Regulation of human mTOR complexes by DEPTOR

The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease

A global analysis of management capacity and ecological outcomes in terrestrial protected areas

Protecting important sites is a key strategy for halting the loss of biodiversity. However, our understanding of the relationship between management inputs and biodiversity outcomes in protected areas (PAs) remains weak. Here, we examine biodiversity outcomes using species population trends in PAs derived from the Living Planet Database in relation to management data derived from the Management Effectiveness Tracking Tool (METT) database for 217 population time-series from 73 PAs. We found a positive relationship between our METT-based scores for Capacity and Resources and changes in vertebrate abundance, consistent with the hypothesis that PAs require adequate resourcing to halt biodiversity loss. Additionally, PA age was negatively correlated with trends for the mammal subsets and PA size negatively correlated with population trends in the global subset. Our study highlights the paucity of appropriate data for rigorous testing of the role of management in maintaining species populations across multiple sites, and describes ways to improve our understanding of PA performance

Differences in adiposity trajectories by birth cohort and childhood social class: evidence from cohorts born in the 1930s, 1950s and 1970s in the west of Scotland

Background Since the 1930s, the environment has become increasingly obesogenic, leading to rising rates of adiposity and socioeconomic inequalities in adiposity. Building on studies comparing body mass index (BMI) for cohorts born over a period of 20 years, we examine the social patterning of BMI and central adiposity for three cohorts born over a 40-year period. Methods Using data from the West of Scotland Twenty-07 study (n=4510), we investigate 20-year trajectories of adiposity for three cohorts born in the 1930s, 1950s and 1970s, allowing us to study 60 years of the lifecourse. Stratified by gender, we employed multilevel models to generate trajectories for BMI and waist-to-height ratio (WHtR) and explored how these trajectories varied by childhood social class. Results Adiposity increased most quickly with age in the youngest cohort, and cohort differences were greater than socioeconomic differences. For example, the smallest cohort difference for BMI, a comparison of men in the 1930s and 1950s cohorts at age 55, was 2.66 (95% CI 2.11 to 3.20) kg/m2, while the largest socioeconomic difference, a comparison of manual and non-manual women at age 64, was 1.18 (95% CI 0.37 to 1.98) kg/m2. Socioeconomic inequalities in adiposity increased with age and were greater for women than for men. The results for WHtR differed in that increases in WHtR accelerated with age while increases in BMI slowed. Conclusions Socioeconomic differences in adiposity accumulate slowly across the lifecourse and are approximately only a third of the adiposity differences between cohorts

Systematic reviews of observational studies of risk of thrombosis and bleeding in urological surgery (ROTBUS) : introduction and methodology

Abstract Background Pharmacological thromboprophylaxis in the peri-operative period involves a trade-off between reduction in venous thromboembolism (VTE) and an increase in bleeding. Baseline risks, in the absence of prophylaxis, for VTE and bleeding are known to vary widely between urological procedures, but their magnitude is highly uncertain. Systematic reviews and meta-analyses addressing baseline risks are uncommon, needed, and require methodological innovation. In this article, we describe the rationale and methods for a series of systematic reviews of the risks of symptomatic VTE and bleeding requiring reoperation in urological surgery. Methods/design We searched MEDLINE from January 1, 2000 until April 10, 2014 for observational studies reporting on symptomatic VTE or bleeding after urological procedures. Additional studies known to experts and studies cited in relevant review articles were added. Teams of two reviewers, independently assessed articles for eligibility, evaluated risk of bias, and abstracted data. We derived best estimates of risk from the median estimates among studies rated at the lowest risk of bias. The primary endpoints were 30-day post-operative risk estimates of symptomatic VTE and bleeding requiring reoperation, stratified by procedure and patient risk factors. Discussion This series of systematic reviews will inform clinicians and patients regarding the trade-off between VTE prevention and bleeding. Our work advances standards in systematic reviews of surgical complications, including assessment of risk of bias, criteria for arriving at best estimates of risk (including modeling of timing of events and dealing with suboptimal data reporting), dealing with subgroups at higher and lower risk of bias, and use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate certainty in estimates of risk. The results will be incorporated in the upcoming European Association Urology Guideline on Thromboprophylaxis. Systematic review registration PROSPERO CRD42014010342

Testing the Accuracy of Aerial Surveys for Large Mammals: An Experiment with African Savanna Elephants (Loxodonta africana)

Accurate counts of animals are critical for prioritizing conservation efforts. Past research, however, suggests that observers on aerial surveys may fail to detect all individuals of the target species present in the survey area. Such errors could bias population estimates low and confound trend estimation. We used two approaches to assess the accuracy of aerial surveys for African savanna elephants (Loxodonta africana) in northern Botswana. First, we used double-observer sampling, in which two observers make observations on the same herds, to estimate detectability of elephants and determine what variables affect it. Second, we compared total counts, a complete survey of the entire study area, against sample counts, in which only a portion of the study area is sampled. Total counts are often considered a complete census, so comparing total counts against sample counts can help to determine if sample counts are underestimating elephant numbers. We estimated that observers detected only 76% ± SE of 2% of elephant herds and 87 ± 1% of individual elephants present in survey strips. Detectability increased strongly with elephant herd size. Out of the four observers used in total, one observer had a lower detection probability than the other three, and detectability was higher in the rear row of seats than the front. The habitat immediately adjacent to animals also affected detectability, with detection more likely in more open habitats. Total counts were not statistically distinguishable from sample counts. Because, however, the double-observer samples revealed that observers missed 13% of elephants, we conclude that total counts may be undercounting elephants as well. These results suggest that elephant population estimates from both sample and total counts are biased low. Because factors such as observer and habitat affected detectability of elephants, comparisons of elephant populations across time or space may be confounded. We encourage survey teams to incorporate detectability analysis in all aerial surveys for mammals

European Code against Cancer 4th Edition:Obesity, body fatness and cancer

AbstractIt is estimated that over half the population of the European Union (EU) is overweight or obese due to an imbalance between energy expenditure and energy intake; this is related to an obesogenic environment of sociocultural, economic and marketing challenges to the control of body weight. Excess body fat is associated with nine cancer sites – oesophagus, colorectum, gall bladder, pancreas, postmenopausal breast, endometrium, ovary, kidney and prostate (advanced) – and 4–38% of these cancers (depending on site and gender) can be attributed to overweight/obesity status. Metabolic alterations which accompany excess body weight are accompanied by increased levels of inflammation, insulin, oestrogens and other hormonal factors. There are some indications that intentional weight loss is associated with reduced cancer incidence (notably in postmenopausal breast and endometrial cancers). Excess body weight is also a risk factor for several other diseases, including diabetes and heart disease, and is related to higher risk of premature death.In reviewing the current evidence related to excess body fat and cancer, the European Code against Cancer Nutrition Working Group has developed the following recommendation: ‘Take action to be a healthy body weight’

Protecting Important Sites for Biodiversity Contributes to Meeting Global Conservation Targets

Protected areas (PAs) are a cornerstone of conservation efforts and now cover nearly 13% of the world's land surface, with the world's governments committed to expand this to 17%. However, as biodiversity continues to decline, the effectiveness of PAs in reducing the extinction risk of species remains largely untested. We analyzed PA coverage and trends in species' extinction risk at globally significant sites for conserving birds (10,993 Important Bird Areas, IBAs) and highly threatened vertebrates and conifers (588 Alliance for Zero Extinction sites, AZEs) (referred to collectively hereafter as ‘important sites’). Species occurring in important sites with greater PA coverage experienced smaller increases in extinction risk over recent decades: the increase was half as large for bird species with>50% of the IBAs at which they occur completely covered by PAs, and a third lower for birds, mammals and amphibians restricted to protected AZEs (compared with unprotected or partially protected sites). Globally, half of the important sites for biodiversity conservation remain unprotected (49% of IBAs, 51% of AZEs). While PA coverage of important sites has increased over time, the proportion of PA area covering important sites, as opposed to less important land, has declined (by 0.45–1.14% annually since 1950 for IBAs and 0.79–1.49% annually for AZEs). Thus, while appropriately located PAs may slow the rate at which species are driven towards extinction, recent PA network expansion has under-represented important sites. We conclude that better targeted expansion of PA networks would help to improve biodiversity trends

Understanding Eating Disorders in Elite Gymnastics

Eating disorders and disordered eating are more common in high performance sports than the general population, and particularly so in high performance aesthetic sports. This paper presents some of the conceptual difficulties in understanding and diagnosing eating disorders in high performance gymnasts. It presents qualitative and quantitative data from a study designed to ascertain the pattern of eating disorder symptoms, depressive symptoms and levels of self-esteem amongst national and international level gymnasts from the UK in the gymnastic disciplines of sport acrobatics, tumbling and rhythmic gymnastics