531 research outputs found

    Gene expression profiling of microglia infected by a highly neurovirulent murine leukemia virus: implications for neuropathogenesis

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    BACKGROUND: Certain murine leukemia viruses (MLVs) are capable of inducing progressive spongiform motor neuron disease in susceptible mice upon infection of the central nervous system (CNS). The major CNS parenchymal target of these neurovirulent retroviruses (NVs) are the microglia, whose infection is largely coincident with neuropathological changes. Despite this close association, the role of microglial infection in disease induction is still unknown. In this paper, we investigate the interaction of the highly virulent MLV, FrCasE, with microglia ex vivo to evaluate whether infection induces specific changes that could account for neurodegeneration. Specifically, we compared microglia infected with FrCasE, a related non-neurovirulent virus (NN) F43/Fr57E, or mock-infected, both at a basic virological level, and at the level of cellular gene expression using quantitative real time RT-PCR (qRT-PCR) and Afffymetrix 430A mouse gene chips. RESULTS: Basic virological comparison of NN, NV, and mock-infected microglia in culture did not reveal differences in virus expression that provided insight into neuropathogenesis. Therefore, microglial analysis was extended to ER stress gene induction based on previous experiments demonstrating ER stress induction in NV-infected mouse brains and cultured fibroblasts. Analysis of message levels for the ER stress genes BiP (grp78), CHOP (Gadd153), calreticulin, and grp58 in cultured microglia, and BiP and CHOP in microglia enriched fractions from infected mouse brains, indicated that FrCasE infection did not induce these ER stress genes either in vitro or in vivo. To broadly identify physiological changes resulting from NV infection of microglia in vitro, we undertook a gene array screen of more than 14,000 well-characterized murine genes and expressed sequence tags (ESTs). This analysis revealed only a small set of gene expression changes between infected and uninfected cells (<18). Remarkably, gene array comparison of NN- and NV-infected microglia revealed only 3 apparent gene expression differences. Validation experiments for these genes by Taqman real-time RT-PCR indicated that only single Ig IL-1 receptor related protein (SIGIRR) transcript was consistently altered in culture; however, SIGIRR changes were not observed in enriched microglial fractions from infected brains. CONCLUSION: The results from this study indicate that infection of microglia by the highly neurovirulent virus, FrCasE, does not induce overt physiological changes in this cell type when assessed ex vivo. In particular, NV does not induce microglial ER stress and thus, FrCasE-associated CNS ER stress likely results from NV interactions with another cell type or from neurodegeneration directly. The lack of NV-induced microglial gene expression changes suggests that FrCasE either affects properties unique to microglia in situ, alters the expression of microglial genes not represented in this survey, or affects microglial cellular processes at a post-transcriptional level. Alternatively, NV-infected microglia may simply serve as an unaffected conduit for persistent dissemination of virus to other neural cells where they produce acute neuropathogenic effects

    A review of transformative strategies for climate mitigation by grasslands

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    Grasslands can significantly contribute to climate mitigation. However, recent trends indicate that human activities have switched their net cooling effect to a warming effect due to management intensification and land conversion. This indicates an urgent need for strategies directed to mitigate climate warming while enhancing productivity and efficiency in the use of land and natural (nutrients, water) resources. Here, we examine the potential of four innovative strategies to slow climate change including: 1) Adaptive multi-paddock grazing that consists of mimicking how ancestral herds roamed the Earth; 2) Agrivoltaics that consists of simultaneously producing food and energy from solar panels on the same land area; 3) Agroforestry with a reverse phenology tree species, Faidherbia (Acacia) albida, that has the unique trait of being photosynthetically active when intercropped herbaceous plants are dormant; and, 4) Enhanced Weathering, a negative emission technology that removes atmospheric CO2 from the atmosphere. Further, we speculate about potential unknown consequences of these different management strategies and identify gaps in knowledge. We find that all these strategies could promote at least some of the following benefits of grasslands: CO2 sequestration, non-CO2 GHG mitigation, productivity, resilience to climate change, and an efficient use of natural resources. However, there are obstacles to be overcome. Mechanistic assessment of the ecological, environmental, and socio-economic consequences of adopting these strategies at large scale are urgently needed to fully assess the potential of grasslands to provide food, energy and environmental security

    Monte Carlo Transmission Line Modeling of Multilayer Optical Coatings for Performance Sensitivity of a Dichroic Filter for the ARIEL Space Telescope

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    Dichroic beamsplitters, or dichroics, are filters that rely on the optical interference that occurs within thin layers to ensure the transmission and reflection of selective wavelengths of an incident beam of light. These optical components consist of a substrate coated on one or both surfaces with multiple layers of thin films, the spectral design and construction of which determine the isolation of particular wavebands. Discrepancies between the measured and expected spectral performance of optical elements with such coatings can largely be attributed to depositions errors and uncertainties in the refractive indices of the materials. Our model uses two-dimensional transmission line modeling to evaluate the transmittance of light through multilayer coatings deposited on a substrate material for given materials, angle of incidence and polarisation. This model allows us to perform Monte Carlo simulations to obtain statistical information about the tolerance of the coating performance to systematic and random uncertainties from the manufacturing process, as well as from environmental changes in space. With the aid of accurate manufacturing recipes and uncertainty amplitudes from commercial manufacturers, this tool can predict variations in the optical performance that result from the propagation of each of these uncertainties for various hypothetical scenarios. One particular application of this study are the dichroics of the ARIEL space telescope. We compare the predicted optical performance with transmission measurements at cryogenic temperatures for one of the ARIEL dichroics, which show the specification compliance of this prototype after many thermal cycles

    Activation of Cytochrome C Peroxidase Function Through Coordinated Foldon Loop Dynamics upon Interaction with Anionic Lipids

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    Cardiolipin (CL) is a mitochondrial anionic lipid that plays important roles in the regulation and signaling of mitochondrial apoptosis. CL peroxidation catalyzed by the assembly of CL-cytochrome c (cyt c) complexes at the inner mitochondrial membrane is a critical checkpoint. The structural changes in the protein, associated with peroxidase activation by CL and different anionic lipids, are not known at a molecular level. To better understand these peripheral protein-lipid interactions, we compare how phosphatidylglycerol (PG) and CL lipids trigger cyt c peroxidase activation, and correlate functional differences to structural and motional changes in membrane-associated cyt c. Structural and motional studies of the bound protein are enabled by magic angle spinning solid state NMR spectroscopy, while lipid peroxidase activity is assayed by mass spectrometry. PG binding results in a surface-bound state that preserves a nativelike fold, which nonetheless allows for significant peroxidase activity, though at a lower level than binding its native substrate CL. Lipid-specific differences in peroxidase activation are found to correlate to corresponding differences in lipid-induced protein mobility, affecting specific protein segments. The dynamics of omega loops C and D are upregulated by CL binding, in a way that is remarkably controlled by the protein:lipid stoichiometry. In contrast to complete chemical denaturation, membrane-induced protein destabilization reflects a destabilization of select cyt c foldons, while the energetically most stable helices are preserved. Our studies illuminate the interplay of protein and lipid dynamics in the creation of lipid peroxidase-active proteolipid complexes implicated in early stages of mitochondrial apoptosis

    Surface-Binding to Cardiolipin Nanodomains Triggers Cytochrome c Pro-apoptotic Peroxidase Activity via Localized Dynamics

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    The peroxidation of cardiolipins by reactive oxygen species, which is regulated and enhanced by cytochrome c (cyt c), is a critical signaling event in mitochondrial apoptosis. We probe the molecular underpinnings of this mitochondrial death signal through structural and functional studies of horse heart cyt c binding to mixed-lipid membranes containing cardiolipin with mono- and polyunsaturated acyl chains. Lipidomics reveal the selective oxidation of polyunsaturated fatty acid (PUFA) cardiolipin (CL), while multidimensional solid-state NMR probes the structure and dynamics of the membrane and the peripherally bound protein. The hydrophilic milieu at the membrane interface stabilizes a native-like fold, but also leads to localized flexibility at the membrane-interacting protein face. PUFA CL acts as both a preferred substrate and a dynamic regulator by affecting the dynamics of the cyt c N70-I85 Ω loop, which covers the heme cavity

    Weak Interaction Matrix Elements and (p,n) Cross Sections

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    This research was sponsored by the National Science Foundation Grant NSF PHY-931478

    Gamow-Teller Strength Distribution for 37-Cl(p,n)37-Ar

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    This research was sponsored by the National Science Foundation Grant NSF PHY-931478

    Application of Focal Conflict Theory to Psychoeducational Groups: Implications for Process, Content, and Leadership

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    Group psychoeducation is a common group type used for a range of purposes. The literature presents balancing content and process as a challenge for psychoeducational group leaders. While the significance of group psychoeducation is supported, practitioners are given little direction for addressing process in these groups. Focal Conflict Theory (FCT) is a model for conceptualizing and intervening in group process that has been applied to therapy and work groups. This article presents the challenges of psychoeducational groups, describes FCT, and discusses its application to psychoeducational groups using case examples. Implications for leaders of psychoeducation groups are discussed
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