The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

An Evaluation of the Precision of Measurement of Ryff’s Psychological Well-Being Scales in a Population Sample

The aim of this study is to assess the effective measurement range of Ryff’s Psychological Well-being scales (PWB). It applies normal ogive item response theory (IRT) methodology using factor analysis procedures for ordinal data based on a limited information estimation approach. The data come from a sample of 1,179 women participating in a midlife follow-up of a national birth cohort study in the UK. The PWB scales incorporate six dimensions: autonomy, positive relations with others, environmental mastery, personal growth, purpose in life and self-acceptance. Scale information functions were calculated to derive standard errors of measurement for estimated scores on each dimension. Construct variance was distinguished from method variance by inclusion of method factors from item wording (positive versus negative). Our IRT analysis revealed that the PWB measures well-being most accurately in the middle range of the score distribution, i.e. for women with average well-being. Score precision diminished at higher levels of well-being, and low well-being was measured more reliably than high well-being. A second-order well-being factor loaded by four of the dimensions achieved higher measurement precision and greater score accuracy across a wider range than any individual dimension. Future development of well-being scales should be designed to include items that are able to discriminate at high levels of well-being

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Demand-side approaches for limiting global warming to 1.5 °C

The Paris Climate Agreement defined an ambition of limiting global warming to 1.5 °C above preindustrial levels. This has triggered research on stringent emission reduction targets and corresponding mitigation pathways across energy economy and societal systems. Driven by methodological considerations, supply side and carbon dioxide removal options feature prominently in the emerging pathway literature, while much less attention has been given to the role of demand-side approaches. This special issue addresses this gap, and aims to broaden and strengthen the knowledge base in this key research and policy area. This editorial paper synthesizes the special issue’s contributions horizontally through three shared themes we identify: policy interventions, demand-side measures, and methodological approaches. The review of articles is supplemented by insights from other relevant literature. Overall, our paper underlines that stringent demand-side policy portfolios are required to drive the pace and direction of deep decarbonization pathways and keep the 1.5 °C target within reach. It confirms that insufficient attention has been paid to demand-side measures, which are found to be inextricably linked to supply-side decarbonization and able to complement supply-side measures. The paper also shows that there is an abundance of demand-side measures to limit warming to 1.5 °C, but it warns that not all of these options are “seen” or captured by current quantitative tools or progress indicators, and some remain insufficiently represented in the current policy discourse. Based on the set of papers presented in the special issue, we conclude that demand-side mitigation in line with the 1.5 °C goal is possible; however, it remains enormously challenging and dependent on both innovative technologies and policies, and behavioral change. Limiting warming to 1.5 °C requires, more than ever, a plurality of methods and integrated behavioral and technology approaches to better support policymaking and resulting policy interventions

Patterns of Spatial Variation of Assemblages Associated with Intertidal Rocky Shores: A Global Perspective

Assemblages associated with intertidal rocky shores were examined for large scale distribution patterns with specific emphasis on identifying latitudinal trends of species richness and taxonomic distinctiveness. Seventy-two sites distributed around the globe were evaluated following the standardized sampling protocol of the Census of Marine Life NaGISA project (www.nagisa.coml.org). There were no clear patterns of standardized estimators of species richness along latitudinal gradients or among Large Marine Ecosystems (LMEs); however, a strong latitudinal gradient in taxonomic composition (i.e., proportion of different taxonomic groups in a given sample) was observed. Environmental variables related to natural influences were strongly related to the distribution patterns of the assemblages on the LME scale, particularly photoperiod, sea surface temperature (SST) and rainfall. In contrast, no environmental variables directly associated with human influences (with the exception of the inorganic pollution index) were related to assemblage patterns among LMEs. Correlations of the natural assemblages with either latitudinal gradients or environmental variables were equally strong suggesting that neither neutral models nor models based solely on environmental variables sufficiently explain spatial variation of these assemblages at a global scale. Despite the data shortcomings in this study (e.g., unbalanced sample distribution), we show the importance of generating biological global databases for the use in large-scale diversity comparisons of rocky intertidal assemblages to stimulate continued sampling and analyses

Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk

Abstract: Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially

Reducing repeat pregnancies in adolescence: applying realist principles as part of a mixed-methods systematic review to explore what works, for whom, how and under what circumstances

BACKGROUND: Previous research has demonstrated emotional, psychological and educational harm to young mothers following unintended conceptions. The UK has one of the highest rates of pregnancies in adolescence in Western Europe with a high proportion of these being repeat pregnancies, making it a topic of interest for public health policy makers, and health and social care practitioners. As part of a wider mixed-methods systematic review, realist principles were applied to synthesise evidence about interventions aiming to reduce repeat pregnancies in adolescence.METHODS: A multi-streamed, mixed-methods systematic review was conducted searching 11 major electronic databases and 9 additional databases from 1995 onwards, using key terms such as pregnancy, teen or adolescent. The principles of realist synthesis were applied to all included literature to uncover theories about what works, for whom, how and in what context. Initial theory areas were developed through evidence scoping, group discussion by the authors and stakeholder engagement to uncover context + mechanism = outcome (CMO) configurations and related narratives.RESULTS: The searches identified 8,664 documents initially, and 403 in repeat searches, filtering to 81 included studies, including qualitative studies, randomised controlled trials, quantitative studies and grey literature. Three CMO configurations were developed. The individual experiences of young mothers' triggered self-efficacy, notions of perceived risks, susceptibility and benefits of pregnancy, resulting in the adolescent taking control of their fertility and sexual encounters. The choice between motherhood and other goals triggered notions of motivations, resulting in the adolescent managing their expectations of motherhood and controlling their fertility and sexual encounters. Barriers and facilitators to accessing services triggered notions of connectedness and self-determination; resulting in interventions that are tailored so they are relevant to young persons, and improve access to services and engagement with the issue of pregnancy in adolescence.CONCLUSIONS: Pregnancy in adolescence is a complex issue with many factors to consider. The conceptual platform described here could help guide policy makers and professionals towards a number of areas that need to be attended to in order to increase the likelihood of an intervention working to prevent rapid repeat pregnancy in adolescence.TRIAL REGISTRATION: PROSPERO CRD42012003168

Shared genetic contribution to ischemic stroke and Alzheimer's disease

Objective Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods Using genome-wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome-wide single-nucleotide polymorphism (SNP) data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10-8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739-74