Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly ...heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (β = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8), especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.
Since the terrorist events of the 11th September 2001, the world as it was once known was changed forever. It was these catastrophic terrorist actions over fifteen years ago that saw the dawn of a ...new era with heightened security across many everyday areas of society that had not previously witnessed such scrutiny or control. Coupling this elevated risk of physical and technical aggression with the ever-increasing global per capita energy demand – there has been witnessed a continually growing reliance on nuclear energy for baseline power generation, a form of electricity production that requires both the necessary international safeguards and controls for its safe use. As more and more of the global energy budget is provided by low-carbon sources (over highly-polluting fossil fuels), the volume of nuclear material in existence will grow substantially – requiring considerable attention and policy to ensure its long-term safety and security.
This commentary describes the vast range of policy challenges faced by the nuclear industry resulting from the rapid technological advancements being made across society, and how these directly (and indirectly) affect global nuclear security, as well as providing a thorough discussion on how best these challenges may be overcome.
•Commentary on the challenges in current nuclear energy generation.•Policy issues faced by continued advancements in nuclear power.•Risks and advantages associated with technological advancements.•Review of implications of terrorist actions on nuclear safety and security.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The personality traits of neuroticism and extraversion are predictive of a number of social and behavioural outcomes and psychiatric disorders. Twin and family studies have reported moderate ...heritability estimates for both traits. Few associations have been reported between genetic variants and neuroticism/extraversion, but hardly any have been replicated. Moreover, the ones that have been replicated explain only a small proportion of the heritability (<~2%). Using genome-wide single-nucleotide polymorphism (SNP) data from ~12,000 unrelated individuals we estimated the proportion of phenotypic variance explained by variants in linkage disequilibrium with common SNPs as 0.06 (s.e. = 0.03) for neuroticism and 0.12 (s.e. = 0.03) for extraversion. In an additional series of analyses in a family-based sample, we show that while for both traits ~45% of the phenotypic variance can be explained by pedigree data (that is, expected genetic similarity) one third of this can be explained by SNP data (that is, realized genetic similarity). A part of the so-called 'missing heritability' has now been accounted for, but some of the reported heritability is still unexplained. Possible explanations for the remaining missing heritability are that: (i) rare variants that are not captured by common SNPs on current genotype platforms make a major contribution; and/ or (ii) the estimates of narrow sense heritability from twin and family studies are biased upwards, for example, by not properly accounting for nonadditive genetic factors and/or (common) environmental factors.
Membrane-permeant biarsenical dyes such as FlAsH and ReAsH fluoresce upon binding to genetically encoded tetracysteine motifs expressed in living cells, yet spontaneous nonspecific background ...staining can prevent detection of weakly expressed or dilute proteins. If the affinity of the tetracysteine peptide could be increased, more stringent dithiol washes should increase the contrast between specific and nonspecific staining. Residues surrounding the tetracysteine motif were randomized and fused to GFP, retrovirally transduced into mammalian cells and iteratively sorted by fluorescence-activated cell sorting for high FRET from GFP to ReAsH in the presence of increasing concentrations of dithiol competitors. The selected sequences show higher fluorescence quantum yields and markedly improved dithiol resistance, culminating in a >20-fold increase in contrast. The selected tetracysteine sequences, HRWCCPGCCKTF and FLNCCPGCCMEP, maintain their enhanced properties as fusions to either terminus of GFP or directly to β-actin. These improved biarsenical-tetracysteine motifs should enable detection of a much broader spectrum of cellular proteins.
Linear plasma generators are cost effective facilities to simulate divertor plasma conditions of present and future fusion reactors. They are used to address important R&D gaps in the science of ...plasma material interactions and towards viable plasma facing components for fusion reactors. Next generation plasma generators have to be able to access the plasma conditions expected on the divertor targets in ITER and future devices. The steady-state linear plasma device MPEX will address this regime with electron temperatures of 1-10 eV and electron densities of 1021​−​1020 m−3. The resulting heat fluxes are about 10 MW m−2. MPEX is designed to deliver those plasma conditions with a novel Radio Frequency plasma source able to produce high density plasmas and heat electron and ions separately with electron Bernstein wave (EBW) heating and ion cyclotron resonance heating with a total installed power of 800 kW. The linear device Proto-MPEX, forerunner of MPEX consisting of 12 water-cooled copper coils, has been operational since May 2014. Its helicon antenna (100 kW, 13.56 MHz) and EC heating systems (200 kW, 28 GHz) have been commissioned and 14 MW m−2 was delivered on target. Furthermore, electron temperatures of about 20 eV have been achieved in combined helicon and ECH heating schemes at low electron densities. Overdense heating with EBW was achieved at low heating powers. The operational space of the density production by the helicon antenna was pushed up to 1.1×1020 m−3 at high magnetic fields of 1.0 T at the target. The experimental results from Proto-MPEX will be used for code validation to enable predictions of the source and heating performance for MPEX. MPEX, in its last phase, will be capable to expose neutron-irradiated samples. In this concept, targets will be irradiated in ORNL's High Flux Isotope Reactor and then subsequently exposed to fusion reactor relevant plasmas in MPEX.
This European Psychiatric Association (EPA) guidance paper is a result of the Working Group on Mental Health Consequences of Economic Crises of the EPA Council of National Psychiatric Associations. ...Its purpose is to identify the impact on mental health in Europe of the economic downturn and the measures that may be taken to respond to it. We performed a review of the existing literature that yields 350 articles on which our conclusions and recommendations are based. Evidence-based tables and recommendations were developed through an expert consensus process. Literature dealing with the consequences of economic turmoil on the health and health behaviours of the population is heterogeneous, and the results are not completely unequivocal. However, there is a broad consensus about the deleterious consequences of economic crises on mental health, particularly on psychological well-being, depression, anxiety disorders, insomnia, alcohol abuse, and suicidal behaviour. Unemployment, indebtedness, precarious working conditions, inequalities, lack of social connectedness, and housing instability emerge as main risk factors. Men at working age could be particularly at risk, together with previous low SES or stigmatized populations. Generalized austerity measures and poor developed welfare systems trend to increase the harmful effects of economic crises on mental health. Although many articles suggest limitations of existing research and provide suggestions for future research, there is relatively little discussion of policy approaches to address the negative impact of economic crises on mental health. The few studies that addressed policy questions suggested that the development of social protection programs such as active labour programs, social support systems, protection for housing instability, and better access to mental health care, particularly at primary care level, is strongly needed.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of ...prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Omitted variable bias occurs in most statistical models. Whenever a confounding variable that is correlated with both dependent and independent variables is omitted from a statistical model, ...estimated effects of included variables are likely to be biased due to omitted variables. This issue is particularly problematic in physics education research where many research studies are quasiexperimental or observational in nature due to ethical and logistical limitations. In this paper, we illustrate the mechanisms behind omitted variable bias in explanatory modeling using authentic data and analytical solutions. We demonstrate that omitting confounding variables that are strongly correlated with included variables and have large effects on the dependent variable can significantly bias estimated effects for included variables. We also find that controlling for variables that are uncorrelated with other variables or have no effect on the dependent variable does not appreciably bias estimated effects and may or may not affect the precision of those estimates. These results suggest that removing from explanatory models variables that are not "statistically significant" can have unintended consequences on model and variable interpretations. Our results underscore the importance of carefully considering why or why not to include a variable in a model, informed by both data and theory.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM, UPUK
Three cognitive constructs are risk factors for eating disorders: undue influence of weight and shape, concern about weight and shape, and body dissatisfaction (BD). Undue influence, a diagnostic ...criterion for eating disorders, is postulated to be closely associated with self-esteem whereas BD is postulated to be closely associated with body mass index (BMI). We understand less about the relationships with concern about weight and shape. The aim of the current investigation was examine the degree of overlap across these five phenotypes in terms of latent genetic and environmental risk factors in order to draw some conclusions about the similarities and differences across the three cognitive variables.
A sample of female Australian twins (n=1056, including 348 complete pairs), mean age 35 years (S.D.=2.11, range 28-40), completed a semi-structured interview about eating pathology and self-report questionnaires. An independent pathways model was used to investigate the overlap of genetic and environmental risk factors for the five phenotypes.
In terms of variance that was not shared with other phenotypes, self-esteem emerged as being separate, with 100% of its variance unshared with the other phenotypes, followed by undue influence (51%) and then concern (34%), BD (28%) and BMI (32%).
In terms of shared genetic risk, undue influence and concern were more closely related than BD, whereas BMI and BD were found to share common sources of risk. With respect to environmental risk factors, concern, BMI and BD were more closely related to each other than to undue influence.
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