Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

A statistical downscaling framework for environmental mapping

In recent years, knowledge extraction from data has become increasingly popular, with many numerical forecasting models, mainly falling into two major categories—chemical transport models (CTMs) and conventional statistical methods. However, due to data and model variability, data-driven knowledge extraction from high-dimensional, multifaceted data in such applications require generalisations of global to regional or local conditions. Typically, generalisation is achieved via mapping global conditions to local ecosystems and human habitats which amounts to tracking and monitoring environmental dynamics in various geographical areas and their regional and global implications on human livelihood. Statistical downscaling techniques have been widely used to extract high-resolution information from regional-scale variables produced by CTMs in climate model. Conventional applications of these methods are predominantly dimensional reduction in nature, designed to reduce spatial dimension of gridded model outputs without loss of essential spatial information. Their downside is twofold—complete dependence on unlabelled design matrix and reliance on underlying distributional assumptions. We propose a novel statistical downscaling framework for dealing with data and model variability. Its power derives from training and testing multiple models on multiple samples, narrowing down global environmental phenomena to regional discordance through dimensional reduction and visualisation. Hourly ground-level ozone observations were obtained from various environmental stations maintained by the US Environmental Protection Agency, covering the summer period (June–August 2005). Regional patterns of ozone are related to local observations via repeated runs and performance assessment of multiple versions of empirical orthogonal functions or principal components and principal fitted components via an algorithm with fully adaptable parameters. We demonstrate how the algorithm can be extended to weather-dependent and other applications with inherent data randomness and model variability via its built-in interdisciplinary computational power that connects data sources with end-users

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Risk Reducing Salpingectomy and Delayed Oophorectomy in high risk women: views of cancer geneticists, genetic counsellors and gynaecological oncologists in the UK

Risk-reducing-salpingectomy and Delayed-Oophorectomy (RRSDO) is being proposed as a two-staged approach in place of RRSO to reduce the risks associated with premature menopause in high-risk women. We report on the acceptability/attitude of UK health professionals towards RRSDO. An anonymised web-based survey was sent to UK Cancer Genetics Group (CGG) and British Gynaecological Cancer Society (BGCS) members to assess attitudes towards RRSDO. Baseline characteristics were described using descriptive statistics. A Chi square test was used to compare categorical, Kendal-tau-b test for ordinal and Mann–Whitney test for continuous variables between two groups. 173/708 (24.4 %) of invitees responded. 71 % respondents (CGG = 57 %/BGCS = 83 %, p = 0.005) agreed with the tubal hypothesis for OC, 55 % (CGG = 42 %/BGCS = 66 %, p = 0.003) had heard of RRSDO and 48 % (CGG = 46 %/BGCS = 50 %) felt evidence was not currently strong enough for introduction into clinical practice. However, 60 % respondents’ (CGG = 48 %/BGCS = 71 %, p = 0.009) favoured offering RRSDO to high-risk women declining RRSO, 77 % only supported RRSDO within a clinical trial (CGG = 78 %/BGCS = 76 %) and 81 % (CGG = 76 %/BGCS = 86 %) advocated a UK-wide registry. Vasomotor symptoms (72 %), impact on sexual function (63 %), osteoporosis (59 %), hormonal-therapy (55 %) and subfertility (48 %) related to premature menopause influenced their choice of RRSDO. Potential barriers to offering the two-stage procedure included lack of data on precise level of benefit (83 %), increased surgical morbidity (79 %), loss of breast cancer risk reduction associated with oophorectomy (68 %), need for long-term follow-up (61 %) and a proportion not undergoing DO (66 %). There were variations in perception between BGCS/CGG members which are probably attributable to differences in clinical focus/expertise between these two groups. Despite concerns, there is reasonable support amongst UK clinicians to offering RRSDO to premenopausal high-risk women wishing to avoid RRSO, within a prospective clinical trial.This work has not been directly funded by any commercial organisation, or charity

A Dutch guideline for the treatment of scoliosis in neuromuscular disorders

<p>Abstract</p> <p>Background</p> <p>Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.</p> <p>Methods</p> <p>The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.</p> <p>Results</p> <p>For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.</p> <p>Conclusion</p> <p>In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders.</p

Irreducible uncertainty in near-term climate projections

Model simulations of the next few decades are widely used in assessments of climate change impacts and as guidance for adaptation. Their non-linear nature reveals a level of irreducible uncertainty which it is important to understand and quantify, especially for projections of near-term regional climate. Here we use large idealised initial condition ensembles of the FAMOUS global climate model with a 1 %/year compound increase in CO2 levels to quantify the range of future temperatures in model-based projections. These simulations explore the role of both atmospheric and oceanic initial conditions and are the largest such ensembles to date. Short-term simulated trends in global temperature are diverse, and cooling periods are more likely to be followed by larger warming rates. The spatial pattern of near-term temperature change varies considerably, but the proportion of the surface showing a warming is more consistent. In addition, ensemble spread in inter-annual temperature declines as the climate warms, especially in the North Atlantic. Over Europe, atmospheric initial condition uncertainty can, for certain ocean initial conditions, lead to 20 year trends in winter and summer in which every location can exhibit either strong cooling or rapid warming. However, the details of the distribution are highly sensitive to the ocean initial condition chosen and particularly the state of the Atlantic meridional overturning circulation. On longer timescales, the warming signal becomes more clear and consistent amongst different initial condition ensembles. An ensemble using a range of different oceanic initial conditions produces a larger spread in temperature trends than ensembles using a single ocean initial condition for all lead times. This highlights the potential benefits from initialising climate predictions from ocean states informed by observations. These results suggest that climate projections need to be performed with many more ensemble members than at present, using a range of ocean initial conditions, if the uncertainty in near-term regional climate is to be adequately quantified

The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase

Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia. Tumour-secreted proteins play a crucial role in these interactions and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis,independent of RANK ligand, which disrupts normal bone homeostasisleading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications

Facial Cosmetics and Attractiveness: Comparing the Effect Sizes of Professionally-Applied Cosmetics and Identity

Forms of body decoration exist in all human cultures. However, in Western societies, women are more likely to engage in appearance modification, especially through the use of facial cosmetics. How effective are cosmetics at altering attractiveness? Previous research has hinted that the effect is not large, especially when compared to the variation in attractiveness observed between individuals due to differences in identity. In order to build a fuller understanding of how cosmetics and identity affect attractiveness, here we examine how professionally-applied cosmetics alter attractiveness and compare this effect with the variation in attractiveness observed between individuals. In Study 1, 33 YouTube models were rated for attractiveness before and after the application of professionally-applied cosmetics. Cosmetics explained a larger proportion of the variation in attractiveness compared with previous studies, but this effect remained smaller than variation caused by differences in attractiveness between individuals. Study 2 replicated the results of the first study with a sample of 45 supermodels, with the aim of examining the effect of cosmetics in a sample of faces with low variation in attractiveness between individuals. While the effect size of cosmetics was generally large, between-person variability due to identity remained larger. Both studies also found interactions between cosmetics and identity-more attractive models received smaller increases when cosmetics were worn. Overall, we show that professionally- applied cosmetics produce a larger effect than self-applied cosmetics, an important theoretical consideration for the field. However, the effect of individual differences in facial appearance is ultimately more important in perceptions of attractiveness

Wear and corrosion interactions on titanium in oral environment : literature review

The oral cavity is a complex environment where corrosive substances from dietary, human saliva, and oral biofilms may accumulate in retentive areas of dental implant systems and prostheses promoting corrosion at their surfaces. Additionally, during mastication, micromovements may occur between prosthetic joints causing a relative motion between contacting surfaces, leading to wear. Both processes (wear and corrosion) result in a bio-tribocorrosion system once that occurs in contact with biological tissues and fluids. This review paper is focused on the aspects related to the corrosion and wear behavior of titanium-based structures in the oral environment. Furthermore, the clinical relevance of the oral environment is focused on the harmful effect that acidic substances and biofilms, formed in human saliva, may have on titanium surfaces. In fact, a progressive degradation of titanium by wear and corrosion (tribocorrosion) mechanisms can take place affecting the performance of titanium-based implant and prostheses. Also, the formation of wear debris and metallic ions due to the tribocorrosion phenomena can become toxic for human tissues. This review gathers knowledge from areas like materials sciences, microbiology, and dentistry contributing to a better understanding of bio-tribocorrosion processes in the oral environment.(undefined