436 research outputs found

    HIC-5: A Mobile Molecular Scaffold Regulating the Anchorage Dependence of Cell Growth

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    HIC-5 is a multidomain LIM protein homologous to paxillin that serves as a molecular scaffold at focal adhesions and in the nucleus. It forms mobile molecular units with LIM-only proteins, PINCH, and CRP2 and translocates in and out of the nucleus via a nuclear export signal (NES). Of note, NES of HIC-5 is distinctive in its sensitivity to the cellular redox state. Recently, the mobile units of HIC-5 have been suggested to be involved in the regulation of the anchorage dependence of cell growth. On loss of adhesion, an increase in reactive oxygen species in the cells modifies NES and stops shuttling, which leads to cell-cycle control. More specifically, the system circumvents nuclear localization of cyclin D1 and transactivates p21Cip1 in detached cells, thereby avoiding anchorage-independent cell growth. Thus, the HIC-5-LIM only protein complex has emerged as a fail-safe system for regulating the anchorage dependence of cell growth

    Slow-roll corrections in multi-field inflation : a separate universes approach

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    In view of cosmological parameters being measured to ever higher precision, theoretical predictions must also be computed to an equally high level of precision. In this work we investigate the impact on such predictions of relaxing some of the simplifying assumptions often used in these computations. In particular, we investigate the importance of slow-roll corrections in the computation of multi-field inflation observables, such as the amplitude of the scalar spectrum P-zeta, its spectral tilt n(s), the tensor-to-scalar ratio r and the non-Gaussianity parameter f(NL). To this end we use the separate universes approach and delta N formalism, which allows us to consider slow-roll corrections to the non-Gaussianity of the primordial curvature perturbation as well as corrections to its two-point statistics. In the context of the delta N expansion, we divide slow-roll corrections into two categories: those associated with calculating the correlation functions of the field perturbations on the initial flat hypersurface and those associated with determining the derivatives of the e-folding number with respect to the field values on the initial flat hypersurface. Using the results of Nakamura & Stewart '96, corrections of the first kind can be written in a compact form. Corrections of the second kind arise from using different levels of slow-roll approximation in solving for the super-horizon evolution, which in turn corresponds to using different levels of slow-roll approximation in the background equations of motion. We consider four different levels of approximation and apply the results to a few example models. The various approximations are also compared to exact numerical solutions.Peer reviewe

    Implantable pneumatically actuated microsystem for renal pressure-mediated transfection in mice.

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    In vivo transfection is an important technique used in biological research and drug therapy development. Previously, we developed a renal pressure-mediated transfection method performed by pressing a kidney after an intravenous injection of naked nucleic acids. Although this is a useful method because of its safety and wide range of applications, an innovative approach for performing this method without repeatedly cutting open the abdomen is required. In this study, we developed an implantable microsystem fabricated by Micro-Electro-Mechanical Systems (MEMS) technologies for renal pressure-mediated transfection. The system consists of a polydimethylsiloxane pneumatic balloon actuator (PBA) used as an actuator to press the target kidney. The PBA of the implanted microsystem can be actuated without opening the abdomen by applying air pressure from outside the body to the pressure-supplying port via a needle. We successfully performed renal pressure-mediated transfection using the newly developed system when the implanted system was activated at 60kPa for 10s. This is the first report of an implantable MEMS-based microsystem that demonstrates in vivo transfection to a kidney using naked plasmid DNA

    The distribution of parenchyma, follicles, and lymphocyte subsets in thymus of patients with myasthenia gravis, with special reference to remission after thymectomy

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    ObjectiveWe sought to examine the distribution of parenchyma, follicles, and lymphocyte subsets in the thymus of patients with myasthenia gravis and to identify determinants of remission after thymectomy.MethodsSixty patients with myasthenia gravis who underwent thymectomy were examined. The thymus was divided into upper, middle, and lower parts. The upper part was defined as the superior horn, the lower part as the inferior horn, and the middle part as tissue located between the 2 horns. The percentage of parenchyma was measured morphometrically. The degree of follicular hyperplasia was classified into 5 grades. The densities of CD3+, CD4+, and CD8+ lymphocytes were classified into 5 grades. The remission of myasthenia gravis after thymectomy was examined with those variables in each part of the thymus.ResultsThe middle part had the highest percentage of parenchyma, the highest grade of follicular hyperplasia, and the highest density of CD3+, CD4+, and CD8+ lymphocytes among the 3 parts (P < .001-.05). The grades of follicular hyperplasia in the middle and lower parts were significantly higher in patients with improvement of myasthenia gravis than in those without (P < .05). The densities of CD3+, CD4+, and CD8+ lymphocytes in the cortex of the middle part were significantly higher in patients with improvement than in those without improvement (P < .01-.05).ConclusionsThe thymus has a heterogeneous distribution of parenchyma, follicles, and lymphocyte subsets. The middle part had the largest parenchyma, the highest grade of follicular hyperplasia, and the highest densities of CD3+, CD4+, and CD8+ lymphocytes among the 3 parts of the thymus. The grade of follicular hyperplasia and the density of these lymphocyte subsets are predictive of improvement in myasthenia gravis after thymectomy

    Critical Point Mutations for Hepatitis C Virus NS3 Proteinase

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    AbstractThe hepatitis C virus NS3 proteinase plays an essential role in processing of HCV nonstructural precursor polyprotein. To detect its processing activity, we developed a simpletrans-cleavage assay. Two recombinant plasmids expressing the NS3 proteinase region and a chimeric substrate polyprotein containing the NS5A/5B cleavage site between maltose binding protein and protein A were co-introduced intoEscherichia colicells. The proteinase processed the substrate at the single site during their polyprotein expression. Deletion analysis indicated that the functionally minimal domain of the NS3 proteinase was composed of 146 amino acids, 1059 to 1204. We isolated several cDNA clones encoding the functional domain of the NS3 proteinase from the sera of patients chronically infected with HCV and determined their proteinase activity by thistrans-cleavage assay. Both active and inactive clones existed in the same patients. Comparative sequence analyses of these clones suggested that certain point mutations seemed to be related to the loss of proteolytic activity. This was confirmed by back mutation experiments. Among the critical mutations, Pro-1168 to Thr and Arg-1135 to Gly were intriguing. These amino acids, which are situated near the oxyanion hole, seem to be essential for maintaining the conformation of the active center of the NS3 proteinase

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