1,671 research outputs found

    Military Law. 2nd ed.

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    Book Reviews

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    Book reviews by Roger Paul Peters, David Bidney, Lester M. Ponder, Edward J. Murphy, Thomas M. Clusserath, and Thomas L. Shaffer

    HIV-1 Coreceptor Activity of CCR5 and Its Inhibition by Chemokines: Independence from G Protein Signaling and Importance of Coreceptor Downmodulation

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    AbstractHIV-1 infection requires the presence of specific chemokine receptors on CD4+ target cells to enable the fusion reactions involved in virus entry. CCR5 is a major fusion coreceptor for macrophage-tropic HIV-1 isolates. HIV-1 entry and fusion are mediated by the viral envelope glycoprotein (Env) and are inhibited by CCR5 ligands, but the mechanisms are unknown. Here, we test the role of G protein signaling and CCR5 surface downmodulation by two separate approaches: direct inactivation of CCR5 signaling by mutagenesis and inactivation of Gi-type G proteins with pertussis toxin. A CCR5 mutant lacking the last 45 amino acids of the cytoplasmic C-terminus (CCR5306) was created that was expressed on transfected cells at levels comparable to cells expressing CCR5 and displayed normal chemokine binding affinity. CCR5 ligands induced calcium flux and receptor downmodulation in cells expressing CCR5, but not in cells expressing CCR5306. Nevertheless, CCR5 or CCR5306, when coexpressed with CD4, supported comparable HIV-1 Env-mediated cell fusion. Consistent with this, treatment of CCR5-expressing cells with pertussis toxin completely blocked ligand-induced transient calcium flux, but did not affect Env-mediated cell fusion or HIV-1 infection. Also, pertussis toxin did not block chemokine inhibition of Env-mediated cell fusion or HIV-1 infection. However, chemokines inhibited Env-mediated cell fusion less efficiently for CCR5306than for CCR5. We conclude that the C-terminal domain of CCR5 is critical for G protein signaling and receptor downmodulation from the surface, but that neither function is required for CCR5 fusion coreceptor activity. The contrasting phenotypes of CCR5 and CCR5306suggest that coreceptor downmodulation and direct blockage of Env interaction sites both contribute to chemokine inhibition of HIV-1 infection

    Biases in Long-term NO2 Averages Inferred from Satellite Observations Due to Cloud Selection Criteria

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    Retrievals of atmospheric trace gas column densities from space are compromised by the presence of clouds, requiring most studies to exclude observations with significant cloud fractions in the instrument's field of view. Using NO2 observations at three ground stations representing urban, suburban, and rural environments, and tropospheric vertical column densities measured by the Ozone Monitoring Instrument (OMI) over each site, we show that the observations from space represent monthly averaged ground-level pollutant conditions well (R=0.86) under relatively cloud-free conditions. However, by analyzing the ground-level data and applying the OMI cloud fraction as a filter, we show there is a significant bias in long-term averaged NO2 as a result of removing the data during cloudy conditions. For the ground-based sites considered in this study, excluding observations on days when OMI-derived cloud fractions were greater than 0.2 causes 12:00-14:00 mean summer mixing ratios to be underestimated by 12%+/-6%, 20%+/-7%, and 40%+/-10% on average (+/-1 standard deviation) at the urban, suburban, and rural sites respectively. This bias was investigated in particular at the rural site, a region where pollutant transport is the main source of NO2, and where longterm observations of NOy were also available. Evidence of changing photochemical conditions and a correlation between clear skies and the transport of cleaner air masses play key roles in explaining the bias. The magnitude of a bias is expected to vary from site to site depending on meteorology and proximity to NOx sources, and decreases when longer averaging times of ground station data (e.g. 24-h) are used for the comparison

    The Diversity of High- and Intermediate-Velocity Clouds: Complex C versus IV Arch

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    We present Far Ultraviolet Spectroscopic Explorer (FUSE) and Space Telescope Imaging Spectrograph (STIS) observations of interstellar ultraviolet absorption lines in the Galactic high-velocity cloud Complex C and the Intermediate Velocity Arch (IV Arch) in direction of the quasar PG 1259+593 (l=120,b=+58 deg). Absorption lines from CII, NI, NII, OI, AlII, SiII, PII, SII, ArI, FeII, and FeIII are used to study the atomic abundances in these two halo clouds at V_LSR=-130 km/s (Complex C) and V_LSR=-55 km/s (IV Arch). The OI/HI ratio provides the best measure of the overall metallicity in the diffuse interstellar medium, because ionization effects do not alter the ratio, and oxygen is at most only lightly depleted from the gas into dust grains. For Complex C, we find an oxygen abundance of 0.093 (+0.125, -0.047) solar, consistent with the idea that Complex C represents the infall of low metallicity gas onto the Milky Way. In contrast, the oxygen abundance in the IV Arch is 0.98 (+1.21,-0.46) solar, which indicates a Galactic origin. We report the detection of an intermediate- velocity absorption component at +60 km/s that is not seen in HI 21cm emission. The clouds along the PG 1259+593 sight line have a variety of properties, proving that multiple processes are responsible for the creation and circulation of intermediate- and high-velocity gas in the Milky Way halo.Comment: 12 pages, 3 tables, 3 figures; accepted for publication in Ap

    The color of a Dalmatian's spots: Linkage evidence to support the TYRP1 gene

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    BACKGROUND: The distinctive coat pattern of a Dalmatian is the result of the interaction of several loci. While the encoded function of these genes is not fully understood, it is known the Piebald, Ticking, and Flecking loci interact to produce the Dalmatian's classic pigmented spots on a white background. The color of the pigmented spots in purebred Dalmatians can either be black or liver, but the locus responsible for color determination is unknown. Studies have been conducted to determine the underlying genes involved in coat color determination in the dog, e.g., in the Labrador Retriever, but none to date have addressed black versus liver in the Dalmatian. RESULTS: A genome scan was conducted in a multi-generational kindred of Dalmatians segregating black and liver spot color. Linkage analysis was performed using a total of 113 polymorphic microsatellite markers from the kindred. Linkage was found between spot color and a single microsatellite marker, FH2319 (LOD = 12.5) on chromosome 11. CONCLUSION: The TYRP1 (Brown) locus is located at position 50.1 Mb on chromosome 11, which is approximately 0.4 Mb from marker FH2319. Given the recent characterization of TYRP1 genetic variations in the dog and the linkage evidence reported here, TYRP1 is likely responsible for the spot color variation of black versus liver seen in the Dalmatian

    Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death.

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    Glutamate is the dominant excitatory neurotransmitter in the brain, but under conditions of metabolic stress it can accumulate to excitotoxic levels. Although pharmacologic modulation of excitatory amino acid receptors is well studied, minimal consideration has been given to targeting mitochondrial glutamate metabolism to control neurotransmitter levels. Here we demonstrate that chemical inhibition of the mitochondrial pyruvate carrier (MPC) protects primary cortical neurons from excitotoxic death. Reductions in mitochondrial pyruvate uptake do not compromise cellular energy metabolism, suggesting neuronal metabolic flexibility. Rather, MPC inhibition rewires mitochondrial substrate metabolism to preferentially increase reliance on glutamate to fuel energetics and anaplerosis. Mobilizing the neuronal glutamate pool for oxidation decreases the quantity of glutamate released upon depolarization and, in turn, limits the positive-feedback cascade of excitotoxic neuronal injury. The finding links mitochondrial pyruvate metabolism to glutamatergic neurotransmission and establishes the MPC as a therapeutic target to treat neurodegenerative diseases characterized by excitotoxicity
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