356 research outputs found

    Maintaining unstructured case bases

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    Oligodendrocytes contribute to motor neuron death in ALS via SOD1 dependent mechanism

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    Oligodendrocytes have recently been implicated in the pathophysiology of ALS. Here we show that, in vitro, mutant SOD1 mouse oligodendrocytes induce wild-type motor neuron hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls, sporadic and familial ALS patients using two different reprogramming methods. All ALS oligodendrocyte lines induced motor neuron death through conditioned medium and in co-culture. Conditioned medium-mediated motor neuron death was associated with decreased lactate production and release, while toxicity in co-culture was lactate independent, demonstrating that motor neuron survival is not only mediated by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in motor neuron rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, while it was ineffective in differentiated oligodendrocytes. Early SOD1 knockdown, in fact, rescued lactate impairment and cell toxicity in all lines tested with exclusion of samples carrying C9orf72 repeat expansions. These did not respond to SOD1 knockdown nor showed lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type some damage might be irreversible. In addition, we demonstrate that C9ORF72 patients represent an independent patient group that might not respond to the same treatment

    The MBA as Careerist: An Analysis of Early-Career Job Change

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    This study examined the job changes of 680 early-career business school graduates. Although a number of anecdotal articles characterize MBAs as overly “careerist” and oriented toward job-hopping, little empirical research has focused on this issue. The research included a direct comparison of job-hopping behavior of MBAs with bachelor S degree graduates, taking into account a number of control variables, including demographic and economic variables. Results indicated that MBAs changed jobs less frequently than bachelor 5 degree graduates, even when a variety of other factors were controlled.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

    Cosmic Ray Diffusion from the Galactic Spiral Arms, Iron Meteorites, and a possible climatic connection?

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    We construct a Galactic cosmic ray (CR) diffusion model while considering that CR sources reside predominantly in the Galactic spiral arms. We find that the CR flux (CRF) reaching the solar system should periodically increase each crossing of a Galactic spiral arm. We search for this signal in the CR exposure age record of Iron meteorites and confirm this prediction. We then check the hypothesis that climate, and in particular the temperature, is affected by the CRF to the extent that glaciations can be induced or completely hindered by possible climatic variations. We find that although the geological evidence for the occurrence of IAEs in the past Eon is not unequivocal, it appears to have a nontrivial correlation with the spiral arm crossings--agreeing in period and phase. Thus, a better timing study of glaciations could either confirm this result as an explanation to the occurrence of IAEs or refute a CRF climatic connection.Comment: 4 Journal pages, 2 figures, revtex4. Appearing today in Phys Rev Let

    Computer-Aided Patient-Specific Coronary Artery Graft Design Improvements Using CFD Coupled Shape Optimizer

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    This study aims to (i) demonstrate the efficacy of a new surgical planning framework for complex cardiovascular reconstructions, (ii) develop a computational fluid dynamics (CFD) coupled multi-dimensional shape optimization method to aid patient-specific coronary artery by-pass graft (CABG) design and, (iii) compare the hemodynamic efficiency of the sequential CABG, i.e., raising a daughter parallel branch from the parent CABG in patient-specific 3D settings. Hemodynamic efficiency of patient-specific complete revascularization scenarios for right coronary artery (RCA), left anterior descending artery (LAD), and left circumflex artery (LCX) bypasses were investigated in comparison to the stenosis condition. Multivariate 2D constraint optimization was applied on the left internal mammary artery (LIMA) graft, which was parameterized based on actual surgical settings extracted from 2D CT slices. The objective function was set to minimize the local variation of wall shear stress (WSS) and other hemodynamic indices (energy dissipation, flow deviation angle, average WSS, and vorticity) that correlate with performance of the graft and risk of re-stenosis at the anastomosis zone. Once the optimized 2D graft shape was obtained, it was translated to 3D using an in-house “sketch-based” interactive anatomical editing tool. The final graft design was evaluated using an experimentally validated second-order non-Newtonian CFD solver incorporating resistance based outlet boundary conditions. 3D patient-specific simulations for the healthy coronary anatomy produced realistic coronary flows. All revascularization techniques restored coronary perfusions to the healthy baseline. Multi-scale evaluation of the optimized LIMA graft enabled significant wall shear stress gradient (WSSG) relief (~34%). In comparison to original LIMA graft, sequential graft also lowered the WSSG by 15% proximal to LAD and diagonal bifurcation. The proposed sketch-based surgical planning paradigm evaluated the selected coronary bypass surgery procedures based on acute hemodynamic readjustments of aorta-CA flow. This methodology may provide a rational to aid surgical decision making in time-critical, patient-specific CA bypass operations before in vivo execution
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