4,914 research outputs found

    Phenylbutyric Acid Rescues Endoplasmic Reticulum Stress-Induced Suppression of APP Proteolysis and Prevents Apoptosis in Neuronal Cells

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    BACKGROUND: The familial and sporadic forms of Alzheimer's disease (AD) have an identical pathology with a severe disparity in the time of onset [1]. The pathological similarity suggests that epigenetic processes may phenocopy the Familial Alzheimer's disease (FAD) mutations within sporadic AD. Numerous groups have demonstrated that FAD mutations in presenilin result in 'loss of function' of gamma-secretase mediated APP cleavage [2], [3], [4], [5]. Accordingly, ER stress is prominent within the pathologically impacted brain regions in AD patients [6] and is reported to inhibit APP trafficking through the secretory pathway [7], [8]. As the maturation of APP and the cleaving secretases requires trafficking through the secretory pathway [9], [10], [11], we hypothesized that ER stress may block trafficking requisite for normal levels of APP cleavage and that the small molecular chaperone 4-phenylbutyrate (PBA) may rescue the proteolytic deficit. METHODOLOGY/PRINCIPAL FINDINGS: The APP-Gal4VP16/Gal4-reporter screen was stably incorporated into neuroblastoma cells in order to assay gamma-secretase mediated APP proteolysis under normal and pharmacologically induced ER stress conditions. Three unrelated pharmacological agents (tunicamycin, thapsigargin and brefeldin A) all repressed APP proteolysis in parallel with activation of unfolded protein response (UPR) signaling-a biochemical marker of ER stress. Co-treatment of the gamma-secretase reporter cells with PBA blocked the repressive effects of tunicamycin and thapsigargin upon APP proteolysis, UPR activation, and apoptosis. In unstressed cells, PBA stimulated gamma-secretase mediated cleavage of APP by 8-10 fold, in the absence of any significant effects upon amyloid production, by promoting APP trafficking through the secretory pathway and the stimulation of the non-pathogenic alpha/gamma-cleavage. CONCLUSIONS/SIGNIFICANCE: ER stress represses gamma-secretase mediated APP proteolysis, which replicates some of the proteolytic deficits associated with the FAD mutations. The small molecular chaperone PBA can reverse ER stress induced effects upon APP proteolysis, trafficking and cellular viability. Pharmaceutical agents, such as PBA, that stimulate alpha/gamma-cleavage of APP by modifying intracellular trafficking should be explored as AD therapeutics

    The Cosmic Horseshoe: Discovery of an Einstein Ring around a Giant Luminous Red Galaxy

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    We report the discovery of an almost complete Einstein ring of diameter 10" in Sloan Digital Sky Survey (SDSS) Data Release 5 (DR5). Spectroscopic data from the 6m telescope of the Special Astrophysical Observatory reveals that the deflecting galaxy has a line-of-sight velocity dispersion in excess of 400 km/s and a redshift of 0.444, whilst the source is a star-forming galaxy with a redshift of 2.379. From its color and luminosity, we conclude that the lens is an exceptionally massive Luminous Red Galaxy (LRG) with a mass within the Einstein radius of 5 x 10^12 solar masses. This remarkable system provides a laboratory for probing the dark matter distribution in LRGs at distances out to 3 effective radii, and studying the properties of high redshift star-forming galaxies.Comment: ApJ (Letters), in pres

    Harnessing the power of complex light propagation in multimode fibers for spatially resolved sensing

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    The propagation of coherent light in multimode optical fibers results in a speckled output that is both complex and sensitive to environmental effects. These properties can be a powerful tool for sensing, as small perturbations lead to significant changes in the output of the fiber. However, the mechanism to encode spatially resolved sensing information into the speckle pattern and the ability to extract this information is thus far unclear. In this paper, we demonstrate that spatially dependent mode coupling is crucial to achieving spatially resolved measurements. We leverage machine learning to quantitatively extract this spatially resolved sensing information from three fiber types with dramatically different characteristics and demonstrate that the fiber with the highest degree of spatially dependent mode coupling provides the greatest accuracy.Comment: 17 pages and 7 figure

    The extinction law in high redshift galaxies

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    We estimate the dust extinction laws in two intermediate redshift galaxies. The dust in the lens galaxy of LBQS1009-0252, which has an estimated lens redshift of zl~0.88, appears to be similar to that of the SMC with no significant feature at 2175 A. Only if the lens galaxy is at a redshift of zl~0.3, completely inconsistent with the galaxy colors, luminosity or location on the fundamental plane, can the data be fit with a normal Galactic extinction curve. The dust in the zl=0.68 lens galaxy for B0218+357, whose reddened image lies behind a molecular cloud, requires a very flat ultraviolet extinction curve with (formally) R(V)=12 +- 2. Both lens systems seem to have unusual extinction curves by Galactic standards.Comment: 15 pages, 3 figures. ApJ in pres

    An evidence review of research on health interventions in humanitarian crises. Final Report

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    This review was conducted to provide a rigorous assessment of the current quality and depth of the evidence-base that informs humanitarian public health programming globally. It assesses the quantity and quality of intervention studies, rather than measuring the actual effectiveness of the intervention itself. The review addresses evidence on interventions in humanitarian crises (including early recovery and forced displacement) for health topics of: communicable disease control water, sanitation and hygiene (WASH) nutrition sexual and reproductive health (SRH), including gender-based violence (GBV) mental health and psychosocial support non-communicable disease (NCD) injury and physical rehabilitation health services health systems. In addition, contextual factors influencing the delivery of health-related interventions are included in the project, consisting of: * access to health services * health assessment methods * coordination * accountability * health worker security * urbanisation. The evidence review used the following two main methods: (i) A series of systematic literature reviews on evidence of humanitarian interventions related to the health topics and on the influence of contextual factors on the interventions. The systematic review on evidence of interventions for the different health topics included quantitative evidence from published and grey literature. The systematic review on the contextual factors included quantitative and qualitative evidence from the published literature. Standard systematic review methodologies were used. (ii) Qualitative individual interviews with expert practitioners, policy makers and academics to identify critical weaknesses and gaps in the evidence base for humanitarian public health actions (including related to the contextual factors) and to recommend priority areas for further research. A series of more general consultations with humanitarian health experts through meetings in London, Geneva, Paris, and New York

    The shape of ecological networks

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    We study the statistics of ecosystems with a variable number of co-evolving species. The species interact in two ways: by prey-predator relationships and by direct competition with similar kinds. The interaction coefficients change slowly through successful adaptations and speciations. We treat them as quenched random variables. These interactions determine long-term topological features of the species network, which are found to agree with those of biological systems.Comment: 4 pages, 2 figure

    Galaxy And Mass Assembly (GAMA)

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    The GAMA survey aims to deliver 250,000 optical spectra (3--7Ang resolution) over 250 sq. degrees to spectroscopic limits of r_{AB} <19.8 and K_{AB}<17.0 mag. Complementary imaging will be provided by GALEX, VST, UKIRT, VISTA, HERSCHEL and ASKAP to comparable flux levels leading to a definitive multi-wavelength galaxy database. The data will be used to study all aspects of cosmic structures on 1kpc to 1Mpc scales spanning all environments and out to a redshift limit of z ~ 0.4. Key science drivers include the measurement of: the halo mass function via group velocity dispersions; the stellar, HI, and baryonic mass functions; galaxy component mass-size relations; the recent merger and star-formation rates by mass, types and environment. Detailed modeling of the spectra, broad SEDs, and spatial distributions should provide individual star formation histories, ages, bulge-disc decompositions and stellar bulge, stellar disc, dust disc, neutral HI gas and total dynamical masses for a significant subset of the sample (~100k) spanning both the giant and dwarf galaxy populations. The survey commenced March 2008 with 50k spectra obtained in 21 clear nights using the Anglo Australian Observatory's new multi-fibre-fed bench-mounted dual-beam spectroscopic system (AAOmega).Comment: Invited talk at IAU 254 (The Galaxy Disk in Cosmological Context, Copenhagen), 6 pages, 5 figures, high quality PDF version available at http://www.eso.org/~jliske/gama

    Distant field BHB stars and the mass of the Galaxy II: Photometry and spectroscopy of UKST candidates 16<B<19.5, 11<R<52 kpc

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    This is the second in a series of papers presenting a new calculation of the mass of the Galaxy based on radial velocities and distances for a sample of faint 16 < B < 21.3 field blue horizontal-branch (BHB) stars. We present accurate BV CCD photometry and spectra for 142 candidate A-type stars selected from ub_jr photometry of UK Schmidt telescope plates in six high-Galactic-latitude fields. Classification of these candidates produces a sample of 60 BHB stars at distances of 11-52 kpc from the Sun (mean 28 kpc), with heliocentric line-of-sight velocities accurate to 15 km/s, and distance errors < 10%. We provide a summary table listing coordinates and velocities of these stars. The measured dispersion of the radial component of the Galactocentric velocity for this sample is 108+-10 km/s, in agreement with a recent study of the distant halo by Sirko and coworkers. Measurements of the Ca II K line indicate that nearly all the stars are metal-poor with a mean [Fe/H] = -1.8 with dispersion 0.5. Subsequent papers will describe a second survey of BHBs to heliocentric distances 70 < R < 125 kpc and present a new estimate of the mass of the Galaxy.Comment: 16 pages, 15 figures. Accepted for publication in MNRA

    Promoting adherence to pelvic floor muscle exercises: analysis of exercise prescription, prompts to exercise, and predictors of exercise diary return, during a randomised controlled trial

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    This is the author accepted manuscript. The final version is available from Springer via the DOI in this recordPaper 286 at IUGA 46th Virtual Annual MeetingNational Institute for Health Research (NIHR
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