190 research outputs found

    Amphetamine Modulates Excitatory Neurotransmission through Endocytosis of the Glutamate Transporter EAAT3 in Dopamine Neurons

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    SummaryAmphetamines modify the brain and alter behavior through mechanisms generally attributed to their ability to regulate extracellular dopamine concentrations. However, the actions of amphetamine are also linked to adaptations in glutamatergic signaling. We report here that when amphetamine enters dopamine neurons through the dopamine transporter, it stimulates endocytosis of an excitatory amino acid transporter, EAAT3, in dopamine neurons. Consistent with this decrease in surface EAAT3, amphetamine potentiates excitatory synaptic responses in dopamine neurons. We also show that the process of internalization is dynamin- and Rho-mediated and requires a unique sequence in the cytosolic C terminus of EAAT3. Introduction of a peptide based on this motif into dopamine neurons blocks the effects of amphetamine on EAAT3 internalization and its action on excitatory responses. These data indicate that the internalization of EAAT3 triggered by amphetamine increases glutamatergic signaling and thus contributes to the effects of amphetamine on neurotransmission

    Geodynamic Evolution of a Forearc Rift in the Southernmost Mariana Arc

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    The southernmost Mariana forearc stretched to accommodate opening of the Mariana Trough backarc basin in late Neogene time, erupting basalts now exposed in the SE Mariana Forearc Rift (SEMFR) 3.7 – 2.7 Ma ago. Today, SEMFR is a broad zone of extension that formed on hydrated, forearc lithosphere and overlies the shallow subducting slab (slab depth ≤ 30 – 50 km). It comprises NW-SE trending subparallel deeps, 3 - 16 km wide, that can be traced ≥ ~ 30 km from the trench almost to the backarc spreading center, the Malaguana-Gadao Ridge (MGR). While forearcs are usually underlain by serpentinized harzburgites too cold to melt, SEMFR crust is mostly composed of Pliocene, low-K basaltic to basaltic andesite lavas that are compositionally similar to arc lavas and backarc basin (BAB) lavas, and thus defines a forearc region that recently witnessed abundant igneous activity in the form of seafloor spreading. SEMFR igneous rocks have low Na8, Ti8, and Fe8, consistent with extensive melting, at ~ 23 ± 6.6 km depth and 1239 ± 40oC, by adiabatic decompression of depleted asthenospheric mantle metasomatized by slab-derived fluids. Stretching of pre-existing forearc lithosphere allowed BAB-like mantle to flow along SEMFR and melt, forming new oceanic crust. Melts interacted with preexisting forearc lithosphere during ascent. SEMFR is no longer magmatically active and post-magmatic tectonic activity dominates the rift

    The Community Climate System Model version 4

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    Author Posting. © American Meteorological Society, 2011. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Climate 24 (2011): 4973–4991, doi:10.1175/2011JCLI4083.1.The fourth version of the Community Climate System Model (CCSM4) was recently completed and released to the climate community. This paper describes developments to all CCSM components, and documents fully coupled preindustrial control runs compared to the previous version, CCSM3. Using the standard atmosphere and land resolution of 1° results in the sea surface temperature biases in the major upwelling regions being comparable to the 1.4°-resolution CCSM3. Two changes to the deep convection scheme in the atmosphere component result in CCSM4 producing El Niño–Southern Oscillation variability with a much more realistic frequency distribution than in CCSM3, although the amplitude is too large compared to observations. These changes also improve the Madden–Julian oscillation and the frequency distribution of tropical precipitation. A new overflow parameterization in the ocean component leads to an improved simulation of the Gulf Stream path and the North Atlantic Ocean meridional overturning circulation. Changes to the CCSM4 land component lead to a much improved annual cycle of water storage, especially in the tropics. The CCSM4 sea ice component uses much more realistic albedos than CCSM3, and for several reasons the Arctic sea ice concentration is improved in CCSM4. An ensemble of twentieth-century simulations produces a good match to the observed September Arctic sea ice extent from 1979 to 2005. The CCSM4 ensemble mean increase in globally averaged surface temperature between 1850 and 2005 is larger than the observed increase by about 0.4°C. This is consistent with the fact that CCSM4 does not include a representation of the indirect effects of aerosols, although other factors may come into play. The CCSM4 still has significant biases, such as the mean precipitation distribution in the tropical Pacific Ocean, too much low cloud in the Arctic, and the latitudinal distributions of shortwave and longwave cloud forcings.National Science Foundation, which sponsors NCAR and the CCSM Project. The project is also sponsored by the U.S. Department of Energy (DOE). Thanks are also due to the many other software engineers and scientists who worked on developing CCSM4, and to the Computational and Information Systems Laboratory at NCAR, which provided the computing resources through the Climate Simulation Laboratory. Hunke was supported within theClimate, Ocean and Sea Ice Modeling project at Los Alamos National Laboratory, which is funded by the Biological and Environmental Research division of the DOE Office of Science. The Los Alamos National Laboratory is operated by theDOENationalNuclear Security Administration under Contract DE-AC52-06NA25396. Raschwas supported by theDOEOffice of Science, Earth System Modeling Program, which is part of the DOE Climate Change Research Program. The Pacific Northwest National Laboratory is operated forDOEbyBattelle Memorial Institute under Contract DE-AC06-76RLO 1830. Worley was supported by the Climate Change Research Division of the Office of Biological and Environmental Research and by the Office ofAdvanced Scientific Computing Research, both in the DOE Office of Science, under Contract DE-AC05-00OR22725 with UT-Batelle, LLC

    PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis

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    The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)- dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a ''TGF-ß responsive gene signature'' in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis. © 2010 Wei et al

    Microvessel changes after post-ischemic benign and malignant hyperemia: experimental study in rats

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    <p>Abstract</p> <p>Background</p> <p>The present investigation was designed to elucidate the use of dynamic contrast enhanced perfusion MR imaging (DCE pMRI) in characterizing hyperemia, including microvessel changes, and to examine whether DCE pMRI can predict benign or malignant hyperemia.</p> <p>Methods</p> <p>Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) by intraluminal suture placement. All rats were randomized to 4 groups: MCAO for 0.5 hours followed by saline treatment (10 ml/kg; group 1); MCAO for 3 hours followed by treatment with saline (group 2) or urokinase (25000 IU/kg; group 3); and MCAO for 6 hours followed by urokinase treatment (group 4). Relative cerebral blood volume (rCBV) and relative maximum slope of increase of the signal intensity time curve (rMSI) were quantitatively analyzed from MRI. Microvessel diameter and blood-brain barrier disruption obtained by laser scanning confocal microscopy (LSCM) as well as transmission electron microscopy (TEM) were obtained for correlative study.</p> <p>Results</p> <p>Benign hyperemia was noticed only in group 1; malignant hyperemia was seen in group 3. Although the rCBV of malignant hyperemia was slightly higher than in benign hyperemia (<it>P </it>> 0.05), the rMSI, on the other hand, was significantly lower (<it>P </it>< 0.05). Fluoro-isothiocyanate dextran (FITC-dextran) extravasations, marked glial end-foot process swelling, and significant vasodilatation were seen in malignant hyperemia, while no or mild leakage of FITC-dextran and slight glial end-foot process swelling occurred in benign hyperemia.</p> <p>Conclusion</p> <p>Our findings indicate that DCE pMRI can characterize post-ischemic hyperemia and correlates well with microvascular damage.</p

    Meta-analysis of prophylactic corticosteroid use in post-ERCP pancreatitis

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    <p>Abstract</p> <p>Background</p> <p>Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography and benefit of pharmacological treatment is unclear. Although prophylactic use of corticosteroid for reduction of pancreatic injury after ERCP has been evaluated, discrepancy about beneficial effect of corticosteroid on pancreatic injury still exists. The aim of current study is to evaluate effectiveness and safety of corticosteroid in prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP).</p> <p>Methods</p> <p>We employed the method recommended by the Cochrane Collaboration to perform a meta-analysis of seven randomized controlled trials (RCTs) of corticosteroid in prevention of post-ERCP pancreatitis (PEP) around the world.</p> <p>Results</p> <p>Most of the seven RCTs were of high quality. When the RCTs were analyzed, odds ratios (OR) for corticosteroid were 1.13 [95% CI (0.89~1.44), p = 0.32] for PEP, 1.61 [95% CI (0.74~3.52), p = 0.23] for severe PEP, 0.92 [95% CI (0.57~1.48), p = 0.73] for post-ERCP hyperamylasemia respectively. The results indicated that there were no beneficial effects of corticosteroid on acute pancreatitis and hyperamylasemia. No evidence of publication bias was found.</p> <p>Conclusion</p> <p>Corticosteroids cannot prevent pancreatic injury after ERCP. Therefore, their use in the prophylaxis of PEP is not recommended.</p

    Aerosol forcing of the position of the intertropical convergence zone since AD1550

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    The position of the intertropical convergence zone is an important control on the distribution of low-latitude precipitation. Its position is largely controlled by hemisphere temperature contrasts1, 2. The release of aerosols by human activities may have resulted in a southward shift of the intertropical convergence zone since the early 1900s (refs 1, 3, 4, 5, 6) by muting the warming of the Northern Hemisphere relative to the Southern Hemisphere over this interval1, 7, 8, but this proposed shift remains equivocal. Here we reconstruct monthly rainfall over Belize for the past 456 years from variations in the carbon isotope composition of a well-dated, monthly resolved speleothem. We identify an unprecedented drying trend since ad 1850 that indicates a southward displacement of the intertropical convergence zone. This drying coincides with increasing aerosol emissions in the Northern Hemisphere and also marks a breakdown in the relationship between Northern Hemisphere temperatures and the position of the intertropical convergence zone observed earlier in the record. We also identify nine short-lived drying events since ad 1550 each following a large volcanic eruption in the Northern Hemisphere. We conclude that anthropogenic aerosol emissions have led to a reduction of rainfall in the northern tropics during the twentieth century, and suggest that geographic changes in aerosol emissions should be considered when assessing potential future rainfall shifts in the tropics

    Integrating Phosphorylation Network with Transcriptional Network Reveals Novel Functional Relationships

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    Phosphorylation and transcriptional regulation events are critical for cells to transmit and respond to signals. In spite of its importance, systems-level strategies that couple these two networks have yet to be presented. Here we introduce a novel approach that integrates the physical and functional aspects of phosphorylation network together with the transcription network in S.cerevisiae, and demonstrate that different network motifs are involved in these networks, which should be considered in interpreting and integrating large scale datasets. Based on this understanding, we introduce a HeRS score (hetero-regulatory similarity score) to systematically characterize the functional relevance of kinase/phosphatase involvement with transcription factor, and present an algorithm that predicts hetero-regulatory modules. When extended to signaling network, this approach confirmed the structure and cross talk of MAPK pathways, inferred a novel functional transcription factor Sok2 in high osmolarity glycerol pathway, and explained the mechanism of reduced mating efficiency upon Fus3 deletion. This strategy is applicable to other organisms as large-scale datasets become available, providing a means to identify the functional relationships between kinases/phosphatases and transcription factors
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