EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans

Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age

Psychosocial risk factors and retinal microvascular signs: the multi-ethnic study of atherosclerosis

The association between psychosocial risk factors and retinal microvascular signs was examined in the Multi-Ethnic Study of Atherosclerosis. Subjects were recruited from Baltimore, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles County, California; New York, New York; and St. Paul, Minnesota. Levels of depressive symptoms, trait anger, trait anxiety, chronic burdens, emotional support, and cynical distrust were assessed by questionnaire (from July 2000 to July 2002). Digital retinal images (from August 2002 to January 2004) from 6,147 participants were used to evaluate retinopathy and retinal vascular caliber. After controlling for potential confounding factors, the authors found that subjects without access to emotional support (Enriched Social Support Instrument score of or = 19) had 60% greater odds of retinopathy (odds ratio = 1.6, 95% confidence interval (CI): 1.3, 2.0). Subjects with high Spielberger trait-anxiety scale scores (> or = 22 vs. or = 16 vs. <16) were also more likely to have retinopathy (odds ratio = 1.4, 95% CI: 1.1, 1.9 and odds ratio = 1.5, 95% CI: 1.2, 1.9), respectively. In this cross-sectional study, lack of emotional support, increased trait anxiety, and more depressive symptoms were associated with retinopathy signs, independently of other known risk factors.http://deepblue.lib.umich.edu/bitstream/2027.42/78377/1/JensenShea2010_AJE.pd

Double quantum dot with integrated charge sensor based on Ge/Si heterostructure nanowires

Coupled electron spins in semiconductor double quantum dots hold promise as the basis for solid-state qubits. To date, most experiments have used III-V materials, in which coherence is limited by hyperfine interactions. Ge/Si heterostructure nanowires seem ideally suited to overcome this limitation: the predominance of spin-zero nuclei suppresses the hyperfine interaction and chemical synthesis creates a clean and defect-free system with highly controllable properties. Here we present a top gate-defined double quantum dot based on Ge/Si heterostructure nanowires with fully tunable coupling between the dots and to the leads. We also demonstrate a novel approach to charge sensing in a one-dimensional nanostructure by capacitively coupling the double dot to a single dot on an adjacent nanowire. The double quantum dot and integrated charge sensor serve as an essential building block required to form a solid-state spin qubit free of nuclear spin.Comment: Related work at http://marcuslab.harvard.edu and http://cmliris.harvard.ed

On the genetic involvement of apoptosis-related genes in Crohn's disease as revealed by an extended association screen using 245 markers: no evidence for new predisposing factors

Crohn's disease (CD) presents as an inflammatory barrier disease with characteristic destructive processes in the intestinal wall. Although the pathomechanisms of CD are still not exactly understood, there is evidence that, in addition to e.g. bacterial colonisation, genetic predisposition contributes to the development of CD. In order to search for predisposing genetic factors we scrutinised 245 microsatellite markers in a population-based linkage mapping study. These microsatellites cover gene loci the encoded protein of which take part in the regulation of apoptosis and (innate) immune processes. Respective loci contribute to the activation/suppression of apoptosis, are involved in signal transduction and cell cycle regulators or they belong to the tumor necrosis factor superfamily, caspase related genes or the BCL2 family. Furthermore, several cytokines as well as chemokines were included. The approach is based on three steps: analyzing pooled DNAs of patients and controls, verification of significantly differing microsatellite markers by genotyping individual DNA samples and, finally, additional reinvestigation of the respective gene in the region covered by the associated microsatellite by analysing single-nucleotide polymorphisms (SNPs). Using this step-wise process we were unable to demonstrate evidence for genetic predisposition of the chosen apoptosis- and immunity-related genes with respect to susceptibility for CD

Cataract research using electronic health records

<p>Abstract</p> <p>Background</p> <p>The eMERGE (electronic MEdical Records and Genomics) network, funded by the National Human Genome Research Institute, is a national consortium formed to develop, disseminate, and apply approaches to research that combine DNA biorepositories with electronic health record (EHR) systems for large-scale, high-throughput genetic research. Marshfield Clinic is one of five sites in the eMERGE network and primarily studied: 1) age-related cataract and 2) HDL-cholesterol levels. The purpose of this paper is to describe the approach to electronic evaluation of the epidemiology of cataract using the EHR for a large biobank and to assess previously identified epidemiologic risk factors in cases identified by electronic algorithms.</p> <p>Methods</p> <p>Electronic algorithms were used to select individuals with cataracts in the Personalized Medicine Research Project database. These were analyzed for cataract prevalence, age at cataract, and previously identified risk factors.</p> <p>Results</p> <p>Cataract diagnoses and surgeries, though not type of cataract, were successfully identified using electronic algorithms. Age specific prevalence of both cataract (22% compared to 17.2%) and cataract surgery (11% compared to 5.1%) were higher when compared to the Eye Diseases Prevalence Research Group. The risk factors of age, gender, diabetes, and steroid use were confirmed.</p> <p>Conclusions</p> <p>Using electronic health records can be a viable and efficient tool to identify cataracts for research. However, using retrospective data from this source can be confounded by historical limits on data availability, differences in the utilization of healthcare, and changes in exposures over time.</p

The role of expertise in dynamic risk assessment: A reflection of the problem-solving strategies used by experienced fireground commanders

Although the concept of dynamic risk assessment has in recent times become more topical in the training manuals of most high risk domains, only a few empirical studies have reported how experts actually carry out this crucial task. The knowledge gap between research and practice in this area therefore calls for more empirical investigation within the naturalistic environment. In this paper, we present and discuss the problem solving strategies employed by sixteen experienced operational firefighters using a qualitative knowledge elicitation tool — the critical decision method. Findings revealed that dynamic risk assessment is not merely a process of weighing the risks of a proposed course of action against its benefits, but rather an experiential and pattern recognition process. The paper concludes by discussing the implications of designing training curriculum for the less experienced officers using the elicited expert knowledge

A Continuum of Cell States Spans Pluripotency and Lineage Commitment in Human Embryonic Stem Cells

Background: Commitment in embryonic stem cells is often depicted as a binary choice between alternate cell states, pluripotency and specification to a particular germ layer or extraembryonic lineage. However, close examination of human ES cell cultures has revealed significant heterogeneity in the stem cell compartment. Methodology/Principal Findings: We isolated subpopulations of embryonic stem cells using surface markers, then examined their expression of pluripotency genes and lineage specific transcription factors at the single cell level, and tested their ability to regenerate colonies of stem cells. Transcript analysis of single embryonic stem cells showed that there is a gradient and a hierarchy of expression of pluripotency genes in the population. Even cells at the top of the hierarchy generally express only a subset of the stem cell genes studied. Many cells co-express pluripotency and lineage specific genes. Cells along the continuum show a progressively decreasing likelihood of self renewal as their expression of stem cell surface markers and pluripotency genes wanes. Most cells that are positive for stem cell surface markers express Oct-4, but only those towards the top of the hierarchy express the nodal receptor TDGF-1 and the growth factor GDF3. Significance: These findings on gene expression in single embryonic stem cells are in concert with recent studies of early mammalian development, which reveal molecular heterogeneity and a stochasticity of gene expression in blastomeres. Our work indicates that only a small fraction of the population resides at the top of the hierarchy, that lineage priming (co-expression of stem cell and lineage specific genes) characterizes pluripotent stem cell populations, and that extrinsic signaling pathways are upstream of transcription factor networks that control pluripotency

Density of Common Complex Ocular Traits in the Aging Eye: Analysis of Secondary Traits in Genome-Wide Association Studies

Genetic association studies are identifying genetic risks for common complex ocular traits such as age-related macular degeneration (AMD). The subjects used for discovery of these loci have been largely from clinic-based, case-control studies. Typically, only the primary phenotype (e.g., AMD) being studied is systematically documented and other complex traits (e.g., affecting the eye) are largely ignored. The purpose of this study was to characterize these other or secondary complex ocular traits present in the cases and controls of clinic-based studies being used for genetic study of AMD. The records of 100 consecutive new patients (of any diagnosis) age 60 or older for which all traits affecting the eye had been recorded systematically were reviewed. The average patient had 3.5 distinct diagnoses. A subset of 10 complex traits was selected for further study because they were common and could be reliably diagnosed. The density of these 10 complex ocular traits increased by 0.017 log-traits/year (P = 0.03), ranging from a predicted 2.74 at age 60 to 4.45 at age 90. Trait-trait association was observed only between AMD and primary vitreomacular traction (P = 0.0009). Only 1% of subjects age 60 or older had no common complex traits affecting the eye. Extrapolations suggested that a study of 2000 similar subjects would have sufficient power to detect genetic association with an odds ratio of 2.0 or less for 4 of these 10 traits. In conclusion, the high prevalence of complex traits affecting the aging eye and the inherent biases in referral patterns leads to the potential for confounding by undocumented secondary traits within case-control studies. In addition to the primary trait, other common ocular phenotypes should be systematically documented in genetic association studies so that adjustments for potential trait-trait associations and other bias can be made and genetic risk variants identified in secondary analyses

Comparison of age-specific cataract prevalence in two population-based surveys 6 years apart

BACKGROUND: In this study, we aimed to compare age-specific cortical, nuclear and posterior subcapsular (PSC) cataract prevalence in two surveys 6 years apart. METHODS: The Blue Mountains Eye Study examined 3654 participants (82.4% of those eligible) in cross-section I (1992–4) and 3509 participants (75.1% of survivors and 85.2% of newly eligible) in cross-section II (1997–2000, 66.5% overlap with cross-section I). Cataract was assessed from lens photographs following the Wisconsin Cataract Grading System. Cortical cataract was defined if cortical opacity comprised ≥ 5% of lens area. Nuclear cataract was defined if nuclear opacity ≥ Wisconsin standard 4. PSC was defined if any present. Any cataract was defined to include persons who had previous cataract surgery. Weighted kappa for inter-grader reliability was 0.82, 0.55 and 0.82 for cortical, nuclear and PSC cataract, respectively. We assessed age-specific prevalence using an interval of 5 years, so that participants within each age group were independent between the two surveys. RESULTS: Age and gender distributions were similar between the two populations. The age-specific prevalence of cortical (23.8% in 1(st), 23.7% in 2(nd)) and PSC cataract (6.3%, 6.0%) was similar. The prevalence of nuclear cataract increased slightly from 18.7% to 23.9%. After age standardization, the similar prevalence of cortical (23.8%, 23.5%) and PSC cataract (6.3%, 5.9%), and the increased prevalence of nuclear cataract (18.7%, 24.2%) remained. CONCLUSION: In two surveys of two population-based samples with similar age and gender distributions, we found a relatively stable cortical and PSC cataract prevalence over a 6-year period. The increased prevalence of nuclear cataract deserves further study