Genes of the Unfolded Protein Response Pathway Harbor Risk Alleles for Primary Open Angle Glaucoma

The statistical power of genome-wide association (GWA) studies to detect risk alleles for human diseases is limited by the unfavorable ratio of SNPs to study subjects. This multiple testing problem can be surmounted with very large population sizes when common alleles of large effects give rise to disease status. However, GWA approaches fall short when many rare alleles may give rise to a common disease, or when the number of subjects that can be recruited is limited. Here, we demonstrate that this multiple testing problem can be overcome by a comparative genomics approach in which an initial genome-wide screen in a genetically amenable model organism is used to identify human orthologues that may harbor risk alleles for adult-onset primary open angle glaucoma (POAG). Glaucoma is a major cause of blindness, which affects over 60 million people worldwide. Several genes have been associated with juvenile onset glaucoma, but genetic factors that predispose to adult onset primary open angle glaucoma (POAG) remain largely unknown. Previous genome-wide analysis in a Drosophila ocular hypertension model identified transcripts with altered regulation and showed induction of the unfolded protein response (UPR) upon overexpression of transgenic human glaucoma-associated myocilin (MYOC). We selected 16 orthologous genes with 62 polymorphic markers and identified in two independent human populations two genes of the UPR that harbor POAG risk alleles, BIRC6 and PDIA5. Thus, effectiveness of the UPR in response to accumulation of misfolded or aggregated proteins may contribute to the pathogenesis of POAG and provide targets for early therapeutic intervention

Opacity effects and shock-in-jet modelling of low-level activity in Cygnus X-3

We present simultaneous dual-frequency radio observations of Cygnus X-3 during a phase of low-level activity. We constrain the minimum variability timescale to be 20 minutes at 43 GHz and 30 minutes at 15 GHz, implying source sizes of 2 to 4 AU. We detect polarized emission at a level of a few per cent at 43 GHz which varies with the total intensity. The delay of approximately 10 minutes between the peaks of the flares at the two frequencies is seen to decrease with time, and we find that synchrotron self-absorption and free-free absorption by entrained thermal material play a larger role in determining the opacity than absorption in the stellar wind of the companion. A shock-in-jet model gives a good fit to the lightcurves at all frequencies, demonstrating that this mechanism, which has previously been used to explain the brighter, longer-lived giant outbursts in this source, is also applicable to these low-level flaring events. Assembling the data from outbursts spanning over two orders of magnitude in flux density shows evidence for a strong correlation between the peak brightness of an event, and the timescale and frequency at which this is attained. Brighter flares evolve on longer timescales and peak at lower frequencies. Analysis of the fitted model parameters suggests that brighter outbursts are due to shocks forming further downstream in the jet, with an increased electron normalisation and magnetic field strength both playing a role in setting the strength of the outburst.Comment: Accepted for publication in MNRAS. 15 pages, 9 figure

Two-way multi-lane traffic model for pedestrians in corridors

We extend the Aw-Rascle macroscopic model of car traffic into a two-way multi-lane model of pedestrian traffic. Within this model, we propose a technique for the handling of the congestion constraint, i.e. the fact that the pedestrian density cannot exceed a maximal density corresponding to contact between pedestrians. In a first step, we propose a singularly perturbed pressure relation which models the fact that the pedestrian velocity is considerably reduced, if not blocked, at congestion. In a second step, we carry over the singular limit into the model and show that abrupt transitions between compressible flow (in the uncongested regions) to incompressible flow (in congested regions) occur. We also investigate the hyperbolicity of the two-way models and show that they can lose their hyperbolicity in some cases. We study a diffusive correction of these models and discuss the characteristic time and length scales of the instability

The Stony Brook / SMARTS Atlas of mostly Southern Novae

We introduce the Stony Brook / SMARTS Atlas of (mostly) Southern Novae. This atlas contains both spectra and photometry obtained since 2003. The data archived in this atlas will facilitate systematic studies of the nova phenomenon and correlative studies with other comprehensive data sets. It will also enable detailed investigations of individual objects. In making the data public we hope to engender more interest on the part of the community in the physics of novae. The atlas is on-line at \url{http://www.astro.sunysb.edu/fwalter/SMARTS/NovaAtlas/} .Comment: 11 figures; 5 table

Reconfiguration, contestation, and decline: conceptualizing mature large technical systems

Large technical systems (LTS) are integral to modern lifestyles but arduous to analyze. In this paper, we advance a conceptualization of LTS using the notion of mature “phases,” drawing from insights into innovation studies, science and technology studies, political science, the sociology of infra- structure, history of technology, and governance. We begin by defining LTS as a unit of analysis and explaining its conceptual utility and novelty, situating it among other prominent sociotechnical theories. Next, we argue that after LTS have moved through the (overlapping) phases proposed by Thomas Hughes of invention, expansion, growth, momentum, and style,mature LTS undergo the additional (overlapping) phases of reconfiguration, contestation (subject to pressures such as drift and crisis), and eventually stagnation and decline. We illustrate these analytical phases with historical case studies and the conceptual literature, and close by suggesting future research to refine and develop the LTS framework, particularly related to more refined typologies, temporal dimensions, and a broadening of system users. We aim to contribute to theoretical debates about the coevolution of LTS as well as empirical discussions about system-related use, socio- technical change, and policy-making

Retailing in the United Kingdom - a synopsis

This paper illustrates the structure of, and trends in, the retail market of the United Kingdom (UK). This industry analysis describes the retail environment compared to continental Europe and considers the regulatory issues which have helped form this retail environment. By using secondary data we describe concentration and consolidation tendencies and explain specific features of the UK retail market. Major trends are identified and discussed, concluding with an outlook on future developments

Sex dimorphism in the myocardial response to aortic stenosis

Objectives: The goal of this study was to explore sex differences in myocardial remodeling in aortic stenosis (AS) by using echocardiography, cardiac magnetic resonance (CMR), and biomarkers. Background: AS is a disease of both valve and left ventricle (LV). Sex differences in LV remodeling are reported in AS and may play a role in disease phenotyping. Methods: This study was a prospective assessment of patients awaiting surgical valve replacement for severe AS using echocardiography, the 6-min walking test, biomarkers (high-sensitivity troponin T and N-terminal pro-brain natriuretic peptide), and CMR with late gadolinium enhancement and extracellular volume fraction, which dichotomizes the myocardium into matrix and cell volumes. LV remodeling was categorized into normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy

ADCY5 couples glucose to insulin secretion in human islets

Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, encoding adenylate cyclase 5, are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk. Despite this, the mechanisms underlying the effects of these polymorphic variants at the level of pancreatic β-cells remain unclear. Here, we show firstly that ADCY5 mRNA expression in islets is lowered by the possession of risk alleles at rs11708067. Next, we demonstrate that ADCY5 is indispensable for coupling glucose, but not GLP-1, to insulin secretion in human islets. Assessed by in situ imaging of recombinant probes, ADCY5 silencing impaired glucose-induced cAMP increases and blocked glucose metabolism toward ATP at concentrations of the sugar &gt;8 mmol/L. However, calcium transient generation and functional connectivity between individual human β-cells were sharply inhibited at all glucose concentrations tested, implying additional, metabolism-independent roles for ADCY5. In contrast, calcium rises were unaffected in ADCY5-depleted islets exposed to GLP-1. Alterations in β-cell ADCY5 expression and impaired glucose signaling thus provide a likely route through which ADCY5 gene polymorphisms influence fasting glucose levels and T2D risk, while exerting more minor effects on incretin action.</p