359 research outputs found

    Functional Selectivity Does Not Predict Antinociceptive/Locomotor Impairing Potencies of NOP Receptor Agonists

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    Nociceptin/orphanin FQ controls several functions, including pain transmission, via stimulation of the N/OFQ peptide (NOP) receptor. Here we tested the hypothesis that NOP biased agonism may be instrumental for identifying innovative analgesics. In vitro experiments were performed with the dynamic mass redistribution label free assay and the NOP non-peptide agonists Ro 65-6570, AT-403 and MCOPPB. In vivo studies were performed in wild type and β-arrestin 2 knockout mice using the formalin, rotarod and locomotor activity tests. In vitro all compounds mimicked the effects of N/OFQ behaving as potent NOP full agonists. In vivo Ro 65-6570 demonstrated a slightly higher therapeutic index (antinociceptive vs. motor impairment effects) in knockout mice. However, all NOP agonists displayed very similar therapeutic index in normal mice despite significant differences in G protein biased agonism. In conclusion the different ability of inducing G protein vs. β-arrestin 2 recruitment of a NOP agonist cannot be applied to predict its antinociceptive vs. motor impairment properties

    Spectro-microscopic measurements of carbonaceous aerosol aging in Central California

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    Carbonaceous aerosols are responsible for large uncertainties in climate models, degraded visibility, and adverse health effects. The Carbonaceous Aerosols and Radiative Effects Study (CARES) was designed to study carbonaceous aerosols in the natural environment of the Central Valley, California, and learn more about their atmospheric formation and aging. This paper presents results from spectro-microscopic measurements of carbonaceous particles collected during CARES at the time of a pollution accumulation event (27–29 June 2010), when in situ measurements indicated an increase in the organic carbon content of aerosols as the Sacramento urban plume aged. Computer-controlled scanning electron microscopy coupled with an energy dispersive X-ray detector (CCSEM/EDX) and scanning transmission X-ray microscopy coupled with near-edge X-ray absorption spectroscopy (STXM/NEXAFS) were used to probe the chemical composition and morphology of individual particles. It was found that the mass of organic carbon on individual particles increased through condensation of secondary organic aerosol. STXM/NEXAFS indicated that the number fraction of homogenous organic particles lacking inorganic inclusions (greater than ~50 nm equivalent circular diameter) increased with plume age, as did the organic mass per particle. Comparison of the CARES spectro-microscopic dataset with a similar dataset obtained in Mexico City during the MILAGRO campaign showed that fresh particles in Mexico City contained three times as much carbon as those sampled during CARES. The number fraction of soot particles at the Mexico City urban site (ranging from 16.6 to 47.3%) was larger than at the CARES urban site (13.4–15.7%), and the most aged samples from CARES contained fewer carbon–carbon double bonds. Differences between carbonaceous particles in Mexico City and California result from different sources, photochemical conditions, gas phase reactants, and secondary organic aerosol precursors. The detailed results provided by these spectro-microscopic measurements will allow for a comprehensive evaluation of aerosol process models used in climate research

    Long-range pollution transport during the MILAGRO-2006 campaign: a case study of a major Mexico City outflow event using free-floating altitude-controlled balloons

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    One of the major objectives of the Megacities Initiative: Local And Global Research Observations (MILAGRO-2006) campaign was to investigate the long-range transport of polluted Mexico City Metropolitan Area (MCMA) outflow and determine its downwind impacts on air quality and climate. Six research aircraft, including the National Center for Atmospheric Research (NCAR) C-130, made extensive chemical, aerosol, and radiation measurements above MCMA and more than 1000 km downwind in order to characterize the evolution of the outflow as it aged and dispersed over the Mesa Alta, Sierra Madre Oriental, Coastal Plain, and Gulf of Mexico. As part of this effort, free-floating Controlled-Meteorological (CMET) balloons, commanded to change altitude via satellite, made repeated profile measurements of winds and state variables within the advecting outflow. In this paper, we present an analysis of the data from two CMET balloons that were launched near Mexico City on the afternoon of 18 March 2006 and floated downwind with the MCMA pollution for nearly 30 h. The repeating profile measurements show the evolving structure of the outflow in considerable detail: its stability and stratification, interaction with other air masses, mixing episodes, and dispersion into the regional background. Air parcel trajectories, computed directly from the balloon wind profiles, show three transport pathways on 18–19 March: (a) high-altitude advection of the top of the MCMA mixed layer, (b) mid-level outflow over the Sierra Madre Oriental followed by decoupling and isolated transport over the Gulf of Mexico, and (c) low-level outflow with entrainment into a cleaner northwesterly jet above the Coastal Plain. The C-130 aircraft intercepted the balloon-based trajectories three times on 19 March, once along each of these pathways; in all three cases, peaks in urban tracer concentrations and LIDAR backscatter are consistent with MCMA pollution. In comparison with the transport models used in the campaign, the balloon-based trajectories appear to shear the outflow far more uniformly and decouple it from the surface, thus forming a thin but expansive polluted layer over the Gulf of Mexico that is well aligned with the aircraft observations. These results provide critical context for the extensive aircraft measurements made during the 18–19 March MCMA outflow event and may have broader implications for modelling and understanding long-range transport

    4′-Amino-2,2′′-dioxo-2,2′′,3,3′′-tetra­hydro-1H-indole-3-spiro-1′-cyclo­pent-3′-ene-2′-spiro-3′′-1H-indole-3′,5′,5′-tricarbonitrile dihydrate

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    In the title compound, C22H12N6O2·2H2O, the cyclo­pentene ring adopts an envelope conformation, with the spiro C atom bonded to the dicyano-substituted C atom deviating by 0.437 (2) Å from the plane of the remaining four atoms in the ring. The puckering and smallest displacement asymmetry parameters for the ring are q 2 = 0.275 (2) Å, ϕ = 212.4 (4)° and Δs(C2) = 2.7 (2). The dihedral angle between the two indole groups is 60.1 (1)°. The structure contains inter­molecular N—H⋯O hydrogen bonds involving the indole groups and O—H⋯O and O—H⋯N hydrogen bonds involving the water mol­ecules

    Black carbon over Mexico: the effect of atmospheric transport on mixing state, mass absorption cross-section, and BC/CO ratios

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    A single particle soot photometer (SP2) was operated on the NCAR C-130 during the MIRAGE campaign (part of MILAGRO), sampling black carbon (BC) over Mexico. The highest BC concentrations were measured over Mexico City (sometimes as much as 2 μg/m<sup>3</sup>) and over hill-fires to the south of the city. The age of plumes outside of Mexico City was determined using a combination of HYSPLIT trajectories, WRF-FLEXPART modeling and CMET balloon tracks. As expected, older, diluted air masses had lower BC concentrations. A comparison of carbon monoxide (CO) and BC suggests a CO background of around 65 ppbv, and a background-corrected BC/CO<sub>net</sub> ratio of 2.89±0.89 (ng/m<sup>3</sup>-STP)/ppbv (average ± standard deviation). This ratio is similar for fresh emissions over Mexico City, as well as for aged airmasses. Comparison of light absorption measured with a particle soot absorption photometer (PSAP) and the SP2 BC suggests a BC mass-normalized absorption cross-section (MAC) of 10.9±2.1 m<sup>2</sup>/g at 660 nm (or 13.1 m<sup>2</sup>/g @ 550 nm, assuming MAC is inversely dependent on wavelength). This appears independent of aging and similar to the expected absorption cross-section for aged BC, but values, particularly in fresh emissions, could be biased high due to instrument artifacts. SP2-derived BC coating indicators show a prominent thinly-coated BC mode over the Mexico City Metropolitan Area (MCMA), while older air masses show both thinly-coated and thickly-coated BC. Some 2-day-old plumes do not show a prominent thickly-coated BC mode, possibly due to preferential wet scavenging of the likely-hydrophilic thickly-coated BC

    NOP Receptor Antagonists Decrease Alcohol Drinking in the Dark in C57BL/6J Mice

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    Background: The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse. Methods: Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge-like alcohol consumption, as measured by the “drinking in the dark” (DID) model in C57BL/6J mice. Results: We found that 2 potent and selective NOP agonists AT-202 (0, 0.3, 1, 3 mg/kg) and AT-312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT-202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol-containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB-612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB-612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB-612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB-612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2-bottle choice DID model that can assess moderate alcohol intake. Conclusions: The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking
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