solution of the inverse problem in vakonomic mechanics.

  9. Computer-Aided Numerical Inversion of Laplace Transform

    Directory of Open Access Journals (Sweden)

    Umesh Kumar

    2000-01-01

    Full Text Available This paper explores the technique for the computer aided numerical inversion of Laplace transform. The inversion technique is based on the properties of a family of three parameter exponential probability density functions. The only limitation in the technique is the word length of the computer being used. The Laplace transform has been used extensively in the frequency domain solution of linear, lumped time invariant networks but its application to the time domain has been limited, mainly because of the difficulty in finding the necessary poles and residues. The numerical inversion technique mentioned above does away with the poles and residues but uses precomputed numbers to find the time response. This technique is applicable to the solution of partially differentiable equations and certain classes of linear systems with time varying components.

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

    Science.gov (United States)

    Nirenberg, Melissa J

    2013-08-01

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

  11. Regulation of Serum Response Factor and Adiponectin by PPARγ Agonist Docosahexaenoic Acid

    Directory of Open Access Journals (Sweden)

    Clayton Johnson

    2011-01-01

    Full Text Available Recent studies indicate that significant health benefits involving the regulation of signaling proteins result from the consumption of omega-3 polyunsaturated fatty acids (ω-3 PUFAs. Serum response factor (SRF is involved in transcriptional regulation of muscle growth and differentiation. SRF levels are increased in the aging heart muscle. It has not been examined whether SRF is made by adipocytes and whether SRF secretion by adipocytes is modulated by PPARγ agonist DHA. Adiponectin is made exclusively by adipocytes. We and others have previously reported that PUFAs such as DHA increase adiponectin levels and secretion in adipocytes. Here we show that DHA downregulates SRF with a simultaneous upregulation of adiponectin and that both these responses are reversible by PPARγ antagonist. Furthermore, there appears to be a direct relationship between DHA exposure and increased levels of membrane-associated high-density adiponectin, as well as lower levels of membrane-associated SRF. Thus, we find that the levels of SRF and adiponectin are inversely related in response to treatment with PPARγ agonist DHA. Decreased levels of SRF along with increase in membrane-associated adiponectin could in part mediate the health benefits of DHA.

  12. Quantum Effects in Inverse Opal Structures

    Science.gov (United States)

    Bleiweiss, Michael; Datta, Timir; Lungu, Anca; Yin, Ming; Iqbal, Zafar; Palm, Eric; Brandt, Bruce

    2002-03-01

    Properties of bismuth inverse opals and carbon opal replicas were studied. The bismuth nanostructures were fabricated by pressure infiltration into porous artificial opal, while the carbon opal replicas were created via CVD. These structures form a regular three-dimensional network in which the bismuth and carbon regions percolate in all directions between the close packed spheres of SiO_2. The sizes of the conducting regions are of the order of tens of nanometers. Static susceptibility of the bismuth inverse opal showed clear deHaas-vanAlphen oscillations. Transport measurements, including Hall, were done using standard ac four and six probe techniques in fields up to 17 T* and temperatures between 4.2 and 200 K. Observations of Shubnikov-deHaas oscillations in magnetoresistance, one-dimensional weak localization, quantum Hall and other effects will be discussed. *Performed at the National High Magnetic Field Lab (NHMFL) FSU, Tallahassee, FL. This work was partially supported by grants from DARPA-nanothermoelectrics, NASA-EPSCOR and the USC nanocenter.

  13. Partial knee replacement - slideshow

    Science.gov (United States)

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

  14. Beginning partial differential equations

    CERN Document Server

    O'Neil, Peter V

    2014-01-01

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

  15. Statistical perspectives on inverse problems

    DEFF Research Database (Denmark)

    Andersen, Kim Emil

    of the interior of an object from electrical boundary measurements. One part of this thesis concerns statistical approaches for solving, possibly non-linear, inverse problems. Thus inverse problems are recasted in a form suitable for statistical inference. In particular, a Bayesian approach for regularisation...... problem is given in terms of probability distributions. Posterior inference is obtained by Markov chain Monte Carlo methods and new, powerful simulation techniques based on e.g. coupled Markov chains and simulated tempering is developed to improve the computational efficiency of the overall simulation......Inverse problems arise in many scientific disciplines and pertain to situations where inference is to be made about a particular phenomenon from indirect measurements. A typical example, arising in diffusion tomography, is the inverse boundary value problem for non-invasive reconstruction...

  16. Size Estimates in Inverse Problems

    KAUST Repository

    Di Cristo, Michele

    2014-01-01

    Detection of inclusions or obstacles inside a body by boundary measurements is an inverse problems very useful in practical applications. When only finite numbers of measurements are available, we try to detect some information on the embedded

  17. Wave-equation dispersion inversion

    KAUST Repository

    Li, Jing; Feng, Zongcai; Schuster, Gerard T.

    2016-01-01

    We present the theory for wave-equation inversion of dispersion curves, where the misfit function is the sum of the squared differences between the wavenumbers along the predicted and observed dispersion curves. The dispersion curves are obtained

  18. Testing earthquake source inversion methodologies

    KAUST Repository

    Page, Morgan T.

    2011-01-01

    Source Inversion Validation Workshop; Palm Springs, California, 11-12 September 2010; Nowadays earthquake source inversions are routinely performed after large earthquakes and represent a key connection between recorded seismic and geodetic data and the complex rupture process at depth. The resulting earthquake source models quantify the spatiotemporal evolution of ruptures. They are also used to provide a rapid assessment of the severity of an earthquake and to estimate losses. However, because of uncertainties in the data, assumed fault geometry and velocity structure, and chosen rupture parameterization, it is not clear which features of these source models are robust. Improved understanding of the uncertainty and reliability of earthquake source inversions will allow the scientific community to use the robust features of kinematic inversions to more thoroughly investigate the complexity of the rupture process and to better constrain other earthquakerelated computations, such as ground motion simulations and static stress change calculations.

  19. Parameter estimation and inverse problems

    CERN Document Server

    Aster, Richard C; Thurber, Clifford H

    2005-01-01

    Parameter Estimation and Inverse Problems primarily serves as a textbook for advanced undergraduate and introductory graduate courses. Class notes have been developed and reside on the World Wide Web for faciliting use and feedback by teaching colleagues. The authors'' treatment promotes an understanding of fundamental and practical issus associated with parameter fitting and inverse problems including basic theory of inverse problems, statistical issues, computational issues, and an understanding of how to analyze the success and limitations of solutions to these probles. The text is also a practical resource for general students and professional researchers, where techniques and concepts can be readily picked up on a chapter-by-chapter basis.Parameter Estimation and Inverse Problems is structured around a course at New Mexico Tech and is designed to be accessible to typical graduate students in the physical sciences who may not have an extensive mathematical background. It is accompanied by a Web site that...

  20. Inversion Therapy: Can It Relieve Back Pain?

    Science.gov (United States)

    Inversion therapy: Can it relieve back pain? Does inversion therapy relieve back pain? Is it safe? Answers from Edward R. Laskowski, M.D. Inversion therapy doesn't provide lasting relief from back ...

  1. Thermal measurements and inverse techniques

    CERN Document Server

    Orlande, Helcio RB; Maillet, Denis; Cotta, Renato M

    2011-01-01

    With its uncommon presentation of instructional material regarding mathematical modeling, measurements, and solution of inverse problems, Thermal Measurements and Inverse Techniques is a one-stop reference for those dealing with various aspects of heat transfer. Progress in mathematical modeling of complex industrial and environmental systems has enabled numerical simulations of most physical phenomena. In addition, recent advances in thermal instrumentation and heat transfer modeling have improved experimental procedures and indirect measurements for heat transfer research of both natural phe

  2. Computation of inverse magnetic cascades

    International Nuclear Information System (INIS)

    Montgomery, D.

    1981-10-01

    Inverse cascades of magnetic quantities for turbulent incompressible magnetohydrodynamics are reviewed, for two and three dimensions. The theory is extended to the Strauss equations, a description intermediate between two and three dimensions appropriate to tokamak magnetofluids. Consideration of the absolute equilibrium Gibbs ensemble for the system leads to a prediction of an inverse cascade of magnetic helicity, which may manifest itself as a major disruption. An agenda for computational investigation of this conjecture is proposed

  3. EDITORIAL: Inverse Problems in Engineering

    Science.gov (United States)

    West, Robert M.; Lesnic, Daniel

    2007-01-01

    Presented here are 11 noteworthy papers selected from the Fifth International Conference on Inverse Problems in Engineering: Theory and Practice held in Cambridge, UK during 11-15 July 2005. The papers have been peer-reviewed to the usual high standards of this journal and the contributions of reviewers are much appreciated. The conference featured a good balance of the fundamental mathematical concepts of inverse problems with a diverse range of important and interesting applications, which are represented here by the selected papers. Aspects of finite-element modelling and the performance of inverse algorithms are investigated by Autrique et al and Leduc et al. Statistical aspects are considered by Emery et al and Watzenig et al with regard to Bayesian parameter estimation and inversion using particle filters. Electrostatic applications are demonstrated by van Berkel and Lionheart and also Nakatani et al. Contributions to the applications of electrical techniques and specifically electrical tomographies are provided by Wakatsuki and Kagawa, Kim et al and Kortschak et al. Aspects of inversion in optical tomography are investigated by Wright et al and Douiri et al. The authors are representative of the worldwide interest in inverse problems relating to engineering applications and their efforts in producing these excellent papers will be appreciated by many readers of this journal.

  4. MELATONIN DAN MELATONIN RECEPTOR AGONIST SEBAGAI PENANGANAN INSOMNIA PRIMER KRONIS

    Directory of Open Access Journals (Sweden)

    Ni Luh Putu Ayu Maha Iswari

    2013-04-01

    Full Text Available Melatonin is a hormone that has an important role in the mechanism of sleep. Hypnotic effects of melatonin and melatonin receptor agonist are mediated via MT1 and MT2 receptors, especially in circadian rhythm pacemaker, suprachiasmatic nucleus, which is worked on the hypothalamic sleep switch. This mechanism is quite different with the GABAergic drugs such as benzodiazepine. Agonist melatonin triggers the initiation of sleep and normalize circadian rhythms so that makes it easier to maintain sleep. The main disadvantage of melatonin in helping sleep maintenance on primary insomnia is that the half life is very short. The solution to this problem is the use of prolonged-release melatonin and melatonin receptor agonist agents such as ramelteon. Melatoninergic agonist does not cause withdrawal effects, dependence, as well as cognitive and psychomotor disorders as often happens on the use of benzodiazepine.  

  5. Experimental characterization of methane inverse diffusion flame

    KAUST Repository

    Elbaz, Ayman M.

    2014-06-26

    This article presents 10-kHz images of OH-PLIF simultaneously with 2-D PIV measurements in an inverse methane diffusion flame. Under a constant fuel flow rate, the central air jet Re was varied, leading to air to fuel velocity ratio, Vr, to vary from 8.3 to 66.5. Starting from Vr = 20.7, the flame is commonly characterized by three distinct zones. The length of the lower fuel entrainment region is inversely proportional to Vr. The flames investigated resemble a string shear layer confining this zone, and converging into the second distinct region, the flame neck zone. The third region is the rest of the flame, which spreads in a jet-like manner. The inverse diffusion flames exhibit varying degrees of partial premixing, depending upon on the velocity ratio Vr, and this region of partial premixing evolves into a well-mixed reaction zone along the flame centerline. The OH distribution correlated with the changes in the mean characteristics of the flow through reduction in the local Reynolds number due to heat release. The existence of a flame suppresses or laminarizes the turbulence at early axial locations and promotes fluctuations at the flame tip for flames with Vr < 49.8. In addition, the flame jet width can be correlated to the OH distribution. In upstream regions of the flames, the breaks in OH are counterbalanced by flame closures and are governed by edge flame propagation. These local extinctions were found to occur at locations where large flow structures were impinging on the flame and are associated with a locally higher strain rate or correlated to the local high strain rates at the flame hole edges without this flow impinging. Another contributor to re-ignition was found to be growing flame kernels. As the flames approach global blow-off, these kernels become the main mechanism for re-ignition further downstream of the flames. At low Vr, laminarization within the early regions of the flame provides an effective shield, preventing the jet flow from

  6. Dopamine D2 receptor radiotracers [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride are indistinguishably inhibited by D2 agonists and antagonists ex vivo

    Energy Technology Data Exchange (ETDEWEB)

    McCormick, Patrick N. [Institute of Medical Science, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada)], E-mail: patrick.mccormick@camhpet.ca; Kapur, Shitij [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); PET Center, Center for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Seeman, Philip [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); Department of Pharmacology, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); Wilson, Alan A. [Department of Psychiatry, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); PET Center, Center for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada)

    2008-01-15

    Introduction: In vitro, the dopamine D2 receptor exists in two states, with high and low affinity for agonists. The high-affinity state is the physiologically active state thought to be involved in dopaminergic illnesses such as schizophrenia. The positron emission tomography radiotracer [{sup 11}C](+)-PHNO ([{sup 11}C](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4] oxazin-9-o l), being a D2 agonist, should selectively label the high-affinity state at tracer dose and therefore be more susceptible to competition by agonist as compared to the antagonist [{sup 3}H]raclopride, which binds to both affinity states. Methods: We tested this prediction using ex vivo dual-radiotracer experiments in conscious rats. D2 antagonists (haloperidol or clozapine), a partial agonist (aripiprazole), a full agonist [(-)-NPA] or the dopamine-releasing drug amphetamine (AMPH) were administered to rats prior to an intravenous coinjection of [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride. Rats were sacrificed 60 min after radiotracer injection. Striatum, cerebellum and plasma samples were counted for {sup 11}C and {sup 3}H. The specific binding ratio {l_brace}SBR, i.e., [%ID/g (striatum)-%ID/g (cerebellum)]/(%ID/g (cerebellum){r_brace} was used as the outcome measure. Results: In response to D2 antagonists, partial agonist or full agonist, [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride SBRs responded indistinguishably in terms of both ED{sub 50} and Hill slope (e.g., (-)-NPA ED{sub 50} values are 0.027 and 0.023 mg/kg for [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride, respectively). In response to AMPH challenge, [{sup 11}C](+)-PHNO and [{sup 3}H]raclopride SBRs were inhibited to the same degree. Conclusions: We have shown that the SBRs of [{sup 11}C](+)-PHNO- and [{sup 3}H]raclopride do not differ in their response to agonist challenge. These results do not support predictions of the in vivo binding behavior of a D2 agonist radiotracer and cast some doubt on the in vivo

  7. Dopamine D2 receptor radiotracers [11C](+)-PHNO and [3H]raclopride are indistinguishably inhibited by D2 agonists and antagonists ex vivo

    International Nuclear Information System (INIS)

    McCormick, Patrick N.; Kapur, Shitij; Seeman, Philip; Wilson, Alan A.

    2008-01-01

    Introduction: In vitro, the dopamine D2 receptor exists in two states, with high and low affinity for agonists. The high-affinity state is the physiologically active state thought to be involved in dopaminergic illnesses such as schizophrenia. The positron emission tomography radiotracer [ 11 C](+)-PHNO ([ 11 C](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4] oxazin-9-o l), being a D2 agonist, should selectively label the high-affinity state at tracer dose and therefore be more susceptible to competition by agonist as compared to the antagonist [ 3 H]raclopride, which binds to both affinity states. Methods: We tested this prediction using ex vivo dual-radiotracer experiments in conscious rats. D2 antagonists (haloperidol or clozapine), a partial agonist (aripiprazole), a full agonist [(-)-NPA] or the dopamine-releasing drug amphetamine (AMPH) were administered to rats prior to an intravenous coinjection of [ 11 C](+)-PHNO and [ 3 H]raclopride. Rats were sacrificed 60 min after radiotracer injection. Striatum, cerebellum and plasma samples were counted for 11 C and 3 H. The specific binding ratio {SBR, i.e., [%ID/g (striatum)-%ID/g (cerebellum)]/(%ID/g (cerebellum)} was used as the outcome measure. Results: In response to D2 antagonists, partial agonist or full agonist, [ 11 C](+)-PHNO and [ 3 H]raclopride SBRs responded indistinguishably in terms of both ED 50 and Hill slope (e.g., (-)-NPA ED 50 values are 0.027 and 0.023 mg/kg for [ 11 C](+)-PHNO and [ 3 H]raclopride, respectively). In response to AMPH challenge, [ 11 C](+)-PHNO and [ 3 H]raclopride SBRs were inhibited to the same degree. Conclusions: We have shown that the SBRs of [ 11 C](+)-PHNO- and [ 3 H]raclopride do not differ in their response to agonist challenge. These results do not support predictions of the in vivo binding behavior of a D2 agonist radiotracer and cast some doubt on the in vivo applicability of the D2 two-state model, as described by in vitro binding experiments

  8. The attitude inversion method of geostationary satellites based on unscented particle filter

    Science.gov (United States)

    Du, Xiaoping; Wang, Yang; Hu, Heng; Gou, Ruixin; Liu, Hao

    2018-04-01

    The attitude information of geostationary satellites is difficult to be obtained since they are presented in non-resolved images on the ground observation equipment in space object surveillance. In this paper, an attitude inversion method for geostationary satellite based on Unscented Particle Filter (UPF) and ground photometric data is presented. The inversion algorithm based on UPF is proposed aiming at the strong non-linear feature in the photometric data inversion for satellite attitude, which combines the advantage of Unscented Kalman Filter (UKF) and Particle Filter (PF). This update method improves the particle selection based on the idea of UKF to redesign the importance density function. Moreover, it uses the RMS-UKF to partially correct the prediction covariance matrix, which improves the applicability of the attitude inversion method in view of UKF and the particle degradation and dilution of the attitude inversion method based on PF. This paper describes the main principles and steps of algorithm in detail, correctness, accuracy, stability and applicability of the method are verified by simulation experiment and scaling experiment in the end. The results show that the proposed method can effectively solve the problem of particle degradation and depletion in the attitude inversion method on account of PF, and the problem that UKF is not suitable for the strong non-linear attitude inversion. However, the inversion accuracy is obviously superior to UKF and PF, in addition, in the case of the inversion with large attitude error that can inverse the attitude with small particles and high precision.

  9. Trial Watch: Toll-like receptor agonists for cancer therapy.

    Science.gov (United States)

    Vacchelli, Erika; Eggermont, Alexander; Sautès-Fridman, Catherine; Galon, Jérôme; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2013-08-01

    Toll-like receptors (TLRs) have long been known for their ability to initiate innate immune responses upon exposure to conserved microbial components such as lipopolysaccharide (LPS) and double-stranded RNA. More recently, this family of pattern recognition receptors has been attributed a critical role in the elicitation of anticancer immune responses, raising interest in the development of immunochemotherapeutic regimens based on natural or synthetic TLR agonists. In spite of such an intense wave of preclinical and clinical investigation, only three TLR agonists are currently licensed by FDA for use in cancer patients: bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis that operates as a mixed TLR2/TLR4 agonist; monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota that functions as a potent agonist of TLR4; and imiquimod, a synthetic imidazoquinoline that activates TLR7. One year ago, in the August and September issues of OncoImmunology , we described the main biological features of TLRs and discussed the progress of clinical studies evaluating the safety and therapeutic potential of TLR agonists in cancer patients. Here, we summarize the latest developments in this exciting area of research, focusing on preclinical studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate the antineoplastic activity of TLR agonists.

  10. Should We Use PPAR Agonists to Reduce Cardiovascular Risk?

    Directory of Open Access Journals (Sweden)

    Jennifer G. Robinson

    2008-01-01

    Full Text Available Trials of peroxisome proliferator-activated receptor (PPAR agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR- agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs are PPAR- agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-/ agonists have had unacceptable adverse effects but more selective agents are in development. PPAR- and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.

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

    DEFF Research Database (Denmark)

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

    2000-01-01

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

  12. Overlapping binding site for the endogenous agonist, small-molecule agonists, and ago-allosteric modulators on the ghrelin receptor

    DEFF Research Database (Denmark)

    Holst, Birgitte; Frimurer, Thomas M; Mokrosinski, Jacek

    2008-01-01

    A library of robust ghrelin receptor mutants with single substitutions at 22 positions in the main ligand-binding pocket was employed to map binding sites for six different agonists: two peptides (the 28-amino-acid octanoylated endogenous ligand ghrelin and the hexapeptide growth hormone......, and PheVI:23 on the opposing face of transmembrane domain (TM) VI. Each of the agonists was also affected selectively by specific mutations. The mutational map of the ability of L-692,429 and GHRP-6 to act as allosteric modulators by increasing ghrelin's maximal efficacy overlapped with the common....... It is concluded that although each of the ligands in addition exploits other parts of the receptor, a large, common binding site for both small-molecule agonists--including ago-allosteric modulators--and the endogenous agonist is found on the opposing faces of TM-III and -VI of the ghrelin receptor....

  13. Partial differential equations

    CERN Document Server

    Evans, Lawrence C

    2010-01-01

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

  14. Stereochemical studies of the monocyclic agouti-related protein (103-122) Arg-Phe-Phe residues: conversion of a melanocortin-4 receptor antagonist into an agonist and results in the discovery of a potent and selective melanocortin-1 agonist.

    Science.gov (United States)

    Joseph, Christine G; Wang, Xiang S; Scott, Joseph W; Bauzo, Rayna M; Xiang, Zhimin; Richards, Nigel G; Haskell-Luevano, Carrie

    2004-12-30

    The agouti-related protein (AGRP) is an endogenous antagonist of the centrally expressed melanocortin receptors. The melanocortin-4 receptor (MC4R) is involved in energy homeostasis, food intake, sexual function, and obesity. The endogenous hAGRP protein is 132 amino acids in length, possesses five disulfide bridges at the C-terminus of the molecule, and is expressed in the hypothalamus of the brain. We have previously reported that a monocyclic hAGRP(103-122) peptide is an antagonist at the melanocortin receptors expressed in the brain. Stereochemical inversion from the endogenous l- to d-isomers of single or multiple amino acid modifications in this monocyclic truncated hAGRP sequence resulted in molecules that are converted from melanocortin receptor antagonists into melanocortin receptor agonists. The Asp-Pro-Ala-Ala-Thr-Ala-Tyr-cyclo[Cys-Arg-DPhe-DPhe-Asn-Ala-Phe-Cys]-Tyr-Ala-Arg-Lys-Leu peptide resulted in a 60 nM melanocortin-1 receptor agonist that is 100-fold selective versus the mMC4R, 1000-fold selective versus the mMC3R, and ca. 180-fold selective versus the mMC5R. In attempts to identify putative ligand-receptor interactions that may be participating in the agonist induced stimulation of the MC4R, selected ligands were docked into a homology molecular model of the mMC4R. These modeling studies have putatively identified hAGRP ligand DArg111-mMC4RAsn115 (TM3) and the hAGRP DPhe113-mMC4RPhe176 (TM4) interactions as important for agonist activity.

  15. Optimization of partial search

    International Nuclear Information System (INIS)

    Korepin, Vladimir E

    2005-01-01

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

  16. Collage-type approach to inverse problems for elliptic PDEs on perforated domains

    Directory of Open Access Journals (Sweden)

    Herb E. Kunze

    2015-02-01

    Full Text Available We present a collage-based method for solving inverse problems for elliptic partial differential equations on a perforated domain. The main results of this paper establish a link between the solution of an inverse problem on a perforated domain and the solution of the same model on a domain with no holes. The numerical examples at the end of the paper show the goodness of this approach.

  17. Inversion of the star transform

    International Nuclear Information System (INIS)

    Zhao, Fan; Schotland, John C; Markel, Vadim A

    2014-01-01

    We define the star transform as a generalization of the broken ray transform introduced by us in previous work. The advantages of using the star transform include the possibility to reconstruct the absorption and the scattering coefficients of the medium separately and simultaneously (from the same data) and the possibility to utilize scattered radiation which, in the case of conventional x-ray tomography, is discarded. In this paper, we derive the star transform from physical principles, discuss its mathematical properties and analyze numerical stability of inversion. In particular, it is shown that stable inversion of the star transform can be obtained only for configurations involving odd number of rays. Several computationally-efficient inversion algorithms are derived and tested numerically. (paper)

  18. Inverse comptonization vs. thermal synchrotron

    International Nuclear Information System (INIS)

    Fenimore, E.E.; Klebesadel, R.W.; Laros, J.G.

    1983-01-01

    There are currently two radiation mechanisms being considered for gamma-ray bursts: thermal synchrotron and inverse comptonization. They are mutually exclusive since thermal synchrotron requires a magnetic field of approx. 10 12 Gauss whereas inverse comptonization cannot produce a monotonic spectrum if the field is larger than 10 11 and is too inefficient relative to thermal synchrotron unless the field is less than 10 9 Gauss. Neither mechanism can explain completely the observed characteristics of gamma-ray bursts. However, we conclude that thermal synchrotron is more consistent with the observations if the sources are approx. 40 kpc away whereas inverse comptonization is more consistent if they are approx. 300 pc away. Unfortunately, the source distance is still not known and, thus, the radiation mechanism is still uncertain

  19. Inverse photoemission of uranium oxides

    International Nuclear Information System (INIS)

    Roussel, P.; Morrall, P.; Tull, S.J.

    2009-01-01

    Understanding the itinerant-localised bonding role of the 5f electrons in the light actinides will afford an insight into their unusual physical and chemical properties. In recent years, the combination of core and valance band electron spectroscopies with theoretic modelling have already made significant progress in this area. However, information of the unoccupied density of states is still scarce. When compared to the forward photoemission techniques, measurements of the unoccupied states suffer from significantly less sensitivity and lower resolution. In this paper, we report on our experimental apparatus, which is designed to measure the inverse photoemission spectra of the light actinides. Inverse photoemission spectra of UO 2 and UO 2.2 along with the corresponding core and valance electron spectra are presented in this paper. UO 2 has been reported previously, although through its inclusion here it allows us to compare and contrast results from our experimental apparatus to the previous Bremsstrahlung Isochromat Spectroscopy and Inverse Photoemission Spectroscopy investigations

  20. Optimization for nonlinear inverse problem

    International Nuclear Information System (INIS)

    Boyadzhiev, G.; Brandmayr, E.; Pinat, T.; Panza, G.F.

    2007-06-01

    The nonlinear inversion of geophysical data in general does not yield a unique solution, but a single model, representing the investigated field, is preferred for an easy geological interpretation of the observations. The analyzed region is constituted by a number of sub-regions where the multi-valued nonlinear inversion is applied, which leads to a multi-valued solution. Therefore, combining the values of the solution in each sub-region, many acceptable models are obtained for the entire region and this complicates the geological interpretation of geophysical investigations. In this paper are presented new methodologies, capable to select one model, among all acceptable ones, that satisfies different criteria of smoothness in the explored space of solutions. In this work we focus on the non-linear inversion of surface waves dispersion curves, which gives structural models of shear-wave velocity versus depth, but the basic concepts have a general validity. (author)

  1. Some Phenomena on Negative Inversion Constructions

    Science.gov (United States)

    Sung, Tae-Soo

    2013-01-01

    We examine the characteristics of NDI (negative degree inversion) and its relation with other inversion phenomena such as SVI (subject-verb inversion) and SAI (subject-auxiliary inversion). The negative element in the NDI construction may be" not," a negative adverbial, or a negative verb. In this respect, NDI has similar licensing…

  2. Auxiliary partial liver transplantation

    NARCIS (Netherlands)

    C.B. Reuvers (Cornelis Bastiaan)

    1986-01-01

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

  3. Partial Remission Definition

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  4. Fundamental partial compositeness

    DEFF Research Database (Denmark)

    Sannino, Francesco; Strumia, Alessandro; Tesi, Andrea

    2016-01-01

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

  5. Partially ordered models

    NARCIS (Netherlands)

    Fernandez, R.; Deveaux, V.

    2010-01-01

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

  6. Partially Hidden Markov Models

    DEFF Research Database (Denmark)

    Forchhammer, Søren Otto; Rissanen, Jorma

    1996-01-01

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

  7. Honesty in partial logic

    NARCIS (Netherlands)

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

    1995-01-01

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

  8. The electrophysiological effects of the serotonin 1A receptor agonist buspirone in emotional face processing.

    Science.gov (United States)

    Bernasconi, Fosco; Kometer, Michael; Pokorny, Thomas; Seifritz, Erich; Vollenweider, Franz X

    2015-04-01

    Emotional face processing is critically modulated by the serotonergic system, and serotonin (5-HT) receptor agonists impair emotional face processing. However, the specific contribution of the 5-HT1A receptor remains poorly understood. Here we investigated the spatiotemporal brain mechanisms underpinning the modulation of emotional face processing induced by buspirone, a partial 5-HT1A receptor agonist. In a psychophysical discrimination of emotional faces task, we observed that the discrimination fearful versus neutral faces were reduced, but not happy versus neutral faces. Electrical neuroimaging analyses were applied to visual evoked potentials elicited by emotional face images, after placebo and buspirone administration. Buspirone modulated response strength (i.e., global field power) in the interval 230-248ms after stimulus onset. Distributed source estimation over this time interval revealed that buspirone decreased the neural activity in the right dorsolateral prefrontal cortex that was evoked by fearful faces. These results indicate temporal and valence-specific effects of buspirone on the neuronal correlates of emotional face processing. Furthermore, the reduced neural activity in the dorsolateral prefrontal cortex in response to fearful faces suggests a reduced attention to fearful faces. Collectively, these findings provide new insights into the role of 5-HT1A receptors in emotional face processing and have implications for affective disorders that are characterized by an increased attention to negative stimuli. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  9. Sirtuin 1 Agonist Minimizes Injury and Improves the Immune Response Following Traumatic Shock.

    Science.gov (United States)

    Luciano, Jason A; Kautza, Benjamin; Darwiche, Sophie; Martinez, Silvia; Stratimirovic, Sladjana; Waltz, Paul; Sperry, Jason; Rosengart, Matthew; Shiva, Sruti; Zuckerbraun, Brian S

    2015-08-01

    Survival from traumatic injury requires a coordinated and controlled inflammatory and immune response. Mitochondrial and metabolic responses to stress have been shown to play a role in these inflammatory and immune responses. We hypothesized that increases in mitochondrial biogenesis via a sirtuin 1 agonist would decrease tissue injury and partially ameliorate the immunosuppression seen following trauma. C57Bl/6 mice were subjected to a multiple trauma model. Mice were pretreated with either 100 mg/kg per day of the sirtuin 1 agonist, Srt1720, via oral gavage for 2 days prior to trauma and extended until the day the animals were killed, or they were pretreated with peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) siRNA via hydrodynamic tail vein injection 48 h prior to trauma. Markers for mitochondrial function and biogenesis were measured in addition to splenocyte proliferative capacity and bacterial clearance. Srt1720 was noted to improve mitochondrial biogenesis, mitochondrial function, and complex IV activity following traumatic injury (P hepatic injury with significant reductions in serum alanine aminotransferase levels seen in mice treated with srt1720. Splenocyte proliferative capacity and intraperitoneal bacterial clearance were evaluated as markers for overall immune function following trauma-hemorrhage. Treatment with Srt1720 minimized the trauma-induced decreases in splenocyte proliferation (P clearance. The PGC1α signaling pathway is an important regulator of mitochondrial function and biogenesis, which can potentially be harnessed to protect against hepatic injury and minimize the immunosuppression that is seen following trauma-hemorrhage.

  10. Profound and Rapid Reduction in Body Temperature Induced by the Melanocortin Receptor Agonists

    Science.gov (United States)

    Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

    2014-01-01

    The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5′AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII’s effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. PMID:25065745

  11. Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists.

    Science.gov (United States)

    Xu, Yuanzhong; Kim, Eun Ran; Fan, Shengjie; Xia, Yan; Xu, Yong; Huang, Cheng; Tong, Qingchun

    2014-08-22

    The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5'AMP. Moreover, β-adrenergic receptors (β-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII's effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Algebraic partial Boolean algebras

    International Nuclear Information System (INIS)

    Smith, Derek

    2003-01-01

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

  13. The Inverse of Banded Matrices

    Science.gov (United States)

    2013-01-01

    indexed entries all zeros. In this paper, generalizing a method of Mallik (1999) [5], we give the LU factorization and the inverse of the matrix Br,n (if it...r ≤ i ≤ r, 1 ≤ j ≤ r, with the remaining un-indexed entries all zeros. In this paper generalizing a method of Mallik (1999) [5...matrices and applications to piecewise cubic approximation, J. Comput. Appl. Math. 8 (4) (1982) 285–288. [5] R.K. Mallik , The inverse of a lower

  14. Size Estimates in Inverse Problems

    KAUST Repository

    Di Cristo, Michele

    2014-01-06

    Detection of inclusions or obstacles inside a body by boundary measurements is an inverse problems very useful in practical applications. When only finite numbers of measurements are available, we try to detect some information on the embedded object such as its size. In this talk we review some recent results on several inverse problems. The idea is to provide constructive upper and lower estimates of the area/volume of the unknown defect in terms of a quantity related to the work that can be expressed with the available boundary data.

  15. -Dimensional Fractional Lagrange's Inversion Theorem

    Directory of Open Access Journals (Sweden)

    F. A. Abd El-Salam

    2013-01-01

    Full Text Available Using Riemann-Liouville fractional differential operator, a fractional extension of the Lagrange inversion theorem and related formulas are developed. The required basic definitions, lemmas, and theorems in the fractional calculus are presented. A fractional form of Lagrange's expansion for one implicitly defined independent variable is obtained. Then, a fractional version of Lagrange's expansion in more than one unknown function is generalized. For extending the treatment in higher dimensions, some relevant vectors and tensors definitions and notations are presented. A fractional Taylor expansion of a function of -dimensional polyadics is derived. A fractional -dimensional Lagrange inversion theorem is proved.

  16. Darwin's "strange inversion of reasoning".

    Science.gov (United States)

    Dennett, Daniel

    2009-06-16

    Darwin's theory of evolution by natural selection unifies the world of physics with the world of meaning and purpose by proposing a deeply counterintuitive "inversion of reasoning" (according to a 19th century critic): "to make a perfect and beautiful machine, it is not requisite to know how to make it" [MacKenzie RB (1868) (Nisbet & Co., London)]. Turing proposed a similar inversion: to be a perfect and beautiful computing machine, it is not requisite to know what arithmetic is. Together, these ideas help to explain how we human intelligences came to be able to discern the reasons for all of the adaptations of life, including our own.

  17. Inverse transport theory and applications

    International Nuclear Information System (INIS)

    Bal, Guillaume

    2009-01-01

    Inverse transport consists of reconstructing the optical properties of a domain from measurements performed at the domain's boundary. This review concerns several types of measurements: time-dependent, time-independent, angularly resolved and angularly averaged measurements. We review recent results on the reconstruction of the optical parameters from such measurements and the stability of such reconstructions. Inverse transport finds applications e.g. in medical imaging (optical tomography, optical molecular imaging) and in geophysical imaging (remote sensing in the Earth's atmosphere). (topical review)

  18. Inverse Interval Matrix: A Survey

    Czech Academy of Sciences Publication Activity Database

    Rohn, Jiří; Farhadsefat, R.

    2011-01-01

    Roč. 22, - (2011), s. 704-719 E-ISSN 1081-3810 R&D Projects: GA ČR GA201/09/1957; GA ČR GC201/08/J020 Institutional research plan: CEZ:AV0Z10300504 Keywords : interval matrix * inverse interval matrix * NP-hardness * enclosure * unit midpoint * inverse sign stability * nonnegative invertibility * absolute value equation * algorithm Subject RIV: BA - General Mathematics Impact factor: 0.808, year: 2010 http://www.math.technion.ac.il/iic/ ela / ela -articles/articles/vol22_pp704-719.pdf

  19. Fractal-Based Methods and Inverse Problems for Differential Equations: Current State of the Art

    Directory of Open Access Journals (Sweden)

    Herb E. Kunze

    2014-01-01

    Full Text Available We illustrate, in this short survey, the current state of the art of fractal-based techniques and their application to the solution of inverse problems for ordinary and partial differential equations. We review several methods based on the Collage Theorem and its extensions. We also discuss two innovative applications: the first one is related to a vibrating string model while the second one considers a collage-based approach for solving inverse problems for partial differential equations on a perforated domain.

  20. Modification of opiate agonist binding by pertussis toxin

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-03-05

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

  1. Ecdysone Agonist: New Insecticides with Novel Mode of Action

    Directory of Open Access Journals (Sweden)

    Y. Andi Trisyono

    2002-12-01

    Full Text Available Development of insect resistance to insecticide has been the major driving force for the development of new insecticides. Awareness and demand from public for more environmentally friendly insecticides have contributed in shifting the trend from using broad spectrum to selective insecticides. As a result, scientists have looked for new target sites beyond the nervous system. Insect growth regulators (IGRs are more selective insecticides than conventional insecticides, and ecdysone agonists are the newest IGRs being commercialized, e.g. tebufenozide, methoxyfenozide, and halofenozide. Ecdysone agonists bind to the ecdysteroid receptors, and they act similarly to the molting hormone 20-hydroxyecdysone. The binding provides larvae or nymphs with a signal to enter a premature and lethal molting cycle. In addition, the ecdysone agonists cause a reduction in the number of eggs laid by female insects. The ecdysone agonists are being developed as selective biorational insecticides. Tebufenozide and methoxyfenozide are used to control lepidopteran insect pests, whereas halofenozide is being used to control coleopteran insect pests. Their selectivity is due to differences in the binding affinity between these compounds to the receptors in insects from different orders. The selectivity of these compounds makes them candidates to be used in combinations with other control strategies to develop integrated pest management programs in agricultural ecosystems. Key words: new insecticides, selectivity, ecdysone agonists

  2. Modification of opiate agonist binding by pertussis toxin

    International Nuclear Information System (INIS)

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

    1986-01-01

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

  3. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction.

    Science.gov (United States)

    Schwabl, Philipp; Hambruch, Eva; Seeland, Berit A; Hayden, Hubert; Wagner, Michael; Garnys, Lukas; Strobel, Bastian; Schubert, Tim-Lukas; Riedl, Florian; Mitteregger, Dieter; Burnet, Michael; Starlinger, Patrick; Oberhuber, Georg; Deuschle, Ulrich; Rohr-Udilova, Nataliya; Podesser, Bruno K; Peck-Radosavljevic, Markus; Reiberger, Thomas; Kremoser, Claus; Trauner, Michael

    2017-04-01

    Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study. In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7days) and cirrhotic (carbon tetrachloride, CCl 4 , 14weeks) portal hypertension, PX20606 (PX,10mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10mg/kg) were gavaged. We then measured portal pressure, intrahepatic vascular resistance, liver fibrosis and bacterial translocation. PX decreased portal pressure in non-cirrhotic PPVL (12.6±1.7 vs. 10.4±1.1mmHg; p=0.020) and cirrhotic CCl 4 (15.2±0.5 vs. 11.8±0.4mmHg; p=0.001) rats. In PPVL animals, we observed less bacterial translocation (-36%; p=0.041), a decrease in lipopolysaccharide binding protein (-30%; p=0.024) and splanchnic tumour necrosis factor α levels (-39%; p=0.044) after PX treatment. In CCl 4 rats, PX decreased fibrotic Sirius Red area (-43%; p=0.005), hepatic hydroxyproline (-66%; pportal pressure (-14%; p=0.041) by restoring endothelial function, 14week PX therapy additionally inhibited sinusoidal remodelling and decreased portal pressure to a greater extent (-22%; p=0.001). In human liver sinusoidal endothelial cells, PX increased eNOS and DDAH expression. The non-steroidal FXR agonist PX20606 ameliorates portal hypertension by reducing liver fibrosis, vascular remodelling and sinusoidal dysfunction. The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut. Copyright

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

    Directory of Open Access Journals (Sweden)

    Gunnar Kleinau

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

  5. Superconductivity in Pb inverse opal

    International Nuclear Information System (INIS)

    Aliev, Ali E.; Lee, Sergey B.; Zakhidov, Anvar A.; Baughman, Ray H.

    2007-01-01

    Type-II superconducting behavior was observed in highly periodic three-dimensional lead inverse opal prepared by infiltration of melted Pb in blue (D = 160 nm), green (D = 220 nm) and red (D = 300 nm) opals and followed by the extraction of the SiO 2 spheres by chemical etching. The onset of a broad phase transition (ΔT = 0.3 K) was shifted from T c = 7.196 K for bulk Pb to T c = 7.325 K. The upper critical field H c2 (3150 Oe) measured from high-field hysteresis loops exceeds the critical field for bulk lead (803 Oe) fourfold. Two well resolved peaks observed in the hysteresis loops were ascribed to flux penetration into the cylindrical void space that can be found in inverse opal structure and into the periodic structure of Pb nanoparticles. The red inverse opal shows pronounced oscillations of magnetic moment in the mixed state at low temperatures, T 0.9T c has been observed for all of the samples studied. The magnetic field periodicity of resistivity modulation is in good agreement with the lattice parameter of the inverse opal structure. We attribute the failure to observe pronounced modulation in magneto-resistive measurement to difficulties in the precision orientation of the sample along the magnetic field

  6. Inverse problem of solar oscillations

    International Nuclear Information System (INIS)

    Sekii, T.; Shibahashi, H.

    1987-01-01

    The authors present some preliminary results of numerical simulation to infer the sound velocity distribution in the solar interior from the oscillation data of the Sun as the inverse problem. They analyze the acoustic potential itself by taking account of some factors other than the sound velocity, and infer the sound velocity distribution in the deep interior of the Sun

  7. Wave-equation dispersion inversion

    KAUST Repository

    Li, Jing

    2016-12-08

    We present the theory for wave-equation inversion of dispersion curves, where the misfit function is the sum of the squared differences between the wavenumbers along the predicted and observed dispersion curves. The dispersion curves are obtained from Rayleigh waves recorded by vertical-component geophones. Similar to wave-equation traveltime tomography, the complicated surface wave arrivals in traces are skeletonized as simpler data, namely the picked dispersion curves in the phase-velocity and frequency domains. Solutions to the elastic wave equation and an iterative optimization method are then used to invert these curves for 2-D or 3-D S-wave velocity models. This procedure, denoted as wave-equation dispersion inversion (WD), does not require the assumption of a layered model and is significantly less prone to the cycle-skipping problems of full waveform inversion. The synthetic and field data examples demonstrate that WD can approximately reconstruct the S-wave velocity distributions in laterally heterogeneous media if the dispersion curves can be identified and picked. The WD method is easily extended to anisotropic data and the inversion of dispersion curves associated with Love waves.

  8. Partially composite Higgs models

    DEFF Research Database (Denmark)

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

    2018-01-01

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

  9. Photogenic partial seizures.

    Science.gov (United States)

    Hennessy, M J; Binnie, C D

    2000-01-01

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

  10. Arthroscopic partial medial meniscectomy

    Directory of Open Access Journals (Sweden)

    Dašić Žarko

    2011-01-01

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

  11. Workflows for Full Waveform Inversions

    Science.gov (United States)

    Boehm, Christian; Krischer, Lion; Afanasiev, Michael; van Driel, Martin; May, Dave A.; Rietmann, Max; Fichtner, Andreas

    2017-04-01

    Despite many theoretical advances and the increasing availability of high-performance computing clusters, full seismic waveform inversions still face considerable challenges regarding data and workflow management. While the community has access to solvers which can harness modern heterogeneous computing architectures, the computational bottleneck has fallen to these often manpower-bounded issues that need to be overcome to facilitate further progress. Modern inversions involve huge amounts of data and require a tight integration between numerical PDE solvers, data acquisition and processing systems, nonlinear optimization libraries, and job orchestration frameworks. To this end we created a set of libraries and applications revolving around Salvus (http://salvus.io), a novel software package designed to solve large-scale full waveform inverse problems. This presentation focuses on solving passive source seismic full waveform inversions from local to global scales with Salvus. We discuss (i) design choices for the aforementioned components required for full waveform modeling and inversion, (ii) their implementation in the Salvus framework, and (iii) how it is all tied together by a usable workflow system. We combine state-of-the-art algorithms ranging from high-order finite-element solutions of the wave equation to quasi-Newton optimization algorithms using trust-region methods that can handle inexact derivatives. All is steered by an automated interactive graph-based workflow framework capable of orchestrating all necessary pieces. This naturally facilitates the creation of new Earth models and hopefully sparks new scientific insights. Additionally, and even more importantly, it enhances reproducibility and reliability of the final results.

  12. Hierarchical partial order ranking

    International Nuclear Information System (INIS)

    Carlsen, Lars

    2008-01-01

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

  13. Principles of agonist recognition in Cys-loop receptors

    Directory of Open Access Journals (Sweden)

    Timothy eLynagh

    2014-04-01

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

  14. In silico discovery of novel Retinoic Acid Receptor agonist structures

    Directory of Open Access Journals (Sweden)

    Samuels Herbert H

    2001-06-01

    Full Text Available Abstract Background Several Retinoic Acid Receptors (RAR agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia. Results We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually to the structure of the receptor with the Internal Coordinates Mechanics (ICM program. Thirty ligand candidates were tested in vitro. Conclusions Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

  15. Long-acting β2-agonists in asthma

    DEFF Research Database (Denmark)

    Jacobson, Glenn A; Raidal, Sharanne; Hostrup, Morten

    2018-01-01

    Long-acting β2-agonists (LABAs) such as formoterol and salmeterol are used for prolonged bronchodilatation in asthma, usually in combination with inhaled corticosteroids (ICSs). Unexplained paradoxical asthma exacerbations and deaths have been associated with LABAs, particularly when used without...... and effects on BHR, particularly that (S)-enantiomers of β2-agonists may be deleterious to asthma control. LABAs display enantioselective pharmacokinetics and pharmacodynamics. Biological plausibility of the deleterious effects of β2-agonists (S)-enantiomers is provided by in vitro and in vivo studies from...... mechanism in rapid asthma deaths. More effort should therefore be applied to investigating potential enantiospecific effects of LABAs on safety, specifically bronchoprotection. Safety studies directly assessing the effects of LABA (S)-enantiomers on BHR are long overdue....

  16. Source inversion in the full-wave tomography; Full wave tomography ni okeru source inversion

    Energy Technology Data Exchange (ETDEWEB)

    Tsuchiya, T [DIA Consultants Co. Ltd., Tokyo (Japan)

    1997-10-22

    In order to consider effects of characteristics of a vibration source in the full-wave tomography (FWT), a study has been performed on a method to invert vibration source parameters together with V(p)/V(s) distribution. The study has expanded an analysis method which uses as the basic the gradient method invented by Tarantola and the partial space method invented by Sambridge, and conducted numerical experiments. The experiment No. 1 has performed inversion of only the vibration source parameters, and the experiment No. 2 has executed simultaneous inversion of the V(p)/V(s) distribution and the vibration source parameters. The result of the discussions revealed that and effective analytical procedure would be as follows: in order to predict maximum stress, the average vibration source parameters and the property parameters are first inverted simultaneously; in order to estimate each vibration source parameter at a high accuracy, the property parameters are fixed, and each vibration source parameter is inverted individually; and the derived vibration source parameters are fixed, and the property parameters are again inverted from the initial values. 5 figs., 2 tabs.

  17. Stable Lévy motion with inverse Gaussian subordinator

    Science.gov (United States)

    Kumar, A.; Wyłomańska, A.; Gajda, J.

    2017-09-01

    In this paper we study the stable Lévy motion subordinated by the so-called inverse Gaussian process. This process extends the well known normal inverse Gaussian (NIG) process introduced by Barndorff-Nielsen, which arises by subordinating ordinary Brownian motion (with drift) with inverse Gaussian process. The NIG process found many interesting applications, especially in financial data description. We discuss here the main features of the introduced subordinated process, such as distributional properties, existence of fractional order moments and asymptotic tail behavior. We show the connection of the process with continuous time random walk. Further, the governing fractional partial differential equations for the probability density function is also obtained. Moreover, we discuss the asymptotic distribution of sample mean square displacement, the main tool in detection of anomalous diffusion phenomena (Metzler et al., 2014). In order to apply the stable Lévy motion time-changed by inverse Gaussian subordinator we propose a step-by-step procedure of parameters estimation. At the end, we show how the examined process can be useful to model financial time series.

  18. Pyramidal resistor networks for electrical impedance tomography with partial boundary measurements

    International Nuclear Information System (INIS)

    Borcea, L; Mamonov, A V; Druskin, V; Vasquez, F Guevara

    2010-01-01

    We introduce an inversion algorithm for electrical impedance tomography (EIT) with partial boundary measurements in two dimensions. It gives stable and fast reconstructions using sparse parameterizations of the unknown conductivity on optimal grids that are computed as part of the inversion. We follow the approach in Borcea et al (2008 Inverse Problems 24 035013) and Vasquez (2006 PhD thesis Rice University, Houston, TX, USA) that connects inverse discrete problems for resistor networks to continuum EIT problems, using optimal grids. The algorithm in Borcea et al (2008 Inverse Problems 24 035013) and Vasquez (2006 PhD Thesis Rice University, Houston, TX, USA) is based on circular resistor networks, and solves the EIT problem with full boundary measurements. It is extended in Borcea et al (2010 Inverse Problems 26 045010) to EIT with partial boundary measurements, using extremal quasi-conformal mappings that transform the problem to one with full boundary measurements. Here we introduce a different class of optimal grids, based on resistor networks with pyramidal topology, that is better suited for the partial measurements setup. We prove the unique solvability of the discrete inverse problem for these networks and develop an algorithm for finding them from the measurements of the Dirichlet to Neumann map. Then, we show how to use the networks to define the optimal grids and to approximate the unknown conductivity. We assess the performance of our approach with numerical simulations and compare the results with those in Borcea et al (2010)

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

    Science.gov (United States)

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

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  20. Investigation of the mechanism of radioprotective action of adrenoceptor agonists

    International Nuclear Information System (INIS)

    Kulinskij, V.I.; Klimova, A.D.; Yashunskij, V.G.; Alpatova, T.V.; 4205700SU)

    1986-01-01

    α-Adrenoceptor agonists of both main groups, i.e. arylalkylamines and imidazolines, have a pronounced radioprotective effect. Their chemical analogs, which fail to stimulate α-adrenoceptors, do not protect mice. The effect of phenylephrine, adrenaline, and noradrenaline comes into play via α 1 -adrenoceptors and that of clonidine, via α 2 -adrenoceptors and also via α 1 -adrenoceptors. Adrenoceptor agonists can probably manifest their radioprotective action via both subtypes of α-adrenoceptors. Possible intracellular mechanisms of the radioprotective action are discussed

  1. Numerical inverse Laplace transformation for determining the system response of linear systems in the time domain

    Science.gov (United States)

    Friedrich, R.; Drewelow, W.

    1978-01-01

    An algorithm is described that is based on the method of breaking the Laplace transform down into partial fractions which are then inverse-transformed separately. The sum of the resulting partial functions is the wanted time function. Any problems caused by equation system forms are largely limited by appropriate normalization using an auxiliary parameter. The practical limits of program application are reached when the degree of the denominator of the Laplace transform is seven to eight.

  2. Agonist-induced platelet reactivity correlates with bleeding in haemato-oncological patients.

    Science.gov (United States)

    Batman, B; van Bladel, E R; van Hamersveld, M; Pasker-de Jong, P C M; Korporaal, S J A; Urbanus, R T; Roest, M; Boven, L A; Fijnheer, R

    2017-11-01

    Prophylactic platelet transfusions are administered to prevent bleeding in haemato-oncological patients. However, bleeding still occurs, despite these transfusions. This practice is costly and not without risk. Better predictors of bleeding are needed, and flow cytometric evaluation of platelet function might aid the clinician in identifying patients at risk of bleeding. This evaluation can be performed within the hour and is not hampered by low platelet count. Our objective was to assess a possible correlation between bleeding and platelet function in thrombocytopenic haemato-oncological patients. Inclusion was possible for admitted haemato-oncology patients aged 18 years and above. Furthermore, an expected need for platelet transfusions was necessary. Bleeding was graded according to the WHO bleeding scale. Platelet reactivity to stimulation by either adenosine diphosphate (ADP), cross-linked collagen-related peptide (CRP-xL), PAR1- or PAR4-activating peptide (AP) was measured using flow cytometry. A total of 114 evaluations were available from 21 consecutive patients. Platelet reactivity in response to stimulation by all four studied agonists was inversely correlated with significant bleeding. Odds ratios (OR) for bleeding were 0·28 for every unit increase in median fluorescence intensity (MFI) [95% confidence interval (CI) 0·11-0·73] for ADP; 0·59 [0·40-0·87] for CRP-xL; 0·59 [0·37-0·94] for PAR1-AP; and 0·43 [0·23-0·79] for PAR4-AP. The platelet count was not correlated with bleeding (OR 0·99 [0·96-1·02]). Agonist-induced platelet reactivity was significantly correlated to bleeding. Platelet function testing could provide a basis for a personalized transfusion regimen, in which platelet transfusions are limited to those at risk of bleeding. © 2017 International Society of Blood Transfusion.

  3. Automated gravity gradient tensor inversion for underwater object detection

    International Nuclear Information System (INIS)

    Wu, Lin; Tian, Jinwen

    2010-01-01

    Underwater abnormal object detection is a current need for the navigation security of autonomous underwater vehicles (AUVs). In this paper, an automated gravity gradient tensor inversion algorithm is proposed for the purpose of passive underwater object detection. Full-tensor gravity gradient anomalies induced by an object in the partial area can be measured with the technique of gravity gradiometry on an AUV. Then the automated algorithm utilizes the anomalies, using the inverse method to estimate the mass and barycentre location of the arbitrary-shaped object. A few tests on simple synthetic models will be illustrated, in order to evaluate the feasibility and accuracy of the new algorithm. Moreover, the method is applied to a complicated model of an abnormal object with gradiometer and AUV noise, and interference from a neighbouring illusive smaller object. In all cases tested, the estimated mass and barycentre location parameters are found to be in good agreement with the actual values

  4. Identification of transcriptional biomarkers by RNA-sequencing for improved detection of β2-agonists abuse in goat skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Luyao Zhao

    Full Text Available In this paper, high-throughput RNA-sequencing (RNA-seq was used to search for transcriptional biomarkers for β2-agonists. In combination with drug mechanisms, a smaller group of genes with higher detection accuracy was screened out. Unknown samples were first predicted by this group of genes, and liquid chromatograph tandem mass spectrometer (LC-MS/MS was applied to positive samples to validate the biomarkers. The results of principal component analysis (PCA, hierarchical cluster analysis (HCA and discriminant analysis (DA indicated that the eight genes screened by high-throughput RNA-seq were able to distinguish samples in the experimental group and control group. Compared with the nine genes selected from an earlier literature, 17 genes including these nine genes were proven to have a more satisfactory effect, which validated the accuracy of gene selection by RNA-seq. Then, six key genes were selected from the 17 genes according to the variable importance in projection (VIP value of greater than 1. The test results using the six genes and 17 genes were similar, revealing that the six genes were critical genes. By using the six genes, three positive samples possibly treated with drugs were screened out from 25 unknown samples through DA and partial least squares discriminant analysis (PLS-DA. Then, the three samples were verified by a standard method, and mapenterol was detected in a sample. Therefore, the six genes can be used as biomarkers to detect β2-agonists. Compared with the previous study, accurate detection of β2-agonists abuse using six key genes is an improvement method, which show great significance in the monitoring of β2-agonists abuse in animal husbandry.

  5. Renormalized nonlinear sensitivity kernel and inverse thin-slab propagator in T-matrix formalism for wave-equation tomography

    International Nuclear Information System (INIS)

    Wu, Ru-Shan; Wang, Benfeng; Hu, Chunhua

    2015-01-01

    We derived the renormalized nonlinear sensitivity operator and the related inverse thin-slab propagator (ITSP) for nonlinear tomographic waveform inversion based on the theory of nonlinear partial derivative operator and its De Wolf approximation. The inverse propagator is based on a renormalization procedure to the forward and inverse transition matrix scattering series. The ITSP eliminates the divergence of the inverse Born series for strong perturbations by stepwise partial summation (renormalization). Numerical tests showed that the inverse Born T-series starts to diverge at moderate perturbation (20% for the given model of Gaussian ball with a radius of 5 wavelength), while the ITSP has no divergence problem for any strong perturbations (up to 100% perturbation for test model). In addition, the ITSP is a non-iterative, marching algorithm with only one sweep, and therefore very efficient in comparison with the iterative inversion based on the inverse-Born scattering series. This convergence and efficiency improvement has potential applications to the iterative procedure of waveform inversion. (paper)

  6. Partially ordered algebraic systems

    CERN Document Server

    Fuchs, Laszlo

    2011-01-01

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

  7. Infinite partial summations

    International Nuclear Information System (INIS)

    Sprung, D.W.L.

    1975-01-01

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

  8. On universal partial words

    OpenAIRE

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

    2016-01-01

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

  9. Partial differential equations

    CERN Document Server

    Agranovich, M S

    2002-01-01

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

  10. Partial differential equations

    CERN Document Server

    Levine, Harold

    1997-01-01

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

  11. Partial differential equations

    CERN Document Server

    Sloan, D; Süli, E

    2001-01-01

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

  12. Elliptic partial differential equations

    CERN Document Server

    Han, Qing

    2011-01-01

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

  13. Generalized Partial Volume

    DEFF Research Database (Denmark)

    Darkner, Sune; Sporring, Jon

    2011-01-01

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

  14. Inverse photon-photon processes

    International Nuclear Information System (INIS)

    Carimalo, C.; Crozon, M.; Kesler, P.; Parisi, J.

    1981-12-01

    We here consider inverse photon-photon processes, i.e. AB → γγX (where A, B are hadrons, in particular protons or antiprotons), at high energies. As regards the production of a γγ continuum, we show that, under specific conditions the study of such processes might provide some information on the subprocess gg γγ, involving a quark box. It is also suggested to use those processes in order to systematically look for heavy C = + structures (quarkonium states, gluonia, etc.) showing up in the γγ channel. Inverse photon-photon processes might thus become a new and fertile area of investigation in high-energy physics, provided the difficult problem of discriminating between direct photons and indirect ones can be handled in a satisfactory way

  15. Analysis of RAE-1 inversion

    Science.gov (United States)

    Hedland, D. A.; Degonia, P. K.

    1974-01-01

    The RAE-1 spacecraft inversion performed October 31, 1972 is described based upon the in-orbit dynamical data in conjunction with results obtained from previously developed computer simulation models. The computer simulations used are predictive of the satellite dynamics, including boom flexing, and are applicable during boom deployment and retraction, inter-phase coast periods, and post-deployment operations. Attitude data, as well as boom tip data, were analyzed in order to obtain a detailed description of the dynamical behavior of the spacecraft during and after the inversion. Runs were made using the computer model and the results were analyzed and compared with the real time data. Close agreement between the actual recorded spacecraft attitude and the computer simulation results was obtained.

  16. Melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 modified at the para position of the benzyl side chain (DPhe): importance for mouse melanocortin-3 receptor agonist versus antagonist activity.

    Science.gov (United States)

    Proneth, Bettina; Pogozheva, Irina D; Portillo, Federico P; Mosberg, Henry I; Haskell-Luevano, Carrie

    2008-09-25

    The melanocortin-3 and -4 receptors (MC3R, MC4R) have been implicated in energy homeostasis and obesity. Whereas the physiological role of the MC4R is extensively studied, little is known about the MC3R. One caveat is the limited availability of ligands that are selective for the MC3R. Previous studies identified Ac-His-DPhe(p-I)-Arg-Trp-NH 2, which possessed partial agonist/antagonist pharmacology at the mMC3R while retaining full nanomolar agonist pharmacology at the mMC4R. These data allowed for the hypothesis that the DPhe position in melanocortin tetrapeptides can be used to examine ligand side-chain determinants important for differentiation of mMC3R agonist versus antagonist activity. A series of 15 DPhe (7) modified Ac-His-DPhe (7)-Arg-Trp-NH 2 tetrapeptides has been synthesized and pharmacologically characterized. Most notable results include the identification of modifications that resulted in potent antagonists/partial agonists at the mMC3R and full, potent agonists at the mMC4R. These SAR studies provide experimental evidence that the molecular mechanism of antagonism at the mMC3R differentiates this subtype from the mMC4R.

  17. Inverse problem in nuclear physics

    International Nuclear Information System (INIS)

    Zakhariev, B.N.

    1976-01-01

    The method of reconstruction of interaction from the scattering data is formulated in the frame of the R-matrix theory in which the potential is determined by position of resonance Esub(lambda) and their reduced widths γ 2 lambda. In finite difference approximation for the Schroedinger equation this new approach allows to make the logics of the inverse problem IP more clear. A possibility of applications of IP formalism to various nuclear systems is discussed. (author)

  18. An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor

    DEFF Research Database (Denmark)

    Els, Sylvia; Schild, Enrico; Petersen, Pia Steen

    2012-01-01

    The ghrelin receptor displays a high constitutive activity suggested to be involved in the regulation of appetite and food intake. Here, we have created peptides with small changes in the core binding motif -wFw- of the hexapeptide KwFwLL-NH(2) that can swap the peptide behavior from inverse......-tryptophane at position 4 with 1-naphthyl-d-alanine (d-1-Nal) and 2-naphthyl-d-alanine (d-2-Nal) induces agonism in functional assays. Competitive binding studies showed a high affinity of the inverse agonist K-(d-1-Nal)-FwLL-NH(2) at the ghrelin receptor. Moreover, mutagenesis studies of the receptor revealed key...

  19. Unilateral removable partial dentures.

    Science.gov (United States)

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

    2017-01-27

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

  20. Elastic reflection waveform inversion with variable density

    KAUST Repository

    Li, Yuanyuan; Li, Zhenchun; Alkhalifah, Tariq Ali; Guo, Qiang

    2017-01-01

    Elastic full waveform inversion (FWI) provides a better description of the subsurface than those given by the acoustic assumption. However it suffers from a more serious cycle skipping problem compared with the latter. Reflection waveform inversion

  1. Thrombopoietin-receptor agonists in haematological disorders: The Danish experience

    DEFF Research Database (Denmark)

    Gudbrandsdottir, Sif; Frederiksen, Henrik; Hasselbalch, Hans

    2011-01-01

    The objective of this study was to investigate the use of thrombopoietin-receptor agonists (TPO-ra) in patients with refractory primary immune thrombocytopenia (ITP) as well as off-label use of TPO-ra in Danish haematology departments. Hospital medical records from 32 of the 39 patients having re...

  2. Use of ß-adrenergic agonists in hybrid catfish

    Science.gov (United States)

    Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

  3. Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonists

    DEFF Research Database (Denmark)

    Christiansen, Elisabeth; Due-Hansen, Maria E; Urban, Christian

    2012-01-01

    FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metaboli...

  4. Biodistribution and dosimetry in humans of two inverse agonists to image cannabinoid CB1 receptors using positron emission tomography

    International Nuclear Information System (INIS)

    Terry, Garth E.; Hirvonen, Jussi; Liow, Jeih-San; Seneca, Nicholas; Morse, Cheryl L.; Pike, Victor W.; Innis, Robert B.; Tauscher, Johannes T.; Schaus, John M.; Phebus, Lee; Felder, Christian C.; Halldin, Christer

    2010-01-01

    Cannabinoid subtype 1 (CB 1 ) receptors are found in nearly every organ in the body, may be involved in several neuropsychiatric and metabolic disorders, and are therefore an active target for pharmacotherapy and biomarker development. We recently reported brain imaging of CB 1 receptors with two PET radioligands: 11 C-MePPEP and 18 F-FMPEP-d 2 . Here we describe the biodistribution and dosimetry estimates for these two radioligands. Seven healthy subjects (four men and three women) underwent whole-body PET scans for 120 min after injection with 11 C-MePPEP. Another seven healthy subjects (two men and five women) underwent whole-body PET scans for 300 min after injection with 18 F-FMPEP-d 2 . Residence times were acquired from regions of interest drawn on tomographic images of visually identifiable organs for both radioligands and from radioactivity excreted in urine for 18 F-FMPEP-d 2 . The effective doses of 11 C-MePPEP and 18 F-FMPEP-d 2 are 4.6 and 19.7 μSv/MBq, respectively. Both radioligands demonstrated high uptake of radioactivity in liver, lung, and brain shortly after injection and accumulated radioactivity in bone marrow towards the end of the scan. After injection of 11 C-MePPEP, radioactivity apparently underwent hepatobiliary excretion only, while radioactivity from 18 F-FMPEP-d 2 showed both hepatobiliary and urinary excretion. 11 C-MePPEP and 18 F-FMPEP-d 2 yield an effective dose similar to other PET radioligands labeled with either 11 C or 18 F. The high uptake in brain confirms the utility of these two radioligands to image CB 1 receptors in brain, and both may also be useful to image CB 1 receptors in the periphery. (orig.)

  5. On a complete topological inverse polycyclic monoid

    Directory of Open Access Journals (Sweden)

    S. O. Bardyla

    2016-12-01

    Full Text Available We give sufficient conditions when a topological inverse $\\lambda$-polycyclic monoid $P_{\\lambda}$ is absolutely $H$-closed in the class of topological inverse semigroups. For every infinite cardinal $\\lambda$ we construct the coarsest semigroup inverse topology $\\tau_{mi}$ on $P_\\lambda$ and give an example of a topological inverse monoid $S$ which contains the polycyclic monoid $P_2$ as a dense discrete subsemigroup.

  6. Tutorial on Online Partial Evaluation

    Directory of Open Access Journals (Sweden)

    William R. Cook

    2011-09-01

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

  7. Inversion: A Most Useful Kind of Transformation.

    Science.gov (United States)

    Dubrovsky, Vladimir

    1992-01-01

    The transformation assigning to every point its inverse with respect to a circle with given radius and center is called an inversion. Discusses inversion with respect to points, circles, angles, distances, space, and the parallel postulate. Exercises related to these topics are included. (MDH)

  8. Probabilistic Geoacoustic Inversion in Complex Environments

    Science.gov (United States)

    2015-09-30

    Probabilistic Geoacoustic Inversion in Complex Environments Jan Dettmer School of Earth and Ocean Sciences, University of Victoria, Victoria BC...long-range inversion methods can fail to provide sufficient resolution. For proper quantitative examination of variability, parameter uncertainty must...project aims to advance probabilistic geoacoustic inversion methods for complex ocean environments for a range of geoacoustic data types. The work is

  9. Type-Directed Partial Evaluation

    DEFF Research Database (Denmark)

    Danvy, Olivier

    1998-01-01

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

  10. Type-Directed Partial Evaluation

    DEFF Research Database (Denmark)

    Danvy, Olivier

    1998-01-01

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

  11. Dopamine agonists and risk: impulse control disorders in Parkinson's disease.

    Science.gov (United States)

    Voon, Valerie; Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J; Hallett, Mark

    2011-05-01

    Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.

  12. Effect of beta-agonists on LAM progression and treatment.

    Science.gov (United States)

    Le, Kang; Steagall, Wendy K; Stylianou, Mario; Pacheco-Rodriguez, Gustavo; Darling, Thomas N; Vaughan, Martha; Moss, Joel

    2018-01-30

    Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2 The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin TSC2 +/- fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function.

  13. Presymplectic current and the inverse problem of the calculus of variations

    NARCIS (Netherlands)

    Khavkine, I.

    2013-01-01

    The inverse problem of the calculus of variations asks whether a given system of partial differential equations (PDEs) admits a variational formulation. We show that the existence of a presymplectic form in the variational bicomplex, when horizontally closed on solutions, allows us to construct a

  14. Simplified solutions of the Cox-Thompson inverse scattering method at fixed energy

    International Nuclear Information System (INIS)

    Palmai, Tamas; Apagyi, Barnabas; Horvath, Miklos

    2008-01-01

    Simplified solutions of the Cox-Thompson inverse quantum scattering method at fixed energy are derived if a finite number of partial waves with only even or odd angular momenta contribute to the scattering process. Based on new formulae various approximate methods are introduced which also prove applicable to the generic scattering events

  15. Complexity analysis of accelerated MCMC methods for Bayesian inversion

    International Nuclear Information System (INIS)

    Hoang, Viet Ha; Schwab, Christoph; Stuart, Andrew M

    2013-01-01

    The Bayesian approach to inverse problems, in which the posterior probability distribution on an unknown field is sampled for the purposes of computing posterior expectations of quantities of interest, is starting to become computationally feasible for partial differential equation (PDE) inverse problems. Balancing the sources of error arising from finite-dimensional approximation of the unknown field, the PDE forward solution map and the sampling of the probability space under the posterior distribution are essential for the design of efficient computational Bayesian methods for PDE inverse problems. We study Bayesian inversion for a model elliptic PDE with an unknown diffusion coefficient. We provide complexity analyses of several Markov chain Monte Carlo (MCMC) methods for the efficient numerical evaluation of expectations under the Bayesian posterior distribution, given data δ. Particular attention is given to bounds on the overall work required to achieve a prescribed error level ε. Specifically, we first bound the computational complexity of ‘plain’ MCMC, based on combining MCMC sampling with linear complexity multi-level solvers for elliptic PDE. Our (new) work versus accuracy bounds show that the complexity of this approach can be quite prohibitive. Two strategies for reducing the computational complexity are then proposed and analyzed: first, a sparse, parametric and deterministic generalized polynomial chaos (gpc) ‘surrogate’ representation of the forward response map of the PDE over the entire parameter space, and, second, a novel multi-level Markov chain Monte Carlo strategy which utilizes sampling from a multi-level discretization of the posterior and the forward PDE. For both of these strategies, we derive asymptotic bounds on work versus accuracy, and hence asymptotic bounds on the computational complexity of the algorithms. In particular, we provide sufficient conditions on the regularity of the unknown coefficients of the PDE and on the

  16. Applied partial differential equations

    CERN Document Server

    Logan, J David

    2004-01-01

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

  17. Inductance loop and partial

    CERN Document Server

    Paul, Clayton R

    2010-01-01

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

  18. Fundamental partial compositeness

    CERN Document Server

    Sannino, Francesco

    2016-11-07

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

  19. Fundamental partial compositeness

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  20. 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.

  1. Partial oxidation process

    International Nuclear Information System (INIS)

    Najjar, M.S.

    1987-01-01

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

  2. Cytokine-induced loss of glucocorticoid function: effect of kinase inhibitors, long-acting β(2-adrenoceptor [corrected] agonist and glucocorticoid receptor ligands.

    Directory of Open Access Journals (Sweden)

    Christopher F Rider

    Full Text Available Acting on the glucocorticoid receptor (NR3C1, glucocorticoids are widely used to treat inflammatory diseases. However, glucocorticoid resistance often leads to suboptimal asthma control. Since glucocorticoid-induced gene expression contributes to glucocorticoid activity, the aim of this study was to use a 2 × glucocorticoid response element (GRE reporter and glucocorticoid-induced gene expression to investigate approaches to combat cytokine-induced glucocorticoid resistance. Pre-treatment with tumor necrosis factor-α (TNF or interleukin-1β inhibited dexamethasone-induced mRNA expression of the putative anti-inflammatory genes RGS2 and TSC22D3, or just TSC22D3, in primary human airway epithelial and smooth muscle cells, respectively. Dexamethasone-induced DUSP1 mRNA was unaffected. In human bronchial epithelial BEAS-2B cells, dexamethasone-induced TSC22D3 and CDKN1C expression (at 6 h was reduced by TNF pre-treatment, whereas DUSP1 and RGS2 mRNAs were unaffected. TNF pre-treatment also reduced dexamethasone-dependent 2×GRE reporter activation. This was partially reversed by PS-1145 and c-jun N-terminal kinase (JNK inhibitor VIII, inhibitors of IKK2 and JNK, respectively. However, neither inhibitor affected TNF-dependent loss of dexamethasone-induced CDKN1C or TSC22D3 mRNA. Similarly, inhibitors of the extracellular signal-regulated kinase, p38, phosphoinositide 3-kinase or protein kinase C pathways failed to attenuate TNF-dependent repression of the 2×GRE reporter. Fluticasone furoate, fluticasone propionate and budesonide were full agonists relative to dexamethasone, while GSK9027, RU24858, des-ciclesonide and GW870086X were partial agonists on the 2×GRE reporter. TNF reduced reporter activity in proportion with agonist efficacy. Full and partial agonists showed various degrees of agonism on RGS2 and TSC22D3 expression, but were equally effective at inducing CDKN1C and DUSP1, and did not affect the repression of CDKN1C or TSC22D3

  3. Melanocortin Tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 Modified at the Para Position of the Benzyl Side Chain (DPhe): Importance for Mouse Melanocortin-3 Receptor Agonist versus Antagonist Activity

    OpenAIRE

    Proneth, Bettina; Pogozheva, Irina D.; Portillo, Federico P.; Mosberg, Henry I.; Haskell-Luevano, Carrie

    2008-01-01

    The melanocortin-3 and -4 receptors (MC3R, MC4R) have been implicated in energy homeostasis and obesity. Whereas the physiological role of the MC4R is extensively studied, little is known about the MC3R. One caveat is the limited availability of ligands that are selective for the MC3R. Previous studies identified Ac-His-DPhe(p-I)-Arg-Trp-NH2, which possessed partial agonist/antagonist pharmacology at the mMC3R while retaining full nanomolar agonist pharmacology at the mMC4R. These data allowe...

  4. Inverse Compton gamma-rays from pulsars

    International Nuclear Information System (INIS)

    Morini, M.

    1983-01-01

    A model is proposed for pulsar optical and gamma-ray emission where relativistic electrons beams: (i) scatter the blackbody photons from the polar cap surface giving inverse Compton gamma-rays and (ii) produce synchrotron optical photons in the light cylinder region which are then inverse Compton scattered giving other gamma-rays. The model is applied to the Vela pulsar, explaining the first gamma-ray pulse by inverse Compton scattering of synchrotron photons near the light cylinder and the second gamma-ray pulse partly by inverse Compton scattering of synchrotron photons and partly by inverse Compton scattering of the thermal blackbody photons near the star surface. (author)

  5. Point-source inversion techniques

    Science.gov (United States)

    Langston, Charles A.; Barker, Jeffrey S.; Pavlin, Gregory B.

    1982-11-01

    A variety of approaches for obtaining source parameters from waveform data using moment-tensor or dislocation point source models have been investigated and applied to long-period body and surface waves from several earthquakes. Generalized inversion techniques have been applied to data for long-period teleseismic body waves to obtain the orientation, time function and depth of the 1978 Thessaloniki, Greece, event, of the 1971 San Fernando event, and of several events associated with the 1963 induced seismicity sequence at Kariba, Africa. The generalized inversion technique and a systematic grid testing technique have also been used to place meaningful constraints on mechanisms determined from very sparse data sets; a single station with high-quality three-component waveform data is often sufficient to discriminate faulting type (e.g., strike-slip, etc.). Sparse data sets for several recent California earthquakes, for a small regional event associated with the Koyna, India, reservoir, and for several events at the Kariba reservoir have been investigated in this way. Although linearized inversion techniques using the moment-tensor model are often robust, even for sparse data sets, there are instances where the simplifying assumption of a single point source is inadequate to model the data successfully. Numerical experiments utilizing synthetic data and actual data for the 1971 San Fernando earthquake graphically demonstrate that severe problems may be encountered if source finiteness effects are ignored. These techniques are generally applicable to on-line processing of high-quality digital data, but source complexity and inadequacy of the assumed Green's functions are major problems which are yet to be fully addressed.

  6. Inversion of GPS meteorology data

    Directory of Open Access Journals (Sweden)

    K. Hocke

    Full Text Available The GPS meteorology (GPS/MET experiment, led by the Universities Corporation for Atmospheric Research (UCAR, consists of a GPS receiver aboard a low earth orbit (LEO satellite which was launched on 3 April 1995. During a radio occultation the LEO satellite rises or sets relative to one of the 24 GPS satellites at the Earth's horizon. Thereby the atmospheric layers are successively sounded by radio waves which propagate from the GPS satellite to the LEO satellite. From the observed phase path increases, which are due to refraction of the radio waves by the ionosphere and the neutral atmosphere, the atmospheric parameter refractivity, density, pressure and temperature are calculated with high accuracy and resolution (0.5–1.5 km. In the present study, practical aspects of the GPS/MET data analysis are discussed. The retrieval is based on the Abelian integral inversion of the atmospheric bending angle profile into the refractivity index profile. The problem of the upper boundary condition of the Abelian integral is described by examples. The statistical optimization approach which is applied to the data above 40 km and the use of topside bending angle profiles from model atmospheres stabilize the inversion. The retrieved temperature profiles are compared with corresponding profiles which have already been calculated by scientists of UCAR and Jet Propulsion Laboratory (JPL, using Abelian integral inversion too. The comparison shows that in some cases large differences occur (5 K and more. This is probably due to different treatment of the upper boundary condition, data runaways and noise. Several temperature profiles with wavelike structures at tropospheric and stratospheric heights are shown. While the periodic structures at upper stratospheric heights could be caused by residual errors of the ionospheric correction method, the periodic temperature fluctuations at heights below 30 km are most likely caused by atmospheric waves (vertically

  7. Introducing the Improved Heaviside Approach to Partial Fraction Decomposition to Undergraduate Students: Results and Implications from a Pilot Study

    Science.gov (United States)

    Man, Yiu-Kwong

    2012-01-01

    Partial fraction decomposition is a useful technique often taught at senior secondary or undergraduate levels to handle integrations, inverse Laplace transforms or linear ordinary differential equations, etc. In recent years, an improved Heaviside's approach to partial fraction decomposition was introduced and developed by the author. An important…

  8. Inverse agonism of SQ 29,548 and Ramatroban on Thromboxane A2 receptor.

    Directory of Open Access Journals (Sweden)

    Raja Chakraborty

    Full Text Available G protein-coupled receptors (GPCRs show some level of basal activity even in the absence of an agonist, a phenomenon referred to as constitutive activity. Such constitutive activity in GPCRs is known to have important pathophysiological roles in human disease. The thromboxane A2 receptor (TP is a GPCR that promotes thrombosis in response to binding of the prostanoid, thromboxane A2. TP dysfunction is widely implicated in pathophysiological conditions such as bleeding disorders, hypertension and cardiovascular disease. Recently, we reported the characterization of a few constitutively active mutants (CAMs in TP, including a genetic variant A160T. Using these CAMs as reporters, we now test the inverse agonist properties of known antagonists of TP, SQ 29,548, Ramatroban, L-670596 and Diclofenac, in HEK293T cells. Interestingly, SQ 29,548 reduced the basal activity of both, WT-TP and the CAMs while Ramatroban was able to reduce the basal activity of only the CAMs. Diclofenac and L-670596 showed no statistically significant reduction in basal activity of WT-TP or CAMs. To investigate the role of these compounds on human platelet function, we tested their effects on human megakaryocyte based system for platelet activation. Both SQ 29,548 and Ramatroban reduced the platelet hyperactivity of the A160T genetic variant. Taken together, our results suggest that SQ 29,548 and Ramatroban are inverse agonists for TP, whereas, L-670596 and Diclofenac are neutral antagonists. Our findings have important therapeutic applications in the treatment of TP mediated pathophysiological conditions.

  9. Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists.

    Science.gov (United States)

    Ogawa, Seiji; Watanabe, Toshihide; Moriyuki, Kazumi; Goto, Yoshikazu; Yamane, Shinsaku; Watanabe, Akio; Tsuboi, Kazuma; Kinoshita, Atsushi; Okada, Takuya; Takeda, Hiroyuki; Tani, Kousuke; Maruyama, Toru

    2016-05-15

    The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in β-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Distributed Cooperative Optimal Control for Multiagent Systems on Directed Graphs: An Inverse Optimal Approach.

    Science.gov (United States)

    Zhang, Huaguang; Feng, Tao; Yang, Guang-Hong; Liang, Hongjing

    2015-07-01

    In this paper, the inverse optimal approach is employed to design distributed consensus protocols that guarantee consensus and global optimality with respect to some quadratic performance indexes for identical linear systems on a directed graph. The inverse optimal theory is developed by introducing the notion of partial stability. As a result, the necessary and sufficient conditions for inverse optimality are proposed. By means of the developed inverse optimal theory, the necessary and sufficient conditions are established for globally optimal cooperative control problems on directed graphs. Basic optimal cooperative design procedures are given based on asymptotic properties of the resulting optimal distributed consensus protocols, and the multiagent systems can reach desired consensus performance (convergence rate and damping rate) asymptotically. Finally, two examples are given to illustrate the effectiveness of the proposed methods.

  11. Seeing the World Topsy-Turvy: The Primary Role of Kinematics in Biological Motion Inversion Effects

    Directory of Open Access Journals (Sweden)

    Sue-Anne Fitzgerald

    2014-04-01

    Full Text Available Physical inversion of whole or partial human body representations typically has catastrophic consequences on the observer's ability to perform visual processing tasks. Explanations usually focus on the effects of inversion on the visual system's ability to exploit configural or structural relationships, but more recently have also implicated motion or kinematic cue processing. Here, we systematically tested the role of both on perceptions of sex from upright and inverted point-light walkers. Our data suggest that inversion results in systematic degradations of the processing of kinematic cues. Specifically and intriguingly, they reveal sex-based kinematic differences: Kinematics characteristic of females generally are resistant to inversion effects, while those of males drive systematic sex misperceptions. Implications of the findings are discussed.

  12. Anomaly detection in random heterogeneous media Feynman-Kac formulae, stochastic homogenization and statistical inversion

    CERN Document Server

    Simon, Martin

    2015-01-01

    This monograph is concerned with the analysis and numerical solution of a stochastic inverse anomaly detection problem in electrical impedance tomography (EIT). Martin Simon studies the problem of detecting a parameterized anomaly in an isotropic, stationary and ergodic conductivity random field whose realizations are rapidly oscillating. For this purpose, he derives Feynman-Kac formulae to rigorously justify stochastic homogenization in the case of the underlying stochastic boundary value problem. The author combines techniques from the theory of partial differential equations and functional analysis with probabilistic ideas, paving the way to new mathematical theorems which may be fruitfully used in the treatment of the problem at hand. Moreover, the author proposes an efficient numerical method in the framework of Bayesian inversion for the practical solution of the stochastic inverse anomaly detection problem.   Contents Feynman-Kac formulae Stochastic homogenization Statistical inverse problems  Targe...

  13. A Novel Class of Small Molecule Agonists with Preference for Human over Mouse TLR4 Activation.

    Directory of Open Access Journals (Sweden)

    Jason D Marshall

    Full Text Available The best-characterized Toll-like receptor 4 (TLR4 ligands are lipopolysaccharide (LPS and its chemically modified and detoxified variant, monophosphoryl lipid A (MPL. Although both molecules are active for human TLR4, they demonstrate a potency preference for mouse TLR4 based on data from transfected cell lines and primary cells of both species. After a high throughput screening process of small molecule libraries, we have discovered a new class of TLR4 agonist with a species preference profile differing from MPL. Products of the 4-component Ugi synthesis reaction were demonstrated to potently trigger human TLR4-transfected HEK cells but not mouse TLR4, although inclusion of the human MD2 with mTLR4 was able to partially recover activity. Co-expression of CD14 was not required for optimal activity of Ugi compounds on transfected cells, as it is for LPS. The species preference profile for the panel of Ugi compounds was found to be strongly active for human and cynomolgus monkey primary cells, with reduced but still substantial activity for most Ugi compounds on guinea pig cells. Mouse, rat, rabbit, ferret, and cotton rat cells displayed little or no activity when exposed to Ugi compounds. However, engineering the human versions of TLR4 and MD2 to be expressed in mTLR4/MD2 deficient mice allowed for robust activity by Ugi compounds both in vitro and in vivo. These findings extend the range of compounds available for development as agonists of TLR4 and identify novel molecules which reverse the TLR4 triggering preference of MPL for mouse TLR4 over human TLR4. Such compounds may be amenable to formulation as more potent human-specific TLR4L-based adjuvants than typical MPL-based adjuvants.

  14. Quantitative photo-acoustic tomography with partial data

    International Nuclear Information System (INIS)

    Chen, Jie; Yang, Yang

    2012-01-01

    Photo-acoustic tomography is a newly developed hybrid imaging modality that combines a high-resolution modality with a high-contrast modality. We analyze the reconstruction of diffusion and absorption parameters in an elliptic equation and extend an earlier result of Bal and Uhlmann (2010 Inverse Problems 26 085010) to the partial data case. We show that the reconstruction can be uniquely determined by the knowledge of four internal data based on well-chosen partial boundary conditions. Stability of this reconstruction is ensured if a convexity condition is satisfied. A similar stability result is obtained without this geometric constraint if 4n well chosen partial boundary conditions are available, where n is the spatial dimension. The set of well chosen boundary measurements is characterized by some complex geometric optics solutions vanishing on a part of the boundary. (paper)

  15. 2-Formyl-komarovicine promotes adiponectin production in human mesenchymal stem cells through PPARγ partial agonism.

    Science.gov (United States)

    Ahn, Sungjin; Lee, Moonyoung; An, Seungchan; Hyun, Sooyeol; Hwang, Jiho; Lee, Jongkook; Noh, Minsoo

    2018-03-01

    Adiponectin is a major adipocytokine secreted from mammalian adipocytes. Relatively low expression of adiponectin is associated with various human metabolic diseases and some cancers. Adiponectin-secreting compounds have therapeutic potential for these diseases. Adipogenesis of human bone marrow-mesenchymal stem cells (hBM-MSCs) has been used as a phenotypic assay to find adiponectin secreting compounds. In a phytochemical library screen, 2-formyl-komarovicine, 1-(quinolin-8-yl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carbaldehyde, isolated from Nitraria komarovii was identified as a potential adiponectin-secreting compound. To validate the results of the impure phytochemical, we synthesized 2-formyl-komarovicine. The synthetic 2-formyl-komarovicine significantly promoted adiponectin production during adipogenesis in hBM-MSCs. In a target identification experiment, 2-formyl-komarovicine bound to peroxisome proliferator-activated receptor γ (PPARγ) in a concentration-dependent manner. Notably, 2-formyl-komarovicine competitively inhibited the adiponectin-promoting activity of a full PPARγ agonist, troglitazone, in hBM-MSCs, which is a pharmacological feature of a partial agonist. The ligand-docking model showed that 2-formyl-komarovicine interacted with the hydrophobic pocket of the PPARγ ligand-binding domain, but lacked an interaction to stabilize helix H12, which is one of the major binding themes of PPARγ partial agonists. We concluded that 2-formyl-komarovicine provides a novel pharmacophore for PPARγ partial agonists to increase adiponectin production. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Inverse problems in systems biology

    International Nuclear Information System (INIS)

    Engl, Heinz W; Lu, James; Müller, Stefan; Flamm, Christoph; Schuster, Peter; Kügler, Philipp

    2009-01-01

    Systems biology is a new discipline built upon the premise that an understanding of how cells and organisms carry out their functions cannot be gained by looking at cellular components in isolation. Instead, consideration of the interplay between the parts of systems is indispensable for analyzing, modeling, and predicting systems' behavior. Studying biological processes under this premise, systems biology combines experimental techniques and computational methods in order to construct predictive models. Both in building and utilizing models of biological systems, inverse problems arise at several occasions, for example, (i) when experimental time series and steady state data are used to construct biochemical reaction networks, (ii) when model parameters are identified that capture underlying mechanisms or (iii) when desired qualitative behavior such as bistability or limit cycle oscillations is engineered by proper choices of parameter combinations. In this paper we review principles of the modeling process in systems biology and illustrate the ill-posedness and regularization of parameter identification problems in that context. Furthermore, we discuss the methodology of qualitative inverse problems and demonstrate how sparsity enforcing regularization allows the determination of key reaction mechanisms underlying the qualitative behavior. (topical review)

  17. Inversion theory and conformal mapping

    CERN Document Server

    Blair, David E

    2000-01-01

    It is rarely taught in an undergraduate or even graduate curriculum that the only conformal maps in Euclidean space of dimension greater than two are those generated by similarities and inversions in spheres. This is in stark contrast to the wealth of conformal maps in the plane. The principal aim of this text is to give a treatment of this paucity of conformal maps in higher dimensions. The exposition includes both an analytic proof in general dimension and a differential-geometric proof in dimension three. For completeness, enough complex analysis is developed to prove the abundance of conformal maps in the plane. In addition, the book develops inversion theory as a subject, along with the auxiliary theme of circle-preserving maps. A particular feature is the inclusion of a paper by Carath�odory with the remarkable result that any circle-preserving transformation is necessarily a M�bius transformation, not even the continuity of the transformation is assumed. The text is at the level of advanced undergr...

  18. LHC Report: 2 inverse femtobarns!

    CERN Multimedia

    Mike Lamont for the LHC Team

    2011-01-01

    The LHC is enjoying a confluence of twos. This morning (Friday 5 August) we passed 2 inverse femtobarns delivered in 2011; the peak luminosity is now just over 2 x1033 cm-2s-1; and recently fill 2000 was in for nearly 22 hours and delivered around 90 inverse picobarns, almost twice 2010's total.   In order to increase the luminosity we can increase of number of bunches, increase the number of particles per bunch, or decrease the transverse beam size at the interaction point. The beam size can be tackled in two ways: either reduce the size of the injected bunches or squeeze harder with the quadrupole magnets situated on either side of the experiments. Having increased the number of bunches to 1380, the maximum possible with a 50 ns bunch spacing, a one day meeting in Crozet decided to explore the other possibilities. The size of the beams coming from the injectors has been reduced to the minimum possible. This has brought an increase in the peak luminosity of about 50% and the 2 x 1033 cm...

  19. Inverse design of multicomponent assemblies

    Science.gov (United States)

    Piñeros, William D.; Lindquist, Beth A.; Jadrich, Ryan B.; Truskett, Thomas M.

    2018-03-01

    Inverse design can be a useful strategy for discovering interactions that drive particles to spontaneously self-assemble into a desired structure. Here, we extend an inverse design methodology—relative entropy optimization—to determine isotropic interactions that promote assembly of targeted multicomponent phases, and we apply this extension to design interactions for a variety of binary crystals ranging from compact triangular and square architectures to highly open structures with dodecagonal and octadecagonal motifs. We compare the resulting optimized (self- and cross) interactions for the binary assemblies to those obtained from optimization of analogous single-component systems. This comparison reveals that self-interactions act as a "primer" to position particles at approximately correct coordination shell distances, while cross interactions act as the "binder" that refines and locks the system into the desired configuration. For simpler binary targets, it is possible to successfully design self-assembling systems while restricting one of these interaction types to be a hard-core-like potential. However, optimization of both self- and cross interaction types appears necessary to design for assembly of more complex or open structures.

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

    OpenAIRE

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

    2014-01-01

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

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

    Science.gov (United States)

    Liu, Jian-Feng; Thorn, David A; Zhang, Yanan; Li, Jun-Xu

    2016-07-01

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

  2. Inverse problems and inverse scattering of plane waves

    CERN Document Server

    Ghosh Roy, Dilip N

    2001-01-01

    The purpose of this text is to present the theory and mathematics of inverse scattering, in a simple way, to the many researchers and professionals who use it in their everyday research. While applications range across a broad spectrum of disciplines, examples in this text will focus primarly, but not exclusively, on acoustics. The text will be especially valuable for those applied workers who would like to delve more deeply into the fundamentally mathematical character of the subject matter.Practitioners in this field comprise applied physicists, engineers, and technologists, whereas the theory is almost entirely in the domain of abstract mathematics. This gulf between the two, if bridged, can only lead to improvement in the level of scholarship in this highly important discipline. This is the book''s primary focus.

  3. Integral geometry and inverse problems for hyperbolic equations

    CERN Document Server

    Romanov, V G

    1974-01-01

    There are currently many practical situations in which one wishes to determine the coefficients in an ordinary or partial differential equation from known functionals of its solution. These are often called "inverse problems of mathematical physics" and may be contrasted with problems in which an equation is given and one looks for its solution under initial and boundary conditions. Although inverse problems are often ill-posed in the classical sense, their practical importance is such that they may be considered among the pressing problems of current mathematical re­ search. A. N. Tihonov showed [82], [83] that there is a broad class of inverse problems for which a particular non-classical definition of well-posed ness is appropriate. This new definition requires that a solution be unique in a class of solutions belonging to a given subset M of a function space. The existence of a solution in this set is assumed a priori for some set of data. The classical requirement of continuous dependence of the solutio...

  4. GnRH antagonist versus long agonist protocols in IVF

    DEFF Research Database (Denmark)

    Lambalk, C B; Banga, F R; Huirne, J A

    2017-01-01

    BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist...... was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH...... in couples undergoing IVF or ICSI. The primary outcome was ongoing pregnancy rate. Secondary outcomes were: live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety with regard to ovarian hyperstimulation syndrome (OHSS). Separate comparisons were performed for the general IVF...

  5. Dopamine agonists and risk: impulse control disorders in Parkinson's; disease

    OpenAIRE

    Voon, Valerie; Gao, Jennifer; Brezing, Christina; Symmonds, Mkael; Ekanayake, Vindhya; Fernandez, Hubert; Dolan, Raymond J.; Hallett, Mark

    2011-01-01

    Impulse control disorders are common in Parkinson's; disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's; disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a ‘Sure’ choice an...

  6. Pharmacophore-driven identification of PPARγ agonists from natural sources

    DEFF Research Database (Denmark)

    Petersen, R. K.; Christensen, Kathrine Bisgaard; Assimopoulou, A. N.

    2011-01-01

    mastic gum fractions, whereas some other sub-fractions exhibited also biological activity towards PPARγ. The results from the present work are two-fold: on the one hand we demonstrate that the pharmacophore model we developed is able to select novel ligand scaffolds that act as PPARγ agonists; while...... at the same time it manifests that natural products are highly relevant for use in virtual screening-based drug discovery....

  7. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis

    OpenAIRE

    Dietrich, Johannes W.; Landgrafe, Gabi; Fotiadou, Elisavet H.

    2012-01-01

    This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of th...

  8. Suppression of atherosclerosis by synthetic REV-ERB agonist

    Energy Technology Data Exchange (ETDEWEB)

    Sitaula, Sadichha [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Billon, Cyrielle [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States); Kamenecka, Theodore M.; Solt, Laura A. [Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458 (United States); Burris, Thomas P., E-mail: burristp@slu.edu [Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104 (United States)

    2015-05-08

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

  9. Dopamine agonist activity of EMD 23,448

    Energy Technology Data Exchange (ETDEWEB)

    Martin, G E; Pettibone, D J [Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania (USA). Dept. of Pharmacology

    1985-01-01

    EMD 23,448 was examined in tests of dopaminergic function and was found to be an atypical dopamine (DA) agonist. EMD 23,448 was a weak or inactive DA agonist when examined in tests of normal postsynaptic DA receptor function: production of stereotypy in the rat (ED/sub 50/ greater than sign 5.0 mg/kg.i.p.); production of emesis in beagles (minimum effective dose = 81..mu..g/kg i.v.); and, enhanced locomotor activity of the mouse (no excitation in doses <=50 mg/i.p.). Moreover, EMD 23,448 was relatively weak in competing for (/sup 3/H)-apomorphine binding to rat striatal membranes (Ki, 205 nM). On the other hand, this indolyl-3-butylamine did activate supersensitive postsynaptic DA receptors. Specifically, it elicited contralateral turning in rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra (ED/sub 50/ value = 0.9 mg/kg) and did elicit stereotypy in rats given chronic daily haloperidol treatments. EMD 23,448 also exerted pharmacological effects in tests designed to measure activation of dopamine autoreceptors. It inhibited the ..gamma..-butyrolactone-induced increase in striatal dopa levels (ED/sub 50/ = 1 mg/kg i.p.) and produced a dose-related fall in the locomotor activity of the mouse. The results are discussed and contrasted with data derived for apomorphine and the putatively selective autoreceptor agonist (+-)-3-PPP.

  10. Dopamine agonist activity of EMD 23,448

    International Nuclear Information System (INIS)

    Martin, G.E.; Pettibone, D.J.

    1985-01-01

    EMD 23,448 was examined in tests of dopaminergic function and was found to be an atypical dopamine (DA) agonist. EMD 23,448 was a weak or inactive DA agonist when examined in tests of normal postsynaptic DA receptor function: production of stereotypy in the rat (ED 50 greater than sign 5.0 mg/kg.i.p.); production of emesis in beagles (minimum effective dose = 81μg/kg i.v.); and, enhanced locomotor activity of the mouse (no excitation in doses 3 H]-apomorphine binding to rat striatal membranes (Ki, 205 nM). On the other hand, this indolyl-3-butylamine did activate supersensitive postsynaptic DA receptors. Specifically, it elicited contralateral turning in rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra (ED 50 value = 0.9 mg/kg) and did elicit stereotypy in rats given chronic daily haloperidol treatments. EMD 23,448 also exerted pharmacological effects in tests designed to measure activation of dopamine autoreceptors. It inhibited the γ-butyrolactone-induced increase in striatal dopa levels (ED 50 = 1 mg/kg i.p.) and produced a dose-related fall in the locomotor activity of the mouse. The results are discussed and contrasted with data derived for apomorphine and the putatively selective autoreceptor agonist (+-)-3-PPP. (Author)

  11. PPAR Agonists and Metabolic Syndrome: An Established Role?

    Directory of Open Access Journals (Sweden)

    Margherita Botta

    2018-04-01

    Full Text Available Therapeutic approaches to metabolic syndrome (MetS are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs, blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C. PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil and myopathy should also be acknowledged.

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

    International Nuclear Information System (INIS)

    Sakolchai, S.

    1987-01-01

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

  13. Partial Actions and Power Sets

    Directory of Open Access Journals (Sweden)

    Jesús Ávila

    2013-01-01

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

  14. Algorithms over partially ordered sets

    DEFF Research Database (Denmark)

    Baer, Robert M.; Østerby, Ole

    1969-01-01

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

  15. Anatomic partial nephrectomy: technique evolution.

    Science.gov (United States)

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

    2015-03-01

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

  16. Partial order infinitary term rewriting

    DEFF Research Database (Denmark)

    Bahr, Patrick

    2014-01-01

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

  17. Wake Vortex Inverse Model User's Guide

    Science.gov (United States)

    Lai, David; Delisi, Donald

    2008-01-01

    NorthWest Research Associates (NWRA) has developed an inverse model for inverting landing aircraft vortex data. The data used for the inversion are the time evolution of the lateral transport position and vertical position of both the port and starboard vortices. The inverse model performs iterative forward model runs using various estimates of vortex parameters, vertical crosswind profiles, and vortex circulation as a function of wake age. Forward model predictions of lateral transport and altitude are then compared with the observed data. Differences between the data and model predictions guide the choice of vortex parameter values, crosswind profile and circulation evolution in the next iteration. Iterations are performed until a user-defined criterion is satisfied. Currently, the inverse model is set to stop when the improvement in the rms deviation between the data and model predictions is less than 1 percent for two consecutive iterations. The forward model used in this inverse model is a modified version of the Shear-APA model. A detailed description of this forward model, the inverse model, and its validation are presented in a different report (Lai, Mellman, Robins, and Delisi, 2007). This document is a User's Guide for the Wake Vortex Inverse Model. Section 2 presents an overview of the inverse model program. Execution of the inverse model is described in Section 3. When executing the inverse model, a user is requested to provide the name of an input file which contains the inverse model parameters, the various datasets, and directories needed for the inversion. A detailed description of the list of parameters in the inversion input file is presented in Section 4. A user has an option to save the inversion results of each lidar track in a mat-file (a condensed data file in Matlab format). These saved mat-files can be used for post-inversion analysis. A description of the contents of the saved files is given in Section 5. An example of an inversion input

  18. Inverse diffusion theory of photoacoustics

    International Nuclear Information System (INIS)

    Bal, Guillaume; Uhlmann, Gunther

    2010-01-01

    This paper analyzes the reconstruction of diffusion and absorption parameters in an elliptic equation from knowledge of internal data. In the application of photoacoustics, the internal data are the amount of thermal energy deposited by high frequency radiation propagating inside a domain of interest. These data are obtained by solving an inverse wave equation, which is well studied in the literature. We show that knowledge of two internal data based on well-chosen boundary conditions uniquely determines two constitutive parameters in diffusion and Schrödinger equations. Stability of the reconstruction is guaranteed under additional geometric constraints of strict convexity. No geometric constraints are necessary when 2n internal data for well-chosen boundary conditions are available, where n is spatial dimension. The set of well-chosen boundary conditions is characterized in terms of appropriate complex geometrical optics solutions

  19. A widespread chromosomal inversion polymorphism contributes to a major life-history transition, local adaptation, and reproductive isolation.

    Directory of Open Access Journals (Sweden)

    David B Lowry

    2010-09-01

    multiple reproductive isolating barriers. These results are consistent with the local adaptation mechanism being responsible for the distribution of the two inversion arrangements across the geographic range of M. guttatus and that locally adaptive inversion effects contribute directly to reproductive isolation. Such a mechanism may be partially responsible for the observation that closely related species often differ by multiple chromosomal rearrangements.

  20. Action understanding as inverse planning.

    Science.gov (United States)

    Baker, Chris L; Saxe, Rebecca; Tenenbaum, Joshua B

    2009-12-01

    Humans are adept at inferring the mental states underlying other agents' actions, such as goals, beliefs, desires, emotions and other thoughts. We propose a computational framework based on Bayesian inverse planning for modeling human action understanding. The framework represents an intuitive theory of intentional agents' behavior based on the principle of rationality: the expectation that agents will plan approximately rationally to achieve their goals, given their beliefs about the world. The mental states that caused an agent's behavior are inferred by inverting this model of rational planning using Bayesian inference, integrating the likelihood of the observed actions with the prior over mental states. This approach formalizes in precise probabilistic terms the essence of previous qualitative approaches to action understanding based on an "intentional stance" [Dennett, D. C. (1987). The intentional stance. Cambridge, MA: MIT Press] or a "teleological stance" [Gergely, G., Nádasdy, Z., Csibra, G., & Biró, S. (1995). Taking the intentional stance at 12 months of age. Cognition, 56, 165-193]. In three psychophysical experiments using animated stimuli of agents moving in simple mazes, we assess how well different inverse planning models based on different goal priors can predict human goal inferences. The results provide quantitative evidence for an approximately rational inference mechanism in human goal inference within our simplified stimulus paradigm, and for the flexible nature of goal representations that human observers can adopt. We discuss the implications of our experimental results for human action understanding in real-world contexts, and suggest how our framework might be extended to capture other kinds of mental state inferences, such as inferences about beliefs, or inferring whether an entity is an intentional agent.

  1. Optimization and inverse problems in electromagnetism

    CERN Document Server

    Wiak, Sławomir

    2003-01-01

    From 12 to 14 September 2002, the Academy of Humanities and Economics (AHE) hosted the workshop "Optimization and Inverse Problems in Electromagnetism". After this bi-annual event, a large number of papers were assembled and combined in this book. During the workshop recent developments and applications in optimization and inverse methodologies for electromagnetic fields were discussed. The contributions selected for the present volume cover a wide spectrum of inverse and optimal electromagnetic methodologies, ranging from theoretical to practical applications. A number of new optimal and inverse methodologies were proposed. There are contributions related to dedicated software. Optimization and Inverse Problems in Electromagnetism consists of three thematic chapters, covering: -General papers (survey of specific aspects of optimization and inverse problems in electromagnetism), -Methodologies, -Industrial Applications. The book can be useful to students of electrical and electronics engineering, computer sci...

  2. Reverse Universal Resolving Algorithm and inverse driving

    DEFF Research Database (Denmark)

    Pécseli, Thomas

    2012-01-01

    Inverse interpretation is a semantics based, non-standard interpretation of programs. Given a program and a value, an inverse interpreter finds all or one of the inputs, that would yield the given value as output with normal forward evaluation. The Reverse Universal Resolving Algorithm is a new...... variant of the Universal Resolving Algorithm for inverse interpretation. The new variant outperforms the original algorithm in several cases, e.g., when unpacking a list using inverse interpretation of a pack program. It uses inverse driving as its main technique, which has not been described in detail...... before. Inverse driving may find application with, e.g., supercompilation, thus suggesting a new kind of program inverter....

  3. The scattering potential of partial derivative wavefields in 3-D elastic orthorhombic media: an inversion prospective

    KAUST Repository

    Oh, Juwon; Alkhalifah, Tariq Ali

    2016-01-01

    that includes large offsets, full azimuth, and multicomponent sensors, the potential for trade-off between the elastic orthorhombic parameters are large. The first step to understanding such trade-off is analysing the scattering potential of each parameter

  4. Partial inversion of elliptic operator to speed up computation of likelihood in Bayesian inference

    KAUST Repository

    Litvinenko, Alexander

    2017-01-01

    we can approximate $F(u)$ on, for instance, multiple coarse meshes. The offered method is well suited for solving multiscale problems. A disadvantage of this method is the assumption that one has to have access to the discretisation and to the procedure of assembling the Galerkin matrix.

  5. Inverse Spectral Results for AKNS Systems with Partial Information on the Potentials

    International Nuclear Information System (INIS)

    Rio, R. del; Grebert, B.

    2001-01-01

    For the AKNS operator on L 2 ([0,1],C 2 ) it is well known that the data of two spectra uniquely determine the corresponding potential φ a.e. on [0,1] (Borg's type Theorem). We prove that, in the case where φ is a-priori known on [a,1], then only a part (depending on a) of two spectra determine φ on [0,1]. Our results include generalizations for Dirac systems of classical results obtained by Hochstadt and Lieberman for the Sturm-Liouville case, where they showed that half of the potential and one spectrum determine all the potential functions. An important ingredient in our strategy is the link between the rate of growth of an entire function and the distribution of its zeros

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

    Science.gov (United States)

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

    2013-01-01

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

  7. Inverse kinematics of OWI-535 robotic arm

    OpenAIRE

    DEBENEC, PRIMOŽ

    2015-01-01

    The thesis aims to calculate the inverse kinematics for the OWI-535 robotic arm. The calculation of the inverse kinematics determines the joint parameters that provide the right pose of the end effector. The pose consists of the position and orientation, however, we will focus only on the second one. Due to arm limitations, we have created our own type of the calculation of the inverse kinematics. At first we have derived it only theoretically, and then we have transferred the derivation into...

  8. Automatic Flight Controller With Model Inversion

    Science.gov (United States)

    Meyer, George; Smith, G. Allan

    1992-01-01

    Automatic digital electronic control system based on inverse-model-follower concept being developed for proposed vertical-attitude-takeoff-and-landing airplane. Inverse-model-follower control places inverse mathematical model of dynamics of controlled plant in series with control actuators of controlled plant so response of combination of model and plant to command is unity. System includes feedback to compensate for uncertainties in mathematical model and disturbances imposed from without.

  9. Lectures on the inverse scattering method

    International Nuclear Information System (INIS)

    Zakharov, V.E.

    1983-06-01

    In a series of six lectures an elementary introduction to the theory of inverse scattering is given. The first four lectures contain a detailed theory of solitons in the framework of the KdV equation, together with the inverse scattering theory of the one-dimensional Schroedinger equation. In the fifth lecture the dressing method is described, while the sixth lecture gives a brief review of the equations soluble by the inverse scattering method. (author)

  10. Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience.

    Science.gov (United States)

    Pokorny, Thomas; Preller, Katrin H; Kraehenmann, Rainer; Vollenweider, Franz X

    2016-04-01

    The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (ppsilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  11. The treatment of Parkinson's disease with dopamine agonists

    Directory of Open Access Journals (Sweden)

    Frank, Wilhelm

    2008-06-01

    Full Text Available Parkinson’s disease is a chronic degenerative organic disease with unknown causes. A disappearance of cells with melanin in the substantia nigra is considered as biological artefact of the disease, which causes a degenerative loss of neurons in the corpus striatum of mesencephalon. This structure produces also the transmitter substance dopamine. Due to this disappearance of cells dopamine is not produced in a sufficient quantity which is needed for movement of the body. The questions of this report are concerned the efficiency and safety of a treatment with dopamine agonists. Furthermore the cost-effectiveness is investigated as well as ethic questions. The goal is to give recommendation for the use of dopamine agonists to the German health system. A systematic literature search was done. The identified studies have different methodological quality and investigate different hypothesis and different outcome criteria. Therefore a qualitative method of information synthesis was chosen. Since the introduction of L-Dopa in the 1960´s it is considered as the most effective substance to reduce all the cardinal symptoms of Parkinson disease. This substance was improved in the course of time. Firstly some additional substances were given (decarbonxylase inhibitors, catechol-o-transferase inhibitors (COMT-inhibitors, monoaminoxydase-inhibitors (MAO-inhibitors and NMDA-antagonists (N-Methyl-d-aspartat-antagonists. In the practical therapy of Parkinson dopamine agonists play an important role, because they directly use the dopamine receptors. The monotherapy of Parkinson disease is basically possible and is used in early stages of the disease. Clinical practise has shown, that an add on therapy with dopamine agonists can led to a reduction of the dose of L-dopa and a reduction of following dyskinesia. The studies for effectiveness include studies for the initial therapy, monotherapy and add-on-therapy. Basically there is a good effectiveness of dopamine

  12. Bayesian approach to inverse statistical mechanics

    Science.gov (United States)

    Habeck, Michael

    2014-05-01

    Inverse statistical mechanics aims to determine particle interactions from ensemble properties. This article looks at this inverse problem from a Bayesian perspective and discusses several statistical estimators to solve it. In addition, a sequential Monte Carlo algorithm is proposed that draws the interaction parameters from their posterior probability distribution. The posterior probability involves an intractable partition function that is estimated along with the interactions. The method is illustrated for inverse problems of varying complexity, including the estimation of a temperature, the inverse Ising problem, maximum entropy fitting, and the reconstruction of molecular interaction potentials.

  13. Time-reversal and Bayesian inversion

    Science.gov (United States)

    Debski, Wojciech

    2017-04-01

    Probabilistic inversion technique is superior to the classical optimization-based approach in all but one aspects. It requires quite exhaustive computations which prohibit its use in huge size inverse problems like global seismic tomography or waveform inversion to name a few. The advantages of the approach are, however, so appealing that there is an ongoing continuous afford to make the large inverse task as mentioned above manageable with the probabilistic inverse approach. One of the perspective possibility to achieve this goal relays on exploring the internal symmetry of the seismological modeling problems in hand - a time reversal and reciprocity invariance. This two basic properties of the elastic wave equation when incorporating into the probabilistic inversion schemata open a new horizons for Bayesian inversion. In this presentation we discuss the time reversal symmetry property, its mathematical aspects and propose how to combine it with the probabilistic inverse theory into a compact, fast inversion algorithm. We illustrate the proposed idea with the newly developed location algorithm TRMLOC and discuss its efficiency when applied to mining induced seismic data.

  14. Inverse Kinematics of a Serial Robot

    Directory of Open Access Journals (Sweden)

    Amici Cinzia

    2016-01-01

    Full Text Available This work describes a technique to treat the inverse kinematics of a serial manipulator. The inverse kinematics is obtained through the numerical inversion of the Jacobian matrix, that represents the equation of motion of the manipulator. The inversion is affected by numerical errors and, in different conditions, due to the numerical nature of the solver, it does not converge to a reasonable solution. Thus a soft computing approach is adopted to mix different traditional methods to obtain an increment of algorithmic convergence.

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

    Czech Academy of Sciences Publication Activity Database

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

    2010-01-01

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

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

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    DEFF Research Database (Denmark)

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

    2002-01-01

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

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

    OpenAIRE

    Antošová, Eliška

    2011-01-01

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

  19. Magic-factor 1, a partial agonist of Met, induces muscle hypertrophy by protecting myogenic progenitors from apoptosis.

    Directory of Open Access Journals (Sweden)

    Marco Cassano

    2008-09-01

    Full Text Available Hepatocyte Growth Factor (HGF is a pleiotropic cytokine of mesenchymal origin that mediates a characteristic array of biological activities including cell proliferation, survival, motility and morphogenesis. Its high affinity receptor, the tyrosine kinase Met, is expressed by a wide range of tissues and can be activated by either paracrine or autocrine stimulation. Adult myogenic precursor cells, the so called satellite cells, express both HGF and Met. Following muscle injury, autocrine HGF-Met stimulation plays a key role in promoting activation and early division of satellite cells, but is shut off in a second phase to allow myogenic differentiation. In culture, HGF stimulation promotes proliferation of muscle precursors thereby inhibiting their differentiation.Magic-Factor 1 (Met-Activating Genetically Improved Chimeric Factor-1 or Magic-F1 is an HGF-derived, engineered protein that contains two Met-binding domains repeated in tandem. It has a reduced affinity for Met and, in contrast to HGF it elicits activation of the AKT but not the ERK signaling pathway. As a result, Magic-F1 is not mitogenic but conserves the ability to promote cell survival. Here we show that Magic-F1 protects myogenic precursors against apoptosis, thus increasing their fusion ability and enhancing muscular differentiation. Electrotransfer of Magic-F1 gene into adult mice promoted muscular hypertrophy and decreased myocyte apoptosis. Magic-F1 transgenic mice displayed constitutive muscular hypertrophy, improved running performance and accelerated muscle regeneration following injury. Crossing of Magic-F1 transgenic mice with alpha-sarcoglycan knock-out mice -a mouse model of muscular dystrophy- or adenovirus-mediated Magic-F1 gene delivery resulted in amelioration of the dystrophic phenotype as measured by both anatomical/histological analysis and functional tests.Because of these features Magic-F1 represents a novel molecular tool to counteract muscle wasting in major muscular diseases such as cachexia or muscular dystrophy.

  20. Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists

    DEFF Research Database (Denmark)

    Qvortrup, Katrine; Jensen, Jakob Feldthusen; Sørensen, Mikael S.

    2017-01-01

    were found to display high affinity for PPARγ with potencies in the micro molar range. Both of these hits were selective against PPARγ, since no activity was measured when tested against PPARα, PPARδ and RXRα. In addition, a novel modelling approach based on multiple individual flexible alignments...... was developed for the identification of ligand binding interactions in PPARγ. In combination with cell-based transactivation experiments, the flexible alignment model provides an excellent analytical tool to evaluate and visualize the effect of ligand chemical structure with respect to receptor binding mode...

  1. Partial agonist of benzodiazepine receptors Ro 19-2088 elicits withdrawal symptoms after short-term administration in immature rats

    Czech Academy of Sciences Publication Activity Database

    Kubová, Hana; Mareš, Pavel

    2012-01-01

    Roč. 61, č. 3 (2012), s. 319-323 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA305/09/0846; GA ČR(CZ) GBP304/12/G069 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : Ro 19-2088 * iatrogenic withdrawal * pentylentetrazol-induced seizures * immature rats Subject RIV: FH - Neurology Impact factor: 1.531, year: 2012

  2. On Degenerate Partial Differential Equations

    OpenAIRE

    Chen, Gui-Qiang G.

    2010-01-01

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

  3. [Acrylic resin removable partial dentures

    NARCIS (Netherlands)

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

    2011-01-01

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

  4. Partial Epilepsy with Auditory Features

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2004-07-01

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

  5. Role of dopamine D4 receptors in copulatory behavior: Studies with selective D4 agonists and antagonists in male rats.

    Science.gov (United States)

    Sanna, Fabrizio; Contini, Andrea; Melis, Maria Rosaria; Argiolas, Antonio

    2015-10-01

    Dopamine influences the anticipatory and consummatory phases of sexual behavior, by acting on receptors of the D2 family (D2, D3 and D4) and in particular of the D2 subtype, although evidence for a role of D4 receptors in erectile function and copulatory behavior is also available. In order to clarify such a role of D4 receptors, the effect of selective D4 receptor agonists and antagonists on copulatory behavior of sexually potent male rats in classic copulation tests with a receptive female, was compared with that of apomorphine and haloperidol, a classic dopamine receptor agonist and antagonist, respectively. PD-168,077 (0.05-0.2mg/kg) and ABT-724 (0.01-0.04mg/kg), two selective D4 receptor agonists, given subcutaneously, improved dose-dependently copulatory behavior as shown by the decrease of mount frequency and post ejaculatory interval induced by PD-168,077, and of mount frequency, ejaculation latency, post ejaculatory and inter intromission intervals induced by ABT-724, and by the increase of ejaculation frequency and copulatory efficacy induced by both drugs. Conversely, L-745,870 (1-5mg/kg), a selective D4 receptor antagonist, given intraperitoneally, impaired dose-dependently copulatory behavior, as shown by the increase in intromission and ejaculation latencies, mount frequency, post ejaculatory interval and the decrease in ejaculation frequency and copulatory efficacy induced by this drug. L-745,870 (5mg/kg) administered before PD-168,077 (0.2mg/kg) or ABT-724 (0.04mg/kg), also abolished completely the facilitatory effects of both PD-168,077 and ABT-724 on sexual behavior. These results confirm the involvement of D4 receptors in specific aspects of male rat copulatory behavior that overlap only partially with those influenced by apomorphine and haloperidol. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. (+)Lysergic acid diethylamide, but not its nonhallucinogenic congeners, is a potent serotonin 5HT1C receptor agonist

    International Nuclear Information System (INIS)

    Burris, K.D.; Breeding, M.; Sanders-Bush, E.

    1991-01-01

    Activation of central serotonin 5HT2 receptors is believed to be the primary mechanism whereby lysergic acid diethylamide (LSD) and other hallucinogens induce psychoactive effects. This hypothesis is based on extensive radioligand binding and electrophysiological and behavioral studies in laboratory animals. However, the pharmacological profiles of 5HT2 and 5HT1C receptors are similar, making it difficult to distinguish between effects due to activation of one or the other receptor. For this reason, it was of interest to investigate the interaction of LSD with 5HT1C receptors. Agonist-stimulated phosphoinositide hydrolysis in rat choroid plexus was used as a direct measure of 5HT1C receptor activation. (+)LSD potently stimulated phosphoinositide hydrolysis in intact choroid plexus and in cultures of choroid plexus epithelial cells, with EC50 values of 9 and 26 nM, respectively. The effect of (+)LSD in both systems was blocked by 5HT receptor antagonists with an order of activity consistent with interaction at 5HT1C receptors. Neither (+)-2-bromo-LSD nor lisuride, two nonhallucinogenic congeners of LSD, were able to stimulate 5HT1C receptors in cultured cells or intact choroid plexus. In contrast, lisuride, like (+)LSD, is a partial agonist at 5HT2 receptors in cerebral cortex slices and in NIH 3T3 cells transfected with 5HT2 receptor cDNA. The present finding that (+)LSD, but not its nonhallucinogenic congeners, is a 5HT1C receptor agonist suggests a possible role for these receptors in mediating the psychoactive effects of LSD

  7. Partial twisting for scalar mesons

    International Nuclear Information System (INIS)

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

    2014-01-01

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

  8. Laterally constrained inversion for CSAMT data interpretation

    Science.gov (United States)

    Wang, Ruo; Yin, Changchun; Wang, Miaoyue; Di, Qingyun

    2015-10-01

    Laterally constrained inversion (LCI) has been successfully applied to the inversion of dc resistivity, TEM and airborne EM data. However, it hasn't been yet applied to the interpretation of controlled-source audio-frequency magnetotelluric (CSAMT) data. In this paper, we apply the LCI method for CSAMT data inversion by preconditioning the Jacobian matrix. We apply a weighting matrix to Jacobian to balance the sensitivity of model parameters, so that the resolution with respect to different model parameters becomes more uniform. Numerical experiments confirm that this can improve the convergence of the inversion. We first invert a synthetic dataset with and without noise to investigate the effect of LCI applications to CSAMT data, for the noise free data, the results show that the LCI method can recover the true model better compared to the traditional single-station inversion; and for the noisy data, the true model is recovered even with a noise level of 8%, indicating that LCI inversions are to some extent noise insensitive. Then, we re-invert two CSAMT datasets collected respectively in a watershed and a coal mine area in Northern China and compare our results with those from previous inversions. The comparison with the previous inversion in a coal mine shows that LCI method delivers smoother layer interfaces that well correlate to seismic data, while comparison with a global searching algorithm of simulated annealing (SA) in a watershed shows that though both methods deliver very similar good results, however, LCI algorithm presented in this paper runs much faster. The inversion results for the coal mine CSAMT survey show that a conductive water-bearing zone that was not revealed by the previous inversions has been identified by the LCI. This further demonstrates that the method presented in this paper works for CSAMT data inversion.

  9. A tutorial on inverse problems for anomalous diffusion processes

    International Nuclear Information System (INIS)

    Jin, Bangti; Rundell, William

    2015-01-01

    of related inverse problems, depending crucially on the specific type of given data and quantity of interest. Further, the study exhibits distinct new features of ‘fractional’ inverse problems, and a partial list of surprising observations is given below. (a) Classical backward diffusion is exponentially ill-posed, whereas time fractional backward diffusion is only mildly ill-posed in the sense of norms on the domain and range spaces. However, this does not imply that the latter always allows a more effective reconstruction. (b) Theoretically, the time fractional sideways problem is severely ill-posed like its classical counterpart, but numerically can be nearly well-posed. (c) The classical Sturm–Liouville problem requires two pieces of spectral data to uniquely determine a general potential, but in the fractional case, one single Dirichlet spectrum may suffice. (d) The space fractional sideways problem can be far more or far less ill-posed than the classical counterpart, depending on the location of the lateral Cauchy data. In many cases, the precise mechanism of these surprising observations is unclear, and awaits further analytical and numerical exploration, which requires new mathematical tools and ingenuities. Further, our findings indicate fractional diffusion inverse problems also provide an excellent case study in the differences between theoretical ill-conditioning involving domain and range norms and the numerical analysis of a finite-dimensional reconstruction procedure. Throughout we will also describe known analytical and numerical results in the literature. (paper)

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

    Directory of Open Access Journals (Sweden)

    Pramita Suwal

    2017-03-01

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

  11. Inverse problem in radionuclide transport

    International Nuclear Information System (INIS)

    Yu, C.

    1988-01-01

    The disposal of radioactive waste must comply with the performance objectives set forth in 10 CFR 61 for low-level waste (LLW) and 10 CFR 60 for high-level waste (HLW). To determine probable compliance, the proposed disposal system can be modeled to predict its performance. One of the difficulties encountered in such a study is modeling the migration of radionuclides through a complex geologic medium for the long term. Although many radionuclide transport models exist in the literature, the accuracy of the model prediction is highly dependent on the model parameters used. The problem of using known parameters in a radionuclide transport model to predict radionuclide concentrations is a direct problem (DP); whereas the reverse of DP, i.e., the parameter identification problem of determining model parameters from known radionuclide concentrations, is called the inverse problem (IP). In this study, a procedure to solve IP is tested, using the regression technique. Several nonlinear regression programs are examined, and the best one is recommended. 13 refs., 1 tab

  12. Inversion based on computational simulations

    International Nuclear Information System (INIS)

    Hanson, K.M.; Cunningham, G.S.; Saquib, S.S.

    1998-01-01

    A standard approach to solving inversion problems that involve many parameters uses gradient-based optimization to find the parameters that best match the data. The authors discuss enabling techniques that facilitate application of this approach to large-scale computational simulations, which are the only way to investigate many complex physical phenomena. Such simulations may not seem to lend themselves to calculation of the gradient with respect to numerous parameters. However, adjoint differentiation allows one to efficiently compute the gradient of an objective function with respect to all the variables of a simulation. When combined with advanced gradient-based optimization algorithms, adjoint differentiation permits one to solve very large problems of optimization or parameter estimation. These techniques will be illustrated through the simulation of the time-dependent diffusion of infrared light through tissue, which has been used to perform optical tomography. The techniques discussed have a wide range of applicability to modeling including the optimization of models to achieve a desired design goal

  13. MODEL SELECTION FOR SPECTROPOLARIMETRIC INVERSIONS

    International Nuclear Information System (INIS)

    Asensio Ramos, A.; Manso Sainz, R.; Martínez González, M. J.; Socas-Navarro, H.; Viticchié, B.; Orozco Suárez, D.

    2012-01-01

    Inferring magnetic and thermodynamic information from spectropolarimetric observations relies on the assumption of a parameterized model atmosphere whose parameters are tuned by comparison with observations. Often, the choice of the underlying atmospheric model is based on subjective reasons. In other cases, complex models are chosen based on objective reasons (for instance, the necessity to explain asymmetries in the Stokes profiles) but it is not clear what degree of complexity is needed. The lack of an objective way of comparing models has, sometimes, led to opposing views of the solar magnetism because the inferred physical scenarios are essentially different. We present the first quantitative model comparison based on the computation of the Bayesian evidence ratios for spectropolarimetric observations. Our results show that there is not a single model appropriate for all profiles simultaneously. Data with moderate signal-to-noise ratios (S/Ns) favor models without gradients along the line of sight. If the observations show clear circular and linear polarization signals above the noise level, models with gradients along the line are preferred. As a general rule, observations with large S/Ns favor more complex models. We demonstrate that the evidence ratios correlate well with simple proxies. Therefore, we propose to calculate these proxies when carrying out standard least-squares inversions to allow for model comparison in the future.

  14. Inverse transport theory of photoacoustics

    International Nuclear Information System (INIS)

    Bal, Guillaume; Jollivet, Alexandre; Jugnon, Vincent

    2010-01-01

    We consider the reconstruction of optical parameters in a domain of interest from photoacoustic data. Photoacoustic tomography (PAT) radiates high-frequency electromagnetic waves into the domain and measures acoustic signals emitted by the resulting thermal expansion. Acoustic signals are then used to construct the deposited thermal energy map. The latter depends on the constitutive optical parameters in a nontrivial manner. In this paper, we develop and use an inverse transport theory with internal measurements to extract information on the optical coefficients from knowledge of the deposited thermal energy map. We consider the multi-measurement setting in which many electromagnetic radiation patterns are used to probe the domain of interest. By developing an expansion of the measurement operator into singular components, we show that the spatial variations of the intrinsic attenuation and the scattering coefficients may be reconstructed. We also reconstruct coefficients describing anisotropic scattering of photons, such as the anisotropy coefficient g(x) in a Henyey–Greenstein phase function model. Finally, we derive stability estimates for the reconstructions

  15. Inverse Problems and Uncertainty Quantification

    KAUST Repository

    Litvinenko, Alexander

    2014-01-06

    In a Bayesian setting, inverse problems and uncertainty quantification (UQ) - the propagation of uncertainty through a computational (forward) modelare strongly connected. In the form of conditional expectation the Bayesian update becomes computationally attractive. This is especially the case as together with a functional or spectral approach for the forward UQ there is no need for time- consuming and slowly convergent Monte Carlo sampling. The developed sampling- free non-linear Bayesian update is derived from the variational problem associated with conditional expectation. This formulation in general calls for further discretisa- tion to make the computation possible, and we choose a polynomial approximation. After giving details on the actual computation in the framework of functional or spectral approximations, we demonstrate the workings of the algorithm on a number of examples of increasing complexity. At last, we compare the linear and quadratic Bayesian update on the small but taxing example of the chaotic Lorenz 84 model, where we experiment with the influence of different observation or measurement operators on the update.

  16. Inverse Problems and Uncertainty Quantification

    KAUST Repository

    Litvinenko, Alexander; Matthies, Hermann G.

    2014-01-01

    In a Bayesian setting, inverse problems and uncertainty quantification (UQ) - the propagation of uncertainty through a computational (forward) modelare strongly connected. In the form of conditional expectation the Bayesian update becomes computationally attractive. This is especially the case as together with a functional or spectral approach for the forward UQ there is no need for time- consuming and slowly convergent Monte Carlo sampling. The developed sampling- free non-linear Bayesian update is derived from the variational problem associated with conditional expectation. This formulation in general calls for further discretisa- tion to make the computation possible, and we choose a polynomial approximation. After giving details on the actual computation in the framework of functional or spectral approximations, we demonstrate the workings of the algorithm on a number of examples of increasing complexity. At last, we compare the linear and quadratic Bayesian update on the small but taxing example of the chaotic Lorenz 84 model, where we experiment with the influence of different observation or measurement operators on the update.

  17. Inverse Free Electron Laser accelerator

    International Nuclear Information System (INIS)

    Fisher, A.; Gallardo, J.; van Steenbergen, A.; Sandweiss, J.

    1992-09-01

    The study of the INVERSE FREE ELECTRON LASER, as a potential mode of electron acceleration, is being pursued at Brookhaven National Laboratory. Recent studies have focussed on the development of a low energy, high gradient, multi stage linear accelerator. The elementary ingredients for the IFEL interaction are the 50 MeV Linac e - beam and the 10 11 Watt CO 2 laser beam of BNL's Accelerator Test Facility (ATF), Center for Accelerator Physics (CAP) and a wiggler. The latter element is designed as a fast excitation unit making use of alternating stacks of Vanadium Permendur (VaP) ferromagnetic laminations, periodically interspersed with conductive, nonmagnetic laminations, which act as eddy current induced field reflectors. Wiggler parameters and field distribution data will be presented for a prototype wiggler in a constant period and in a ∼ 1.5 %/cm tapered period configuration. The CO 2 laser beam will be transported through the IFEL interaction region by means of a low loss, dielectric coated, rectangular waveguide. Short waveguide test sections have been constructed and have been tested using a low power cw CO 2 laser. Preliminary results of guide attenuation and mode selectivity will be given, together with a discussion of the optical issues for the IFEL accelerator. The IFEL design is supported by the development and use of 1D and 3D simulation programs. The results of simulation computations, including also wiggler errors, for a single module accelerator and for a multi-module accelerator will be presented

  18. Inverse problems and uncertainty quantification

    KAUST Repository

    Litvinenko, Alexander

    2013-12-18

    In a Bayesian setting, inverse problems and uncertainty quantification (UQ)— the propagation of uncertainty through a computational (forward) model—are strongly connected. In the form of conditional expectation the Bayesian update becomes computationally attractive. This is especially the case as together with a functional or spectral approach for the forward UQ there is no need for time- consuming and slowly convergent Monte Carlo sampling. The developed sampling- free non-linear Bayesian update is derived from the variational problem associated with conditional expectation. This formulation in general calls for further discretisa- tion to make the computation possible, and we choose a polynomial approximation. After giving details on the actual computation in the framework of functional or spectral approximations, we demonstrate the workings of the algorithm on a number of examples of increasing complexity. At last, we compare the linear and quadratic Bayesian update on the small but taxing example of the chaotic Lorenz 84 model, where we experiment with the influence of different observation or measurement operators on the update.

  19. Nalfurafine hydrochloride, a selective κ opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys

    Directory of Open Access Journals (Sweden)

    Kaoru Nakao

    2016-01-01

    Full Text Available Nalfurafine hydrochloride [(E-N-[17-(cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl-N-methylprop-2-enamide monohydrochloride; nalfurafine] is used in Japan as an antipruritic for the treatment of intractable pruritus in patients undergoing hemodialysis or with chronic liver disease. It is a potent and selective agonist at the κ opioid receptor, but also has weak and partial agonist activity at μ opioid receptors. Opioids, especially those acting at μ receptors, carry a risk of abuse. This is an important factor in the consideration of therapeutic risk vs. benefit in clinical use and the potential for misuse as a public health problem. It is therefore necessary to carefully evaluate the reinforcing effects of nalfurafine. To this end, we investigated intravenous self-administration of nalfurafine in rhesus monkeys. The number of self-administration of nalfurafine at doses of 0.0625, 0.125 and 0.25 μg/kg/infusion was not higher than that of saline in rhesus monkeys that frequently self-administered pentazocine (0.25 mg/kg/infusion. These results indicate that nalfurafine has no reinforcing effect in rhesus monkeys in the intravenous self-administration paradigm.

  20. Nonlinear perturbations of systems of partial differential equations with constant coefficients

    Directory of Open Access Journals (Sweden)

    Carmen J. Vanegas

    2000-01-01

    Full Text Available In this article, we show the existence of solutions to boundary-value problems, consisting of nonlinear systems of partial differential equations with constant coefficients. For this purpose, we use the right inverse of an associated operator and a fix point argument. As illustrations, we apply this method to Helmholtz equations and to second order systems of elliptic equations.

  1. Third Harmonic Imaging using a Pulse Inversion

    DEFF Research Database (Denmark)

    Rasmussen, Joachim; Du, Yigang; Jensen, Jørgen Arendt

    2011-01-01

    The pulse inversion (PI) technique can be utilized to separate and enhance harmonic components of a waveform for tissue harmonic imaging. While most ultrasound systems can perform pulse inversion, only few image the 3rd harmonic component. PI pulse subtraction can isolate and enhance the 3rd...

  2. Resolution analysis in full waveform inversion

    NARCIS (Netherlands)

    Fichtner, A.; Trampert, J.

    2011-01-01

    We propose a new method for the quantitative resolution analysis in full seismic waveform inversion that overcomes the limitations of classical synthetic inversions while being computationally more efficient and applicable to any misfit measure. The method rests on (1) the local quadratic

  3. Abel inverse transformation applied to plasma diagnostics

    International Nuclear Information System (INIS)

    Zhu Shiyao

    1987-01-01

    Two methods of Abel inverse transformation are applied to two different test profiles. The effects of random errors of input data, position uncertainty and number of points of input data on the accuracy of inverse transformation have been studied. The two methods are compared in each other

  4. Novel kinin B1 receptor agonists with improved pharmacological profiles.

    Science.gov (United States)

    Côté, Jérôme; Savard, Martin; Bovenzi, Veronica; Bélanger, Simon; Morin, Josée; Neugebauer, Witold; Larouche, Annie; Dubuc, Céléna; Gobeil, Fernand

    2009-04-01

    There is some evidence to suggest that inducible kinin B1 receptors (B1R) may play beneficial and protecting roles in cardiovascular-related pathologies such as hypertension, diabetes, and ischemic organ diseases. Peptide B1R agonists bearing optimized pharmacological features (high potency, selectivity and stability toward proteolysis) hold promise as valuable therapeutic agents in the treatment of these diseases. In the present study, we used solid-phase methodology to synthesize a series of novel peptide analogues based on the sequence of Sar[dPhe(8)]desArg(9)-bradykinin, a relatively stable peptide agonist with moderate affinity for the human B1R. We evaluated the pharmacological properties of these peptides using (1) in vitro competitive binding experiments on recombinant human B1R and B2R (for index of selectivity determination) in transiently transfected human embryonic kidney 293 cells (HEK-293T cells), (2) ex vivo vasomotor assays on isolated human umbilical veins expressing endogenous human B1R, and (3) in vivo blood pressure tests using anesthetized lipopolysaccharide-immunostimulated rabbits. Key chemical modifications at the N-terminus, the positions 3 and 5 on Sar[dPhe(8)]desArg(9)-bradykinin led to potent analogues. For example, peptides 18 (SarLys[Hyp(3),Cha(5), dPhe(8)]desArg(9)-bradykinin) and 20 (SarLys[Hyp(3),Igl(5), dPhe(8)]desArg(9)-bradykinin) outperformed the parental molecule in terms of affinity, functional potency and duration of action in vitro and in vivo. These selective agonists should be valuable in future animal and human studies to investigate the potential benefits of B1R activation.

  5. Forward modeling. Route to electromagnetic inversion

    Energy Technology Data Exchange (ETDEWEB)

    Groom, R; Walker, P [PetRos EiKon Incorporated, Ontario (Canada)

    1996-05-01

    Inversion of electromagnetic data is a topical subject in the literature, and much time has been devoted to understanding the convergence properties of various inverse methods. The relative lack of success of electromagnetic inversion techniques is partly attributable to the difficulties in the kernel forward modeling software. These difficulties come in two broad classes: (1) Completeness and robustness, and (2) convergence, execution time and model simplicity. If such problems exist in the forward modeling kernel, it was demonstrated that inversion can fail to generate reasonable results. It was suggested that classical inversion techniques, which are based on minimizing a norm of the error between data and the simulated data, will only be successful when these difficulties in forward modeling kernels are properly dealt with. 4 refs., 5 figs.

  6. Stochastic Gabor reflectivity and acoustic impedance inversion

    Science.gov (United States)

    Hariri Naghadeh, Diako; Morley, Christopher Keith; Ferguson, Angus John

    2018-02-01

    To delineate subsurface lithology to estimate petrophysical properties of a reservoir, it is possible to use acoustic impedance (AI) which is the result of seismic inversion. To change amplitude to AI, removal of wavelet effects from the seismic signal in order to get a reflection series, and subsequently transforming those reflections to AI, is vital. To carry out seismic inversion correctly it is important to not assume that the seismic signal is stationary. However, all stationary deconvolution methods are designed following that assumption. To increase temporal resolution and interpretation ability, amplitude compensation and phase correction are inevitable. Those are pitfalls of stationary reflectivity inversion. Although stationary reflectivity inversion methods are trying to estimate reflectivity series, because of incorrect assumptions their estimations will not be correct, but may be useful. Trying to convert those reflection series to AI, also merging with the low frequency initial model, can help us. The aim of this study was to apply non-stationary deconvolution to eliminate time variant wavelet effects from the signal and to convert the estimated reflection series to the absolute AI by getting bias from well logs. To carry out this aim, stochastic Gabor inversion in the time domain was used. The Gabor transform derived the signal’s time-frequency analysis and estimated wavelet properties from different windows. Dealing with different time windows gave an ability to create a time-variant kernel matrix, which was used to remove matrix effects from seismic data. The result was a reflection series that does not follow the stationary assumption. The subsequent step was to convert those reflections to AI using well information. Synthetic and real data sets were used to show the ability of the introduced method. The results highlight that the time cost to get seismic inversion is negligible related to general Gabor inversion in the frequency domain. Also

  7. Inverse m-matrices and ultrametric matrices

    CERN Document Server

    Dellacherie, Claude; San Martin, Jaime

    2014-01-01

    The study of M-matrices, their inverses and discrete potential theory is now a well-established part of linear algebra and the theory of Markov chains. The main focus of this monograph is the so-called inverse M-matrix problem, which asks for a characterization of nonnegative matrices whose inverses are M-matrices. We present an answer in terms of discrete potential theory based on the Choquet-Deny Theorem. A distinguished subclass of inverse M-matrices is ultrametric matrices, which are important in applications such as taxonomy. Ultrametricity is revealed to be a relevant concept in linear algebra and discrete potential theory because of its relation with trees in graph theory and mean expected value matrices in probability theory. Remarkable properties of Hadamard functions and products for the class of inverse M-matrices are developed and probabilistic insights are provided throughout the monograph.

  8. Recurrent Neural Network for Computing Outer Inverse.

    Science.gov (United States)

    Živković, Ivan S; Stanimirović, Predrag S; Wei, Yimin

    2016-05-01

    Two linear recurrent neural networks for generating outer inverses with prescribed range and null space are defined. Each of the proposed recurrent neural networks is based on the matrix-valued differential equation, a generalization of dynamic equations proposed earlier for the nonsingular matrix inversion, the Moore-Penrose inversion, as well as the Drazin inversion, under the condition of zero initial state. The application of the first approach is conditioned by the properties of the spectrum of a certain matrix; the second approach eliminates this drawback, though at the cost of increasing the number of matrix operations. The cases corresponding to the most common generalized inverses are defined. The conditions that ensure stability of the proposed neural network are presented. Illustrative examples present the results of numerical simulations.

  9. Fast wavelet based sparse approximate inverse preconditioner

    Energy Technology Data Exchange (ETDEWEB)

    Wan, W.L. [Univ. of California, Los Angeles, CA (United States)

    1996-12-31

    Incomplete LU factorization is a robust preconditioner for both general and PDE problems but unfortunately not easy to parallelize. Recent study of Huckle and Grote and Chow and Saad showed that sparse approximate inverse could be a potential alternative while readily parallelizable. However, for special class of matrix A that comes from elliptic PDE problems, their preconditioners are not optimal in the sense that independent of mesh size. A reason may be that no good sparse approximate inverse exists for the dense inverse matrix. Our observation is that for this kind of matrices, its inverse entries typically have piecewise smooth changes. We can take advantage of this fact and use wavelet compression techniques to construct a better sparse approximate inverse preconditioner. We shall show numerically that our approach is effective for this kind of matrices.

  10. Cardiovascular safety and benefits of GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Dalsgaard, Niels B; Brønden, Andreas; Lauritsen, Tina Vilsbøll

    2017-01-01

    INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss...... and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients...

  11. Discovery of a potent and selective GPR120 agonist

    DEFF Research Database (Denmark)

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel

    2012-01-01

    GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation...... is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist....

  12. Mechanical stress activates NMDA receptors in the absence of agonists

    OpenAIRE

    Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

    2017-01-01

    While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor i...

  13. FCJ-165 Obama Trolling: Memes, Salutes and an Agonistic Politics in the 2012 Presidential Election

    Directory of Open Access Journals (Sweden)

    Benjamin Burroughs

    2013-12-01

    Full Text Available During the 2012 presidential campaign an explosion of photo-shopped images circulated that depicted President Obama as unpatriotic. The ‘crotch salute’, ‘left-hand salute’, and ‘Veterans Day non-salute’ serve as case studies for understanding the role of trolling in the public sphere and Internet politics in an era of social networks and circulation. This paper tracks the cultural practices and logics of ‘sharing’ political memes and conceptualises memes as part of an agonistic public sphere and media ecology. Obama trolling is facilitated through the techno-cultural affordances of memes, which can only become public because of their mimetic form and sterilised partial anonymity. The paper seeks to conceptualise trolling as a broader cultural practice, which can be considered political. Normative assumptions about these memes would portray this trafficking as destructive to deliberative democracy but when understood as a generative cultural practice, trolling becomes central to articulating political emotions in social networks. Photo-shopped Obama salutes, in addition to Big Bird, binder, and bayonet memes, express not only political identities but also larger cultural values within networked popular culture.

  14. Magnetic behavior of partially exchange-coupled particles

    International Nuclear Information System (INIS)

    Oliva, M.I.; Bercoff, P.G.; Bertorello, H.R.

    2005-01-01

    A system of particle pairs with partial exchange coupling is studied, considering identical particles and a fixed angle between their anisotropy axes. The energy of each pair is calculated in terms of the extent of interaction, β, as a function of the applied demagnetizing field. Using the probability per unit time for the inversion of magnetization, the coercive field H c and the viscosity S of the system are calculated. An unexpected result is that fully coupled particles are more stable against temperature than the uncoupled particles

  15. The Good, the Bad, and the Ugly: Agonistic Behaviour in Juvenile Crocodilians

    OpenAIRE

    Brien, Matthew L.; Lang, Jeffrey W.; Webb, Grahame J.; Stevenson, Colin; Christian, Keith A.

    2013-01-01

    We examined agonistic behaviour in seven species of hatchling and juvenile crocodilians held in small groups (N = 4) under similar laboratory conditions. Agonistic interactions occurred in all seven species, typically involved two individuals, were short in duration (5-15 seconds), and occurred between 1600-2200 h in open water. The nature and extent of agonistic interactions, the behaviours displayed, and the level of conspecific tolerance varied among species. Discrete postures, non-contact...

  16. Innate Immune Responses to TLR2 and TLR4 Agonists Differ between Baboons, Chimpanzees and Humans

    Science.gov (United States)

    Brinkworth, Jessica F.; Pechenkina, Ekaterina A.; Silver, Jack; Goyert, Sanna M.

    2012-01-01

    Background African catarrhine primates differ in bacterial disease susceptibility. Methods Human, chimpanzee, and baboon blood was stimulated with TLR-detected bacterial agonists and cytokine/chemokine induction assessed by real-time pcr. Results Humans and chimpanzees shared similar cytokine/chemokine responses, while baboon cytokine/chemokine induction differed. Generally, responses were agonist-independent. Conclusions These primates tend to generate species rather than agonist–specific responses to bacterial agonists. PMID:22978822

  17. Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan.

    Science.gov (United States)

    Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Takagi, Mai; Sei, Kazunari; Yang, Min; Hirotsuji, Junji; Hu, Jianying; Nishikawa, Jun-ichi; Nakanishi, Tsuyoshi; Ike, Michihiko

    2010-04-01

    This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) alpha in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan. To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARalpha agonist contamination in the river basins. RARalpha agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARalpha agonists are always present and widespread in the rivers. Comparative investigation of RARalpha and estrogen receptor alpha agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARalpha agonist contamination was entirely different from that of the estrogenic compound contamination. This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARalpha agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARalpha agonists in the rivers. Although a trial conducted to identify RARalpha agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARalpha agonistic activity were not RAs (natural RAR ligands) and 4-oxo-RAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China. These findings suggest that there are unknown RARalpha agonists with high

  18. Developments in inverse photoemission spectroscopy

    International Nuclear Information System (INIS)

    Sheils, W.; Leckey, R.C.G.; Riley, J.D.

    1996-01-01

    In the 1950's and 1960's, Photoemission Spectroscopy (PES) established itself as the major technique for the study of the occupied electronic energy levels of solids. During this period the field divided into two branches: X-ray Photoemission Spectroscopy (XPS) for photon energies greater than ∼l000eV, and Ultra-violet Photoemission Spectroscopy (UPS) for photon energies below ∼100eV. By the 1970's XPS and UPS had become mature techniques. Like XPS, BIS (at x-ray energies) does not have the momentum-resolving ability of UPS that has contributed much to the understanding of the occupied band structures of solids. BIS moved into a new energy regime in 1977 when Dose employed a Geiger-Mueller tube to obtain density of unoccupied states data from a tantalum sample at a photon energy of ∼9.7eV. At similar energies, the technique has since become known as Inverse Photoemission Spectroscopy (IPS), in acknowledgment of its complementary relationship to UPS and to distinguish it from the higher energy BIS. Drawing on decades of UPS expertise, IPS has quickly moved into areas of interest where UPS has been applied; metals, semiconductors, layer compounds, adsorbates, ferromagnets, and superconductors. At La Trobe University an IPS facility has been constructed. This presentation reports on developments in the experimental and analytical techniques of IPS that have been made there. The results of a study of the unoccupied bulk and surface bands of GaAs are presented

  19. Physics of partially ionized plasmas

    CERN Document Server

    Krishan, Vinod

    2016-01-01

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

  20. Partially massless fields during inflation

    Science.gov (United States)

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

    2018-04-01

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

  1. Identification of polymorphic inversions from genotypes

    Directory of Open Access Journals (Sweden)

    Cáceres Alejandro

    2012-02-01

    Full Text Available Abstract Background Polymorphic inversions are a source of genetic variability with a direct impact on recombination frequencies. Given the difficulty of their experimental study, computational methods have been developed to infer their existence in a large number of individuals using genome-wide data of nucleotide variation. Methods based on haplotype tagging of known inversions attempt to classify individuals as having a normal or inverted allele. Other methods that measure differences between linkage disequilibrium attempt to identify regions with inversions but unable to classify subjects accurately, an essential requirement for association studies. Results We present a novel method to both identify polymorphic inversions from genome-wide genotype data and classify individuals as containing a normal or inverted allele. Our method, a generalization of a published method for haplotype data 1, utilizes linkage between groups of SNPs to partition a set of individuals into normal and inverted subpopulations. We employ a sliding window scan to identify regions likely to have an inversion, and accumulation of evidence from neighboring SNPs is used to accurately determine the inversion status of each subject. Further, our approach detects inversions directly from genotype data, thus increasing its usability to current genome-wide association studies (GWAS. Conclusions We demonstrate the accuracy of our method to detect inversions and classify individuals on principled-simulated genotypes, produced by the evolution of an inversion event within a coalescent model 2. We applied our method to real genotype data from HapMap Phase III to characterize the inversion status of two known inversions within the regions 17q21 and 8p23 across 1184 individuals. Finally, we scan the full genomes of the European Origin (CEU and Yoruba (YRI HapMap samples. We find population-based evidence for 9 out of 15 well-established autosomic inversions, and for 52 regions

  2. Introduction to partial differential equations

    CERN Document Server

    Greenspan, Donald

    2000-01-01

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

  3. A Joint Method of Envelope Inversion Combined with Hybrid-domain Full Waveform Inversion

    Science.gov (United States)

    CUI, C.; Hou, W.

    2017-12-01

    Full waveform inversion (FWI) aims to construct high-precision subsurface models by fully using the information in seismic records, including amplitude, travel time, phase and so on. However, high non-linearity and the absence of low frequency information in seismic data lead to the well-known cycle skipping problem and make inversion easily fall into local minima. In addition, those 3D inversion methods that are based on acoustic approximation ignore the elastic effects in real seismic field, and make inversion harder. As a result, the accuracy of final inversion results highly relies on the quality of initial model. In order to improve stability and quality of inversion results, multi-scale inversion that reconstructs subsurface model from low to high frequency are applied. But, the absence of very low frequencies (time domain and inversion in the frequency domain. To accelerate the inversion, we adopt CPU/GPU heterogeneous computing techniques. There were two levels of parallelism. In the first level, the inversion tasks are decomposed and assigned to each computation node by shot number. In the second level, GPU multithreaded programming is used for the computation tasks in each node, including forward modeling, envelope extraction, DFT (discrete Fourier transform) calculation and gradients calculation. Numerical tests demonstrated that the combined envelope inversion + hybrid-domain FWI could obtain much faithful and accurate result than conventional hybrid-domain FWI. The CPU/GPU heterogeneous parallel computation could improve the performance speed.

  4. Long-acting beta(2)-agonists in management of childhood asthma

    DEFF Research Database (Denmark)

    Bisgaard, H

    2000-01-01

    This review assesses the evidence regarding the use of long-acting beta(2)-agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled......, long-acting beta(2)-agonists provide effective bronchodilatation and bronchoprotection when used as intermittent, single-dose treatment of asthma in children, but not when used as regular treatment. Future studies should examine the positioning of long-acting beta(2)-agonists as an "as needed" rescue...... medication instead of short-acting beta(2)-agonists for pediatric asthma management....

  5. Hypertrophic effect of inhaled beta -agonist with and without concurrent exercise training

    DEFF Research Database (Denmark)

    Jessen, Søren; Onslev, Johan; Lemminger, Anders

    2018-01-01

    INTRODUCTION: Due to a high prevalence of asthma and exercise-induced bronchoconstriction in elite athletes, there is a high use of beta2 -adrenoceptor agonists (beta2 -agonists) in the athletic population. While anabolic in rodents, no study has been able to detect hypertrophy in humans after...... chronic beta2 -agonist inhalation. METHODS: We investigated if inhaled beta2 -agonist, terbutaline, alters body composition and metabolic rate with and without concurrent exercise training in healthy young men. Sixty-seven participants completed a four-week intervention of daily terbutaline (8×0.5 mg...

  6. Agonist-induced affinity alterations of a central nervous system. cap alpha. -bungarotoxin receptor

    Energy Technology Data Exchange (ETDEWEB)

    Lukas, R.J.; Bennett, E.L.

    1979-01-01

    The ability of cholinergic agonists to block the specific interaction of ..cap alpha..-bungarotoxin (..cap alpha..-Bgt) with membrane-bound sites derived from rat brain is enhanced when membranes are preincubated with agonist. Thus, pretreatment of ..cap alpha..-Bgt receptors with agonist (but not antagonist) causes transformation of sites to a high-affinity form toward agonist. This change in receptor state occurs with a half-time on the order of minutes, and is fully reversible on dilution of agonist. The results are consistent with the identity of ..cap alpha..-Bgt binding sites as true central nicotinic acetylcholine receptors. Furthermore, this agonist-induced alteration in receptor state may represent an in vitro correlate of physiological desensitization. As determined from the effects of agonist on toxin binding isotherms, and on the rate of toxin binding to specific sites, agonist inhibition of toxin binding to the high-affinity state is non-competitive. This result suggests that there may exist discrete toxin-binding and agonist-binding sites on central toxin receptors.

  7. [Acrylic resin removable partial dentures].

    Science.gov (United States)

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

    2011-01-01

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

  8. AMP is an adenosine A1 receptor agonist.

    Science.gov (United States)

    Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A; Jin, Jian; Janzen, William P; Frye, Stephen V; Zylka, Mark J

    2012-02-17

    Numerous receptors for ATP, ADP, and adenosine exist; however, it is currently unknown whether a receptor for the related nucleotide adenosine 5'-monophosphate (AMP) exists. Using a novel cell-based assay to visualize adenosine receptor activation in real time, we found that AMP and a non-hydrolyzable AMP analog (deoxyadenosine 5'-monophosphonate, ACP) directly activated the adenosine A(1) receptor (A(1)R). In contrast, AMP only activated the adenosine A(2B) receptor (A(2B)R) after hydrolysis to adenosine by ecto-5'-nucleotidase (NT5E, CD73) or prostatic acid phosphatase (PAP, ACPP). Adenosine and AMP were equipotent human A(1)R agonists in our real-time assay and in a cAMP accumulation assay. ACP also depressed cAMP levels in mouse cortical neurons through activation of endogenous A(1)R. Non-selective purinergic receptor antagonists (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and suramin) did not block adenosine- or AMP-evoked activation. Moreover, mutation of His-251 in the human A(1)R ligand binding pocket reduced AMP potency without affecting adenosine potency. In contrast, mutation of a different binding pocket residue (His-278) eliminated responses to AMP and to adenosine. Taken together, our study indicates that the physiologically relevant nucleotide AMP is a full agonist of A(1)R. In addition, our study suggests that some of the physiological effects of AMP may be direct, and not indirect through ectonucleotidases that hydrolyze this nucleotide to adenosine.

  9. NKT-cell glycolipid agonist as adjuvant in synthetic vaccine.

    Science.gov (United States)

    Liu, Zheng; Guo, Jun

    2017-11-27

    NKT cells are CD1d-restricted, glycolipid antigen-reactive, immunoregulatory T lymphocytes that can serve as a bridge between the innate and adaptive immunities. NKT cells have a wide range of therapeutic application in autoimmunity, transplant biology, infectious disease, cancer, and vaccinology. Rather than triggering "danger signal" and eliciting an innate immune response, αGalCer-based NKT-cell agonist act via a unique mechanism, recruiting NKT cells which play a T helper-like role even without peptide as Th epitope. Importantly, the non-polymorphism of CD1d render glycolipid a universal helper epitope, offering the potential to simplify the vaccine construct capable of eliciting consistent immune response in different individuals. This review details recent advances in the design of synthetic vaccines using NKT-cell agonist as adjuvant, highlighting the role of organic synthesis and conjugation technique to enhance the immunological actives and to simplify the vaccine constructs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Mood Disorders, Circadian Rhythms, Melatonin and Melatonin Agonists

    Directory of Open Access Journals (Sweden)

    M.A. Quera Salva

    2012-04-01

    Full Text Available Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC. Melatonin (N-acetyl-5-hydroxytryptamine is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.

  11. Identification of agonists for a group of human odorant receptors

    Directory of Open Access Journals (Sweden)

    Daniela eGonzalez-Kristeller

    2015-03-01

    Full Text Available Olfaction plays a critical role in several aspects of the human life. Odorants are detected by hundreds of odorant receptors (ORs which belong to the superfamily of G protein-coupled receptors. These receptors are expressed in the olfactory sensory neurons of the nose. The information provided by the activation of different combinations of ORs in the nose is transmitted to the brain, leading to odorant perception and emotional and behavioral responses. There are ~400 intact human ORs, and to date only a small percentage of these receptors (~10% have known agonists. The determination of the specificity of the human ORs will contribute to a better understanding of how odorants are discriminated by the olfactory system. In this work, we aimed to identify human specific ORs, that is, ORs that are present in humans but absent from other species, and their corresponding agonists. To do this, we first selected 22 OR gene sequences from the human genome with no counterparts in the mouse, rat or dog genomes. Then we used a heterologous expression system to screen a subset of these human ORs against a panel of odorants of biological relevance, including foodborne aroma volatiles. We found that different types of odorants are able to activate some of these previously uncharacterized human ORs.

  12. Trial Watch: Toll-like receptor agonists in oncological indications.

    Science.gov (United States)

    Aranda, Fernando; Vacchelli, Erika; Obrist, Florine; Eggermont, Alexander; Galon, Jérôme; Sautès-Fridman, Catherine; Cremer, Isabelle; Henrik Ter Meulen, Jan; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2014-01-01

    Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.

  13. How does agonistic behaviour differ in albino and pigmented fish?

    Directory of Open Access Journals (Sweden)

    Ondřej Slavík

    2016-04-01

    Full Text Available In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics.

  14. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    Science.gov (United States)

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

  15. S-matrix to potential inversion of low-energy. alpha. - sup 12 C phase shifts

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, S.G.; Mackintosh, R.S. (Open Univ., Milton Keynes (UK). Dept. of Physics)

    1990-10-22

    The IP S-matrix to potential inversion procedure is applied to phase shifts for selected partial waves over a range of energies below the inelastic threshold for {alpha}-{sup 12}C scattering. The phase shifts were determined by Plaga et al. Potentials found by Buck and Rubio to fit the low-energy alpha cluster resonances need only an increased attraction in the surface to accurately reproduce the phase-shift behaviour. Substantial differences between the potentials for odd and even partial waves are necessary. The surface tail of the potential is postulated to be a threshold effect. (orig.).

  16. S-Matrix to potential inversion of low-energy α-12C phase shifts

    Science.gov (United States)

    Cooper, S. G.; Mackintosh, R. S.

    1990-10-01

    The IP S-matrix to potential inversion procedure is applied to phase shifts for selected partial waves over a range of energies below the inelastic threshold for α-12C scattering. The phase shifts were determined by Plaga et al. Potentials found by Buck and Rubio to fit the low-energy alpha cluster resonances need only an increased attraction in the surface to accurately reproduce the phase-shift behaviour. Substantial differences between the potentials for odd and even partial waves are necessary. The surface tail of the potential is postulated to be a threshold effect.

  17. Support minimized inversion of acoustic and elastic wave scattering

    International Nuclear Information System (INIS)

    Safaeinili, A.

    1994-01-01

    This report discusses the following topics on support minimized inversion of acoustic and elastic wave scattering: Minimum support inversion; forward modelling of elastodynamic wave scattering; minimum support linearized acoustic inversion; support minimized nonlinear acoustic inversion without absolute phase; and support minimized nonlinear elastic inversion

  18. Cold atoms at unitarity and inverse square interaction

    Energy Technology Data Exchange (ETDEWEB)

    Bhaduri, R K [Department of Physics and Astronomy, McMaster University, Hamilton L8S 4M1 (Canada); Murthy, M V N [The Institute of Mathematical Sciences, Chennai 600113 (India); Srivastava, M K [Department of Physics, Indian Institute of Technology, Roorkee 247667 (India)

    2009-12-14

    Consider two identical atoms in a spherical harmonic oscillator interacting with a zero-range interaction which is tuned to produce an s-wave zero-energy bound state. The quantum spectrum of the system is known to be exactly solvable. We note that the same partial wave quantum spectrum is obtained by the one-dimensional scale-invariant inverse square potential. Long known as the Calogero-Sutherland-Moser (CSM) model, it leads to the fractional exclusion statistics (FES) of Haldane and Wu. The statistical parameter is deduced from the analytically calculated second virial coefficient. When FES is applied to a Fermi gas at unitarity, it gives good agreement with experimental data without the use of any free parameter.

  19. Numerical computation of FCT equilibria by inverse equilibrium method

    International Nuclear Information System (INIS)

    Tokuda, Shinji; Tsunematsu, Toshihide; Takeda, Tatsuoki

    1986-11-01

    FCT (Flux Conserving Tokamak) equilibria were obtained numerically by the inverse equilibrium method. The high-beta tokamak ordering was used to get the explicit boundary conditions for FCT equilibria. The partial differential equation was reduced to the simultaneous quasi-linear ordinary differential equations by using the moment method. The regularity conditions for solutions at the singular point of the equations can be expressed correctly by this reduction and the problem to be solved becomes a tractable boundary value problem on the quasi-linear ordinary differential equations. This boundary value problem was solved by the method of quasi-linearization, one of the shooting methods. Test calculations show that this method provides high-beta tokamak equilibria with sufficiently high accuracy for MHD stability analysis. (author)

  20. Resolving the existence of Higgsinos in the LHC inverse problem

    International Nuclear Information System (INIS)

    Jung, Sunghoon

    2014-01-01

    The LHC inverse problem is infamously challenging when neutralinos and charginos are heavy and pure and other superparticles are decoupled. This limit is becoming more relevant to particle physics nowadays. Fortunately, in this limit, Higgsinos produce a distinctive signature if they are the LSPs or NLSPs. The identifying signature is the presence of equal numbers of Z bosons and Higgs bosons in NLSP productions and subsequent decays at hadron colliders. The signature is derived from the Goldstone equivalence theorem by which partial widths into Z and Higgs bosons are inherently related and from the fact that Higgsinos consist of two indistinguishable neutralinos. Thus it is valid in general for many supersymmetry models; exceptions may happen when Higgsino NLSPs decay to weakly coupled LSPs such as axinos or gravitinos.

  1. 3rd Annual Workshop on Inverse Problem

    CERN Document Server

    2015-01-01

    This proceeding volume is based on papers presented on the Third Annual Workshop on Inverse Problems which was organized by the Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, and took place in May 2013 in Stockholm. The purpose of this workshop was to present new analytical developments and numerical techniques for solution of inverse problems for a wide range of applications in acoustics, electromagnetics, optical fibers, medical imaging, geophysics, etc. The contributions in this volume reflect these themes and will be beneficial to researchers who are working in the area of applied inverse problems.

  2. Inverse problems in the Bayesian framework

    International Nuclear Information System (INIS)

    Calvetti, Daniela; Somersalo, Erkki; Kaipio, Jari P

    2014-01-01

    The history of Bayesian methods dates back to the original works of Reverend Thomas Bayes and Pierre-Simon Laplace: the former laid down some of the basic principles on inverse probability in his classic article ‘An essay towards solving a problem in the doctrine of chances’ that was read posthumously in the Royal Society in 1763. Laplace, on the other hand, in his ‘Memoirs on inverse probability’ of 1774 developed the idea of updating beliefs and wrote down the celebrated Bayes’ formula in the form we know today. Although not identified yet as a framework for investigating inverse problems, Laplace used the formalism very much in the spirit it is used today in the context of inverse problems, e.g., in his study of the distribution of comets. With the evolution of computational tools, Bayesian methods have become increasingly popular in all fields of human knowledge in which conclusions need to be drawn based on incomplete and noisy data. Needless to say, inverse problems, almost by definition, fall into this category. Systematic work for developing a Bayesian inverse problem framework can arguably be traced back to the 1980s, (the original first edition being published by Elsevier in 1987), although articles on Bayesian methodology applied to inverse problems, in particular in geophysics, had appeared much earlier. Today, as testified by the articles in this special issue, the Bayesian methodology as a framework for considering inverse problems has gained a lot of popularity, and it has integrated very successfully with many traditional inverse problems ideas and techniques, providing novel ways to interpret and implement traditional procedures in numerical analysis, computational statistics, signal analysis and data assimilation. The range of applications where the Bayesian framework has been fundamental goes from geophysics, engineering and imaging to astronomy, life sciences and economy, and continues to grow. There is no question that Bayesian

  3. NLSE: Parameter-Based Inversion Algorithm

    Science.gov (United States)

    Sabbagh, Harold A.; Murphy, R. Kim; Sabbagh, Elias H.; Aldrin, John C.; Knopp, Jeremy S.

    Chapter 11 introduced us to the notion of an inverse problem and gave us some examples of the value of this idea to the solution of realistic industrial problems. The basic inversion algorithm described in Chap. 11 was based upon the Gauss-Newton theory of nonlinear least-squares estimation and is called NLSE in this book. In this chapter we will develop the mathematical background of this theory more fully, because this algorithm will be the foundation of inverse methods and their applications during the remainder of this book. We hope, thereby, to introduce the reader to the application of sophisticated mathematical concepts to engineering practice without introducing excessive mathematical sophistication.

  4. Inverse problems for the Boussinesq system

    International Nuclear Information System (INIS)

    Fan, Jishan; Jiang, Yu; Nakamura, Gen

    2009-01-01

    We obtain two results on inverse problems for a 2D Boussinesq system. One is that we prove the Lipschitz stability for the inverse source problem of identifying a time-independent external force in the system with observation data in an arbitrary sub-domain over a time interval of the velocity and the data of velocity and temperature at a fixed positive time t 0 > 0 over the whole spatial domain. The other one is that we prove a conditional stability estimate for an inverse problem of identifying the two initial conditions with a single observation on a sub-domain

  5. Population inversion in a stationary recombining plasma

    International Nuclear Information System (INIS)

    Otsuka, M.

    1980-01-01

    Population inversion, which occurs in a recombining plasma when a stationary He plasma is brought into contact with a neutral gas, is examined. With hydrogen as a contact gas, noticeable inversion between low-lying levels of H as been found. The overpopulation density is of the order of 10 8 cm -3 , which is much higher then that (approx. =10 5 cm -3 ) obtained previously with He as a contact gas. Relations between these experimental results and the conditions for population inversion are discussed with the CR model

  6. Inverse Raman effect: applications and detection techniques

    International Nuclear Information System (INIS)

    Hughes, L.J. Jr.

    1980-08-01

    The processes underlying the inverse Raman effect are qualitatively described by comparing it to the more familiar phenomena of conventional and stimulated Raman scattering. An experession is derived for the inverse Raman absorption coefficient, and its relationship to the stimulated Raman gain is obtained. The power requirements of the two fields are examined qualitatively and quantitatively. The assumption that the inverse Raman absorption coefficient is constant over the interaction length is examined. Advantages of the technique are discussed and a brief survey of reported studies is presented

  7. Inverse Raman effect: applications and detection techniques

    Energy Technology Data Exchange (ETDEWEB)

    Hughes, L.J. Jr.

    1980-08-01

    The processes underlying the inverse Raman effect are qualitatively described by comparing it to the more familiar phenomena of conventional and stimulated Raman scattering. An experession is derived for the inverse Raman absorption coefficient, and its relationship to the stimulated Raman gain is obtained. The power requirements of the two fields are examined qualitatively and quantitatively. The assumption that the inverse Raman absorption coefficient is constant over the interaction length is examined. Advantages of the technique are discussed and a brief survey of reported studies is presented.

  8. Multiparameter Optimization for Electromagnetic Inversion Problem

    Directory of Open Access Journals (Sweden)

    M. Elkattan

    2017-10-01

    Full Text Available Electromagnetic (EM methods have been extensively used in geophysical investigations such as mineral and hydrocarbon exploration as well as in geological mapping and structural studies. In this paper, we developed an inversion methodology for Electromagnetic data to determine physical parameters of a set of horizontal layers. We conducted Forward model using transmission line method. In the inversion part, we solved multi parameter optimization problem where, the parameters are conductivity, dielectric constant, and permeability of each layer. The optimization problem was solved by simulated annealing approach. The inversion methodology was tested using a set of models representing common geological formations.

  9. BOOK REVIEW: Inverse Problems. Activities for Undergraduates

    Science.gov (United States)

    Yamamoto, Masahiro

    2003-06-01

    This book is a valuable introduction to inverse problems. In particular, from the educational point of view, the author addresses the questions of what constitutes an inverse problem and how and why we should study them. Such an approach has been eagerly awaited for a long time. Professor Groetsch, of the University of Cincinnati, is a world-renowned specialist in inverse problems, in particular the theory of regularization. Moreover, he has made a remarkable contribution to educational activities in the field of inverse problems, which was the subject of his previous book (Groetsch C W 1993 Inverse Problems in the Mathematical Sciences (Braunschweig: Vieweg)). For this reason, he is one of the most qualified to write an introductory book on inverse problems. Without question, inverse problems are important, necessary and appear in various aspects. So it is crucial to introduce students to exercises in inverse problems. However, there are not many introductory books which are directly accessible by students in the first two undergraduate years. As a consequence, students often encounter diverse concrete inverse problems before becoming aware of their general principles. The main purpose of this book is to present activities to allow first-year undergraduates to learn inverse theory. To my knowledge, this book is a rare attempt to do this and, in my opinion, a great success. The author emphasizes that it is very important to teach inverse theory in the early years. He writes; `If students consider only the direct problem, they are not looking at the problem from all sides .... The habit of always looking at problems from the direct point of view is intellectually limiting ...' (page 21). The book is very carefully organized so that teachers will be able to use it as a textbook. After an introduction in chapter 1, sucessive chapters deal with inverse problems in precalculus, calculus, differential equations and linear algebra. In order to let one gain some insight

  10. Elastic orthorhombic anisotropic parameter inversion: An analysis of parameterization

    KAUST Repository

    Oh, Juwon; Alkhalifah, Tariq Ali

    2016-01-01

    The resolution of a multiparameter full-waveform inversion (FWI) is highly influenced by the parameterization used in the inversion algorithm, as well as the data quality and the sensitivity of the data to the elastic parameters because the scattering patterns of the partial derivative wavefields (PDWs) vary with parameterization. For this reason, it is important to identify an optimal parameterization for elastic orthorhombic FWI by analyzing the radiation patterns of the PDWs for many reasonable model parameterizations. We have promoted a parameterization that allows for the separation of the anisotropic properties in the radiation patterns. The central parameter of this parameterization is the horizontal P-wave velocity, with an isotropic scattering potential, influencing the data at all scales and directions. This parameterization decouples the influence of the scattering potential given by the P-wave velocity perturbation fromthe polar changes described by two dimensionless parameter perturbations and from the azimuthal variation given by three additional dimensionless parameters perturbations. In addition, the scattering potentials of the P-wave velocity perturbation are also decoupled from the elastic influences given by one S-wave velocity and two additional dimensionless parameter perturbations. The vertical S-wave velocity is chosen with the best resolution obtained from S-wave reflections and converted waves, little influence on P-waves in conventional surface seismic acquisition. The influence of the density on observed data can be absorbed by one anisotropic parameter that has a similar radiation pattern. The additional seven dimensionless parameters describe the polar and azimuth variations in the P- and S-waves that we may acquire, with some of the parameters having distinct influences on the recorded data on the earth's surface. These characteristics of the new parameterization offer the potential for a multistage inversion from high symmetry

  11. Elastic orthorhombic anisotropic parameter inversion: An analysis of parameterization

    KAUST Repository

    Oh, Juwon

    2016-09-15

    The resolution of a multiparameter full-waveform inversion (FWI) is highly influenced by the parameterization used in the inversion algorithm, as well as the data quality and the sensitivity of the data to the elastic parameters because the scattering patterns of the partial derivative wavefields (PDWs) vary with parameterization. For this reason, it is important to identify an optimal parameterization for elastic orthorhombic FWI by analyzing the radiation patterns of the PDWs for many reasonable model parameterizations. We have promoted a parameterization that allows for the separation of the anisotropic properties in the radiation patterns. The central parameter of this parameterization is the horizontal P-wave velocity, with an isotropic scattering potential, influencing the data at all scales and directions. This parameterization decouples the influence of the scattering potential given by the P-wave velocity perturbation fromthe polar changes described by two dimensionless parameter perturbations and from the azimuthal variation given by three additional dimensionless parameters perturbations. In addition, the scattering potentials of the P-wave velocity perturbation are also decoupled from the elastic influences given by one S-wave velocity and two additional dimensionless parameter perturbations. The vertical S-wave velocity is chosen with the best resolution obtained from S-wave reflections and converted waves, little influence on P-waves in conventional surface seismic acquisition. The influence of the density on observed data can be absorbed by one anisotropic parameter that has a similar radiation pattern. The additional seven dimensionless parameters describe the polar and azimuth variations in the P- and S-waves that we may acquire, with some of the parameters having distinct influences on the recorded data on the earth\\'s surface. These characteristics of the new parameterization offer the potential for a multistage inversion from high symmetry

  12. Retrieving global aerosol sources from satellites using inverse modeling

    Directory of Open Access Journals (Sweden)

    O. Dubovik

    2008-01-01

    Full Text Available Understanding aerosol effects on global climate requires knowing the global distribution of tropospheric aerosols. By accounting for aerosol sources, transports, and removal processes, chemical transport models simulate the global aerosol distribution using archived meteorological fields. We develop an algorithm for retrieving global aerosol sources from satellite observations of aerosol distribution by inverting the GOCART aerosol transport model.

    The inversion is based on a generalized, multi-term least-squares-type fitting, allowing flexible selection and refinement of a priori algorithm constraints. For example, limitations can be placed on retrieved quantity partial derivatives, to constrain global aerosol emission space and time variability in the results. Similarities and differences between commonly used inverse modeling and remote sensing techniques are analyzed. To retain the high space and time resolution of long-period, global observational records, the algorithm is expressed using adjoint operators.

    Successful global aerosol emission retrievals at 2°×2.5 resolution were obtained by inverting GOCART aerosol transport model output, assuming constant emissions over the diurnal cycle, and neglecting aerosol compositional differences. In addition, fine and coarse mode aerosol emission sources were inverted separately from MODIS fine and coarse mode aerosol optical thickness data, respectively. These assumptions are justified, based on observational coverage and accuracy limitations, producing valuable aerosol source locations and emission strengths. From two weeks of daily MODIS observations during August 2000, the global placement of fine mode aerosol sources agreed with available independent knowledge, even though the inverse method did not use any a priori information about aerosol sources, and was initialized with a "zero aerosol emission" assumption. Retrieving coarse mode aerosol emissions was less successful

  13. Identification of Loss-of-Coolant Accidents in LWRs by Inverse Models

    International Nuclear Information System (INIS)

    Cholewa, Wojciech; Frid, Wiktor; Bednarski, Marcin

    2004-01-01

    This paper describes a novel diagnostic method based on inverse models that could be applied to identification of transients and accidents in nuclear power plants. In particular, it is shown that such models could be successfully applied to identification of loss-of-coolant accidents (LOCAs). This is demonstrated for LOCA scenarios for a boiling water reactor. Two classes of inverse models are discussed: local models valid only in a selected neighborhood of an unknown element in the data set, representing a state of a considered object, and global models, in the form of partially unilateral models, valid over the whole learning data set. An interesting and useful property of local inverse models is that they can be considered as example-based models, i.e., models that are spanned on particular sets of pattern data. It is concluded that the optimal diagnostic method should combine the advantages of both models, i.e., the high quality of results obtained from a local inverse model and the information about the confidence interval for the expected output provided by a partially unilateral model

  14. Parachute technique for partial penectomy

    Directory of Open Access Journals (Sweden)

    Fernando Korkes

    2010-04-01

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

  15. Semi-analytic equations to the Cox-Thompson inverse scattering method at fixed energy for special cases

    International Nuclear Information System (INIS)

    Palmai, T.; Apagyi, B.; Horvath, M.

    2008-01-01

    Solution of the Cox-Thompson inverse scattering problem at fixed energy 1-3 is reformulated resulting in semi-analytic equations. The new set of equations for the normalization constants and the nonphysical (shifted) angular momenta are free of matrix inversion operations. This simplification is a result of treating only the input phase shifts of partial waves of a given parity. Therefore, the proposed method can be applied for identical particle scattering of the bosonic type (or for certain cases of identical fermionic scattering). The new formulae are expected to be numerically more efficient than the previous ones. Based on the semi-analytic equations an approximate method is proposed for the generic inverse scattering problem, when partial waves of arbitrary parity are considered. (author)

  16. Parametric optimization of inverse trapezoid oleophobic surfaces

    DEFF Research Database (Denmark)

    Cavalli, Andrea; Bøggild, Peter; Okkels, Fridolin

    2012-01-01

    In this paper, we introduce a comprehensive and versatile approach to the parametric shape optimization of oleophobic surfaces. We evaluate the performance of inverse trapezoid microstructures in terms of three objective parameters: apparent contact angle, maximum sustainable hydrostatic pressure...

  17. An inverse method for radiation transport

    Energy Technology Data Exchange (ETDEWEB)

    Favorite, J. A. (Jeffrey A.); Sanchez, R. (Richard)

    2004-01-01

    Adjoint functions have been used with forward functions to compute gradients in implicit (iterative) solution methods for inverse problems in optical tomography, geoscience, thermal science, and other fields, but only once has this approach been used for inverse solutions to the Boltzmann transport equation. In this paper, this approach is used to develop an inverse method that requires only angle-independent flux measurements, rather than angle-dependent measurements as was done previously. The method is applied to a simplified form of the transport equation that does not include scattering. The resulting procedure uses measured values of gamma-ray fluxes of discrete, characteristic energies to determine interface locations in a multilayer shield. The method was implemented with a Newton-Raphson optimization algorithm, and it worked very well in numerical one-dimensional spherical test cases. A more sophisticated optimization method would better exploit the potential of the inverse method.

  18. The Transmuted Generalized Inverse Weibull Distribution

    Directory of Open Access Journals (Sweden)

    Faton Merovci

    2014-05-01

    Full Text Available A generalization of the generalized inverse Weibull distribution the so-called transmuted generalized inverse Weibull distribution is proposed and studied. We will use the quadratic rank transmutation map (QRTM in order to generate a flexible family of probability distributions taking the generalized inverseWeibull distribution as the base value distribution by introducing a new parameter that would offer more distributional flexibility. Various structural properties including explicit expressions for the moments, quantiles, and moment generating function of the new distribution are derived. We propose the method of maximum likelihood for estimating the model parameters and obtain the observed information matrix. A real data set are used to compare the flexibility of the transmuted version versus the generalized inverse Weibull distribution.

  19. Parameterization analysis and inversion for orthorhombic media

    KAUST Repository

    Masmoudi, Nabil

    2018-01-01

    Accounting for azimuthal anisotropy is necessary for the processing and inversion of wide-azimuth and wide-aperture seismic data because wave speeds naturally depend on the wave propagation direction. Orthorhombic anisotropy is considered the most

  20. Wave-equation reflection traveltime inversion

    KAUST Repository

    Zhang, Sanzong; Schuster, Gerard T.; Luo, Yi

    2011-01-01

    The main difficulty with iterative waveform inversion using a gradient optimization method is that it tends to get stuck in local minima associated within the waveform misfit function. This is because the waveform misfit function is highly nonlinear