738 research outputs found

    PDE8 controls CD4(+) T cell motility through the PDE8A-Raf-1 kinase signaling complex

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    The levels of cAMP are regulated by phosphodiesterase enzymes (PDEs), which are targets for the treatment of inflammatory disorders. We have previously shown that PDE8 regulates T cell motility. Here, for the first time, we report that PDE8A exerts part of its control of T cell function through the V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase signaling pathway. To examine T cell motility under physiologic conditions, we analyzed T cell interactions with endothelial cells and ligands in flow assays. The highly PDE8-selective enzymatic inhibitor PF-04957325 suppresses adhesion of in vivo myelin oligodendrocyte glycoprotein (MOG) activated inflammatory CD4(+) T effector (Teff) cells to brain endothelial cells under shear stress. Recently, PDE8A was shown to associate with Raf-1 creating a compartment of low cAMP levels around Raf-1 thereby protecting it from protein kinase A (PKA) mediated inhibitory phosphorylation. To test the function of this complex in Teff cells, we used a cell permeable peptide that selectively disrupts the PDE8A-Raf-1 interaction. The disruptor peptide inhibits the Teff-endothelial cell interaction more potently than the enzymatic inhibitor. Furthermore, the LFA-1/ICAM-1 interaction was identified as a target of disruptor peptide mediated reduction of adhesion, spreading and locomotion of Teff cells under flow. Mechanistically, we observed that disruption of the PDE8A-Raf-1 complex profoundly alters Raf-1 signaling in Teff cells. Collectively, our studies demonstrate that PDE8A inhibition by enzymatic inhibitors or PDE8A-Raf-1 kinase complex disruptors decreases Teff cell adhesion and migration under flow, and represents a novel approach to target T cells in inflammation

    Beam test results for the FiberGLAST instrument

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    The FiberGLAST scintillating fiber telescope is a large-area instrument concept for NASA\u27s GLAST program. The detector is designed for high-energy gamma-ray astronomy, and uses plastic scintillating fibers to combine a photon pair tracking telescope and a calorimeter into a single instrument. A small prototype detector has been tested with high energy photons at the Thomas Jefferson National Accelerator Facility. We report on the result of this beam test, including scintillating fiber performance, photon track reconstruction, angular resolution, and detector efficiency

    Estimation of GRB detection by FiberGLAST

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    FiberGLAST is one of several instrument concepts being developed for possible inclusion as the primary Gamma-ray Large Area Space Telescope (GLAST) instrument. The predicted FiberGLAST effective area is more than 12,000 cm2 for energies between 30 MeV and 300 GeV, with a field of view that is essentially flat from 0°–80°. The detector will achieve a sensitivity more than 10 times that of EGRET. We present results of simulations that illustrate the sensitivity of FiberGLAST for the detection of gamma-ray bursts

    Development and testing of a fiber/multianode photomultiplier system for use on FiberGLAST

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    A scintillating fiber detector is currently being studied for the NASA Gamma-Ray Large Area Space Telescope (GLAST) mission. This detector utilizes modules composed of a thin converter sheet followed by an x, y plane of scintillating fibers to examine the shower of particles created by high energy gamma-rays interacting in the converter material. The detector is composed of a tracker with 90 such modular planes and a calorimeter with 36 planes. The two major component of this detector are the scintillating fibers and their associated photodetectors. Here we present current status of development and test result of both of these. The Hamamatsu R5900-00-M64 multianode photomultiplier tube (MAPMT) is the baseline readout device. A characterization of this device has been performed including noise, cross- talk, gain variation, vibration, and thermal/vacuum test. A prototype fiber/MAPMT system has been tested at the Center for Advanced Microstructures and Devices at Louisiana State University with a photon beam and preliminary results are presented

    'Tough'-constructions and their derivation

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    This article addresses the syntax of the notorious 'tough' (-movement) construction (TC) in English. TCs exhibit a range of apparently contradictory empirical properties suggesting that their derivation involves the application of both A-movement and A'-movement operations. Given that within previous Principles and Parameters models TCs have remained “unexplained and in principle unexplainable” (Holmberg 2000: 839) due to incompatibility with constraints on theta-assignment, locality, and Case, this article argues that the phase-based implementation of the Minimalist program (Chomsky 2000, 2001, 2004) permits a reanalysis of null wh-operators capable of circumventing the previous theoretical difficulties. Essentially, 'tough'-movement consists of A-moving a constituent out of a “complex” null operator which has already undergone A'-movement, a “smuggling” construction in the terms of Collins (2005a,b

    The Democratic Biopolitics of PrEP

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    PrEP (Pre-Exposure Prophylaxis) is a relatively new drug-based HIV prevention technique and an important means to lower the HIV risk of gay men who are especially vulnerable to HIV. From the perspective of biopolitics, PrEP inscribes itself in a larger trend of medicalization and the rise of pharmapower. This article reconstructs and evaluates contemporary literature on biopolitical theory as it applies to PrEP, by bringing it in a dialogue with a mapping of the political debate on PrEP. As PrEP changes sexual norms and subjectification, for example condom use and its meaning for gay subjectivity, it is highly contested. The article shows that the debate on PrEP can be best described with the concepts ‘sexual-somatic ethics’ and ‘democratic biopolitics’, which I develop based on the biopolitical approach of Nikolas Rose and Paul Rabinow. In contrast, interpretations of PrEP which are following governmentality studies or Italian Theory amount to either farfetched or trivial positions on PrEP, when seen in light of the political debate. Furthermore, the article is a contribution to the scholarship on gay subjectivity, highlighting how homophobia and homonormativity haunts gay sex even in liberal environments, and how PrEP can serve as an entry point for the destigmatization of gay sexuality and transformation of gay subjectivity. ‘Biopolitical democratization’ entails making explicit how medical technology and health care relates to sexual subjectification and ethics, to strengthen the voice of (potential) PrEP users in health politics, and to renegotiate the profit and power of Big Pharma
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