695 research outputs found

    Symbolic semantics and bisimulation for full LOTOS

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    Elucidating an amorphous form stabilization mechanism of tenapanor hydrochloride: crystal structure analysis using Xray diffraction, NMR crystallography and molecular modelling

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    By the combined use of powder and single crystal X-ray diffraction, solid-state NMR, and molecular modelling, the crystal structures of two systems containing the unusually large tenapanor drug molecule have been determined: the free form, ANHY and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallography investigations were found essential for the final assignment, and were used to validate the crystal structure of ANHY. From the structural informatics analysis of ANHY and 2HCl, conformational ring differences in one part of the molecule were observed which influences the relative orientation of a methyl group on a ring nitrogen and thereby impacts the crystallizability of the dihydrochloride salt. From quantum chemistry calculations, the dynamics between different ring conformations in tenapanor is predicted to be fast. Addition of HCl to tenapanor results in general in a mixture of protonated ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qualitatively verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amount of the crystalline material 2HCl, which originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between minor and major conformations of ANHY in solution. Thus, by controlling the solution pH value to well below the pKa of ANHY, the equilibrium between ANHY and 2HCl can be controlled and by this mechanism the crystallization of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized

    The quetiapine active metabolite N-Desalkylquetiapine and the neurotensin NTS1 receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats

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    Major depressive disorder (MDD) is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that are apparent following one week of quetiapine treatment, and it is possible that the active metabolite N-Desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 are suggestive of antidepressant efficacy, but the effects of a NTS1 receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of the N-Desalkylquetiapine, the neurotensin NTS1 receptor agonist PD14916, quetiapine, the tricylic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate (DRL) 72 s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. The typical antipsychotic drug raclopride decreased both reinforcers and responses. These data suggest that N-Desalklyquetiapine likely contributes to quetiapine’s antidepressant efficacy and identifies NTS1 receptor activation as a potential novel pharmacologic strategy for antidepressant drugs

    Radio Observations of HD 80606 Near Planetary Periastron

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    This paper reports Very Large Array observations at 325 and 1425 MHz (90cm and 20cm) during and near the periastron passage of HD 80606b on 2007 November 20. We obtain flux density limits (3-sigma) of 1.7 mJy and 48 microJy at 325 and 1425 MHz, respectively, equivalent to planetary luminosity limits of 2.3 x 10^{24} erg/s and 2.7 x 10^{23} erg/s. These are well above the Jovian value (at 40 MHz) of 2 x 10^{18} erg/s. The motivation for these observations was that the planetary magnetospheric emission is driven by a stellar wind-planetary magnetosphere interaction so that the planetary luminosity would be elevated. Near periastron, HD 80606b might be as much as 3000 times more luminous than Jupiter. Recent transit observations of HD 80606b provide stringent constraints on the planetary mass and radius, and, because of the planet's highly eccentric orbit, its rotation period is likely to be "pseudo-synchronized" to its orbital period, allowing a robust estimate of the former. We are able to make robust estimates of the emission frequency of the planetary magnetospheric emission and find it to be around 60--90 MHz. We compare HD 80606b to other high-eccentricity systems and assess the detection possibilities for both near-term and more distant future systems. Of the known high eccentricity planets, only HD 80606b is likely to be detectable, as HD 20782B b and HD 4113b are both likely to have weaker magnetic field strengths. Both the forthcoming "EVLA low band" system and the Low Frequency Array may be able to improve upon our limits for HD 80606b, and do so at a more optimum frequency. If the low-frequency component of the Square Kilometre Array (SKA-lo) and a future lunar radio array are able to approach their thermal noise limits, they should be able to detect an HD 80606b-like planet, unless the planet's luminosity increases by substantially less than a factor of 3000.Comment: 9 pages; accepted for publication in A

    Brazil's Engagement in International Development Cooperation: The State of the Debate

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    The international development cooperation architecture has changed dramatically over the last decade. The global context, characterised by a lingering financial crisis and the emergence of new powers, has brought South‚ÄďSouth Development Cooperation (SSDC) to the core of international development debate. The growing influence of emerging countries, such as the BRICS (Brazil, Russia, India, China and South Africa), as development cooperation providers requires a deeper understanding of how and to what extent these countries are promoting sustainable and inclusive development by cooperating with partners in the global South. To be able to answer these questions, the national dynamics need to be unpacked by mapping institutions, ideas, and interests informing decision-making processes, and shaping, not only policy priorities, but also the effectiveness of development cooperation. Brazil is in the spotlight and Brazilian cooperation, in all its different modalities (from technical, scientific and technological, educational, and humanitarian cooperation to contributions to international organisations, refugee support and protection, and peace operations), has risen to unprecedented levels in recent years. According to official data, Brazilian development cooperation increased from US160millionin2005tomorethanUS160 million in 2005 to more than US900 million in 2010. In that period, the country‚Äôs technical cooperation disbursements grew almost fourfold and its humanitarian cooperation expanded from less than half a million dollars in 2005 to US$161 million in 2010. However, interviews and the current budget freeze on the Brazilian Cooperation Agency‚Äôs (ABC) activities indicate that the upward trend may have changed in the last three years.UK Department for International Developmen

    HD 17156b: A Transiting Planet with a 21.2 Day Period and an Eccentric Orbit

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    We report the detection of transits by the 3.1 M_Jup companion to the V=8.17 G0V star HD 17156. The transit was observed by three independant observers on Sept. 9/10, 2007 (two in central Italy and one in the Canary Islands), who obtained detections at confidence levels of 3.0 sigma, 5.3 sigma, and 7.9 sigma, respectively. The observations were carried out under the auspices of the Transitsearch.org network, which organizes follow-up photometric transit searches of known planet-bearing stars during the time intervals when transits are expected to possibly occur. Analyses of the 7.9 sigma data set indicates a transit depth d=0.0062+/-0.0004, and a transit duration t=186+/-5 min. These values are consistent with the transit of a Jupiter-sized planet with an impact parameter b=a*cos(i)/R_star ~ 0.8. This planet occupies a unique regime among known transiting extrasolar planets, both as a result of its large orbital eccentricity (e=0.67) and long orbital period (P=21.2 d). The planet receives a 26-fold variation in insolation during the course of its orbit, which will make it a useful object for characterization of exoplanetary atmospheric dynamics.Comment: Accepted for publication to A&A, 4 pages, 2 figure

    Modelling Immunological Systems using PEPA: a preliminary report

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    We present preliminary work on modelling aspects of the immune system using process algebra. The problem addressed is how T-helper cell populations respond to co-infections with parasites making conflicting immunological demands. Our goal is to build PEPA models of alternative hypotheses around T-helper cell behaviour and to evaluate those with respect to experimental data

    Arago (1810): the first experimental result against the ether

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    95 years before Special Relativity was born, Arago attempted to detect the absolute motion of the Earth by measuring the deflection of starlight passing through a prism fixed to the Earth. The null result of this experiment gave rise to the Fresnel's hypothesis of an ether partly dragged by a moving substance. In the context of Einstein's Relativity, the sole frame which is privileged in Arago's experiment is the proper frame of the prism, and the null result only says that Snell's law is valid in that frame. We revisit the history of this premature first evidence against the ether theory and calculate the Fresnel's dragging coefficient by applying the Huygens' construction in the frame of the prism. We expose the dissimilar treatment received by the ray and the wave front as an unavoidable consequence of the classical notions of space and time.Comment: 16 pages. To appear in European Journal of Physic

    Strain-induced kinetics of intergrain defects as the mechanism of slow dynamics in the nonlinear resonant response of humid sandstone bars

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    A closed-form description is proposed to explain nonlinear and slow dynamics effects exhibited by sandstone bars in longitudinal resonance experiments. Along with the fast subsystem of longitudinal nonlinear displacements we examine the strain-dependent slow subsystem of broken intergrain and interlamina cohesive bonds. We show that even the simplest but phenomenologically correct modelling of their mutual feedback elucidates the main experimental findings typical for forced longitudinal oscillations of sandstone bars, namely, (i) hysteretic behavior of a resonance curve on both its up- and down-slopes, (ii) linear softening of resonant frequency with increase of driving level, and (iii) gradual recovery (increase) of resonant frequency at low dynamical strains after the sample was conditioned by high strains. In order to reproduce the highly nonlinear elastic features of sandstone grained structure a realistic non-perturbative form of strain potential energy was adopted. In our theory slow dynamics associated with the experimentally observed memory of peak strain history is attributed to strain-induced kinetic changes in concentration of ruptured inter-grain and inter-lamina cohesive bonds causing a net hysteretic effect on the elastic Young's modulus. Finally, we explain how enhancement of hysteretic phenomena originates from an increase in equilibrium concentration of ruptured cohesive bonds that are due to water saturation.Comment: 5 pages, 3 figure
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