Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome

Werner syndrome is a progeroid disorder characterized by premature age-related phenotypes. Although it is well established that autosomal recessive mutations in the WRN gene is responsible for Werner syndrome, the molecular alterations that lead to disease phenotype remain still unidentified

TLR9-induced interferon β is associated with protection from gammaherpesvirus-induced exacerbation of lung fibrosis

Abstract Background We have shown previously that murine gammaherpesvirus 68 (γHV68) infection exacerbates established pulmonary fibrosis. Because Toll-like receptor (TLR)-9 may be important in controlling the immune response to γHV68 infection, we examined how TLR-9 signaling effects exacerbation of fibrosis in response to viral infection, using models of bleomycin- and fluorescein isothiocyanate-induced pulmonary fibrosis in wild-type (Balb/c) and TLR-9-/- mice. Results We found that in the absence of TLR-9 signaling, there was a significant increase in collagen deposition following viral exacerbation of fibrosis. This was not associated with increased viral load in TLR-9-/- mice or with major alterations in T helper (Th)1 and Th2 cytokines. We examined alveolar epithelial-cell apoptosis in both strains, but this could not explain the altered fibrotic outcomes. As expected, TLR-9-/- mice had a defect in the production of interferon (IFN)-β after viral infection. Balb/c fibroblasts infected with γHV68 in vitro produced more IFN-β than did infected TLR-9-/- fibroblasts. Accordingly, in vitro infection of Balb/c fibroblasts resulted in reduced proliferation rates whereas infection of TLR-9-/- fibroblasts did not. Finally, therapeutic administration of CpG oligodeoxynucleotides ameliorated bleomycin-induced fibrosis in wild-type mice. Conclusions These results show a protective role for TLR-9 signaling in murine models of lung fibrosis, and highlight differences in the biology of TLR-9 between mice and humans.http://deepblue.lib.umich.edu/bitstream/2027.42/112877/1/13069_2011_Article_57.pd

Progress towards high-performance, steady-state spherical torus

Research on the spherical torus (or spherical tokamak) (ST) is being pursued to explore the scientific benefits of modifying the field line structue fro that in more moderate aspect ratio devices. The ST experiments are being conducted in various US research facilities. The area of power and particle handling is expected to be challenging because of the higher power density expected in the ST relative to that in conventional aspect-ratio tokamaks

Progress towards high-performance, steady-state spherical torus

Research on the spherical torus (or spherical tokamak) (ST) is being pursued to explore the scientific benefits of modifying the field line structue fro that in more moderate aspect ratio devices. The ST experiments are being conducted in various US research facilities. The area of power and particle handling is expected to be challenging because of the higher power density expected in the ST relative to that in conventional aspect-ratio tokamaks

Progress towards high-performance, steady-state spherical torus

Research on the spherical torus (or spherical tokamak) (ST) is being pursued to explore the scientific benefits of modifying the field line structure from that in more moderate aspect ratio devices, such as the conventional tokamak. The ST experiments are being conducted in various US research facilities including the MA-class National Spherical Torus Experiment (NSTX) at Princeton, and three medium sized ST research facilities: PEGASUS at University of Wisconsin, HIT-II at University of Washington, and CDX-U at Princeton. In the context of the fusion energy development path being formulated in the US, an ST-based Component Test Facility (CTF) and, ultimately a Demo device, are being discussed. For these, it is essential to develop high performance, steady-state operational scenarios. The relevant scientific issues are energy confinement, MHD stability at high beta (), non-inductive sustainment, Ohmic-solenoid-free start-up, and power and particle handling. In the confinement area, the NSTX experiments have shown that the confinement can be up to 50% better than the ITER-98-pby2 H-mode scaling, consistent with the requirements for an ST-based CTF and Demo. In NSTX, CTF-relevant average toroidal beta values beta(T) of up to 35% with a near unity central beta(T) have been obtained. NSTX will be exploring advanced regimes where beta(T) up to 40% can be sustained through active stabilization of resistive wall modes. To date, the most successful technique for non-inductive sustainment in NSTX is the high beta poloidal regime, where discharges with a high non-inductive fraction (similar to60% bootstrap current+NBI current drive) were sustained over the resistive skin time. Research on radio-frequency (RF) based heating and current drive utilizing high harmonic fast wave and electron Bernstein wave is also pursued on NSTX, PEGASUS, and CDX-U. For non-inductive start-up, the coaxial helicity injection, developed in HIT/HIT-II, has been adopted on NSTX to test the method up to I-p similar to 500 kA. In parallel, start-up using a RF current drive and only external poloidal field coils are being developed on NSTX. The area of power and particle handling is expected to be challenging because of the higher power density expected in the ST relative to that in conventional aspect-ratio tokamaks. Due to its promise for power and particle handling, liquid lithium is being studied in CDX-U as a potential plasma-facing surface for a fusion reactor.This research was supported by DoE contract DE-AC02-76CH03073 and DoE Grant DE-FG02-96ER54375

Advancing the understanding of autism disease mechanisms through genetics.

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies