Pathological changes within the cerebral vasculature in Alzheimer's disease:New perspectives

Cerebrovascular disease underpins vascular dementia (VaD), but structural and functional changes to the cerebral vasculature contribute to disease pathology and cognitive decline in Alzheimer's disease (AD). In this review, we discuss the contribution of cerebral amyloid angiopathy and non‐amyloid small vessel disease in AD, and the accompanying changes to the density, maintenance and remodelling of vessels (including alterations to the composition and function of the cerebrovascular basement membrane). We consider how abnormalities of the constituent cells of the neurovascular unit – particularly of endothelial cells and pericytes – and impairment of the blood‐brain barrier (BBB) impact on the pathogenesis of AD. We also discuss how changes to the cerebral vasculature are likely to impair Aβ clearance – both intra‐periarteriolar drainage (IPAD) and transport of Aβ peptides across the BBB, and how impaired neurovascular coupling and reduced blood flow in relation to metabolic demand increase amyloidogenic processing of APP and the production of Aβ. We review the vasoactive properties of Aβ peptides themselves, and the probable bi‐directional relationship between vascular dysfunction and Aβ accumulation in AD. Lastly, we discuss recent methodological advances in transcriptomics and imaging that have provided novel insights into vascular changes in AD, and recent advances in assessment of the retina that allow in vivo detection of vascular changes in the early stages of AD

Artemisia scoparia enhances adipocyte development and endocrine function in vitro and enhances insulin action in vivo

Background: Failure of adipocytes to expand during periods of energy excess can result in undesirable metabolic consequences such as ectopic fat accumulation and insulin resistance. Blinded screening studies have indicated that Artemisia scoparia (SCO) extracts can enhance adipocyte differentiation and lipid accumulation in cultured adipocytes. The present study tested the hypothesis that SCO treatment modulates fat cell development and function in vitro and insulin sensitivity in adipose tissue in vivo. Methods: In vitro experiments utilized a Gal4-PPARγ ligand binding domain (LBD) fusion protein-luciferase reporter assay to examine PPARγ activation. To investigate the ability of SCO to modulate adipogenesis and mature fat cell function in 3T3-L1 cells, neutral lipid accumulation, gene expression, and protein secretion were measured by Oil Red O staining, qRT-PCR, and immunoblotting, respectively. For the in vivo experiments, diet-induced obese (DIO) C57BL/6J mice were fed a high-fat diet (HFD) or HFD containing 1% w/w SCO for four weeks. Body weight and composition, food intake, and fasting glucose and insulin levels were measured. Phospho-activation and expression of insulin-sensitizing proteins in epididymal adipose tissue (eWAT) were measured by immunoblotting. Results: Ethanolic extracts of A. scoparia significantly activated the PPARγ LBD and enhanced lipid accumulation in differentiating 3T3-L1 cells. SCO increased the transcription of several PPARγ target genes in differentiating 3T3-L1 cells and rescued the negative effects of tumor necrosis factor α on production and secretion of adiponectin and monocyte chemoattractant protein-1 in fully differentiated fat cells. DIO mice treated with SCO had elevated adiponectin levels and increased phosphorylation of AMPKα in eWAT when compared to control mice. In SCO-treated mice, these changes were also associated with decreased fasting insulin and glucose levels. Conclusion: SCO has metabolically beneficial effects on adipocytes in vitro and adipose tissue in vivo, highlighting its potential as a metabolically favorable botanical supplement. © 2014 Richard et al

Long-Term Preservation of Cones and Improvement in Visual Function Following Gene Therapy in a Mouse Model of Leber Congenital Amaurosis Caused by Guanylate Cyclase-1 Deficiency

Leber congenital amaurosis (LCA) is a severe retinal dystrophy manifesting from early infancy as poor vision or blindness. Loss-of-function mutations in GUCY2D cause LCA1 and are one of the most common causes of LCA, accounting for 20% of all cases. Human GUCY2D and mouse Gucy2e genes encode guanylate cyclase-1 (GC), which is responsible for restoring the dark state in photoreceptors after light exposure. The Glicy2e(-/-) mouse shows partially diminished rod function, but an absence of cone function before degeneration. Although the cones appear morphologically normal, they exhibit mislocalization of proteins involved in phototransduction. In this study we tested the efficacy of an rAAV2/8 vector containing the human rhodopsin kinase promoter and the human GUCY2D gene. Following subretinal delivery of the vector in Glicy2e(-/-) mice, GC1 protein was detected in the rod and cone outer segments, and in transduced areas of retina cone transducin was appropriately localized to cone outer segments. Moreover, we observed a dose-dependent restoration of rod and cone function and an improvement in visual behavior of the treated mice. Most importantly, cone preservation was observed in transduced areas up to 6 months post injection. To date, this is the most effective rescue of the Glicy2e(-/-) mouse model of LCA and we propose that a vector, similar to the one used in this study, could be suitable for use in a clinical trial of gene therapy for LCA1

Differential Modulation of Retinal Degeneration by Ccl2 and Cx3cr1 Chemokine Signalling

Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2−/−/Crb1Rd8/RD8, Cx3cr1−/−/Crb1Rd8/RD8 and CCl2−/−/Cx3cr1−/−/Crb1Rd8/RD8 mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling

A Lagrangian snow evolution system for sea ice applications (SnowModel-LG): Part II-analyses

Sea ice thickness is a critical variable, both as a climate indicator and for forecasting sea ice conditions on seasonal and longer time scales. The lack of snow depth and density information is a major source of uncertainty in current thickness retrievals from laser and radar altimetry. In response to this data gap, a new Lagrangian snow evolution model (SnowModel‐LG) was developed to simulate snow depth, density, and grain size on a pan‐Arctic scale, daily from August 1980 through July 2018. In this study, we evaluate the results from this effort against various data sets, including those from Operation IceBridge, ice mass balance buoys, snow buoys, MagnaProbes, and rulers. We further compare modeled snow depths forced by two reanalysis products (Modern Era Retrospective‐Analysis for Research and Applications, Version 2 and European Centre for Medium‐Range Weather Forecasts Reanalysis, 5th Generation) with those from two historical climatologies, as well as estimates over first‐year and multiyear ice from satellite passive microwave observations. Our results highlight the ability of our SnowModel‐LG implementation to capture observed spatial and seasonal variability in Arctic snow depth and density, as well as the sensitivity to the choice of reanalysis system used to simulate snow depths. Since 1980, snow depth is found to decrease throughout most regions of the Arctic Ocean, with statistically significant trends during the cold season months in the marginal ice zones around the Arctic Ocean and slight positive trends north of Greenland and near the pole

Influence of laser polarization on collective electron dynamics in ultraintense laser-foil interactions

The collective response of electrons in an ultrathin foil target irradiated by an ultraintense laser pulse is investigated experimentally and via 3D particle-in-cell simulations. It is shown that if the target is sufficiently thin that the laser induces significant radiation pressure, but not thin enough to become relativistically transparent to the laser light, the resulting relativistic electron beam is elliptical, with the major axis of the ellipse directed along the laser polarization axis. When the target thickness is decreased such that it becomes relativistically transparent early in the interaction with the laser pulse, diffraction of the transmitted laser light occurs through a so called 'relativistic plasma aperture', inducing structure in the spatial-intensity profile of the beam of energetic electrons. It is shown that the electron beam profile can be modified by variation of the target thickness and degree of ellipticity in the laser polarization

Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis

Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium–specific 65-kD protein (RPE65) is associated with poor vision at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clinically significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. We detected no change in retinal responses on electroretinography. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65. (ClinicalTrials.gov number, NCT00643747.)Supported by grants from the U.K. Department of Health, the British Retinitis Pigmentosa Society, and the Special Trustees of Moorfields Eye Hospital, and by the Sir Jules Thorn Charitable Trust, the Wellcome Trust, the European Union (EVI-Genoret and Clinigene programs), the Medical Research Council, Foundation Fighting Blindness, Fight for Sight, the Ulverscroft Foundation, Fighting Blindness (Ireland), Moorfields Eye Hospital, and Institute of Ophthalmology Biomedical Research Centre for Ophthalmology, University College London

Towards optical polarization control of laser-driven proton acceleration in foils undergoing relativistic transparency

Control of the collective response of plasma particles to intense laser light is intrinsic to relativistic optics, the development of compact laser-driven particle and radiation sources, as well as investigations of some laboratory astrophysics phenomena. We recently demonstrated that a relativistic plasma aperture produced in an ultra-thin foil at the focus of intense laser radiation can induce diffraction, enabling polarization-based control of the collective motion of plasma electrons. Here we show that under these conditions the electron dynamics are mapped into the beam of protons accelerated via strong charge-separation-induced electrostatic fields. It is demonstrated experimentally and numerically via 3D particle-in-cell simulations that the degree of ellipticity of the laser polarization strongly influences the spatial-intensity distribution of the beam of multi-MeV protons. The influence on both sheath accelerated and radiation pressure accelerated protons is investigated. This approach opens up new routes to control laser-driven ion sources

A search for debris disks in the Herschel -ATLAS

Aims. We aim to demonstrate that the Herschel-ATLAS (H-ATLAS) is suitable for a blind and unbiased survey for debris disks by identifying candidate debris disks associated with main sequence stars in the initial science demonstration field of the survey. We show that H-ATLAS reveals a population of far-infrared/sub-mm sources that are associated with stars or star-like objects on the SDSS main-sequence locus. We validate our approach by comparing the properties of the most likely candidate disks to those of the known population. Methods. We use a photometric selection technique to identify main sequence stars in the SDSS DR7 catalogue and a Bayesian Likelihood Ratio method to identify H-ATLAS catalogue sources associated with these main sequence stars. Following this photometric selection we apply distance cuts to identify the most likely candidate debris disks and rule out the presence of contaminating galaxies using UKIDSS LAS K-band images. Results. We identify 78 H-ATLAS sources associated with SDSS point sources on the main-sequence locus, of which two are the most likely debris disk candidates: H-ATLAS J090315.8 and H-ATLAS J090240.2. We show that they are plausible candidates by comparing their properties to the known population of debris disks. Our initial results indicate that bright debris disks are rare, with only 2 candidates identified in a search sample of 851 stars. We also show that H-ATLAS can derive useful upper limits for debris disks associated with Hipparcos stars in the field and outline the future prospects for our debris disk search programme.Funding for the SDSS and SDSS-II has been provided by the Alfred P. Sloan Foundation, the Participating Institutions, the National Science Foundation, the U.S. Department of Energy, the National Aeronautics and Space Administration, the Japanese Monbukagakusho, the Max Planck Society, and the Higher Education Funding Council for England. The UKIDSS project is defined in Lawrence et al. (2007). UKIDSS uses the UKIRT Wide Field Camera (WFCAM; Casali et al. 2007). The photometric system is described in Hambly et al. (2008), and the calibration is described in Hodgkin et al. (2009). The pipeline processing and science archive are described in Hambly et al. (2008). M.A.T. would like to thank two of our undergraduate project students, Sam Richards and Max Podger, who carried out initial database searches and also David Pinfield and Ralf Napiwotski for discussions on low mass stars

Herschel-ATLAS: The angular correlation function of submillimetre galaxies at high and low redshift

We present measurements of the angular correlation function of galaxies selected from the first field of the H-ATLAS survey. Careful removal of the background from galactic cirrus is essential, and currently dominates the uncertainty in our measurements. For our 250 μm-selected sample we detect no significant clustering, consistent with the expectation that the 250 μm-selected sources are mostly normal galaxies at z <∼ 1. For our 350 μm and 500 μm-selected samples we detect relatively strong clustering with correlation amplitudes A of 0.2 and 1.2 at 1’, but with relatively large uncertainties. For samples which preferentially select high redshift galaxies at z ∼ 2−3 we detect significant strong clustering, leading to an estimate of r0 ∼ 7−11 h−1 Mpc. The slope of our clustering measurements is very steep, δ ∼ 2. The measurements are consistent with the idea that sub-mm sources consist of a low redshift population of normal galaxies and a high redshift population of highly clustered star-bursting galaxie