Showing papers by "University of Exeter published in 2014"

Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Increasing frequency of extreme El Niño events due to greenhouse warming

Abstract: Extreme El Nino events cause global disruption of weather patterns and affect ecosystems and agriculture through changes in rainfall. Model projections show that a doubling in the occurrence of such extreme episodes is caused by increased surface warming of the eastern equatorial Pacific Ocean, which results in the atmospheric conditions required for these event to occur.

Recent Arctic amplification and extreme mid-latitude weather

Abstract: The Arctic region has warmed more than twice as fast as the global average — a phenomenon known as Arctic amplification. The rapid Arctic warming has contributed to dramatic melting of Arctic sea ice and spring snow cover, at a pace greater than that simulated by climate models. These profound changes to the Arctic system have coincided with a period of ostensibly more frequent extreme weather events across the Northern Hemisphere mid-latitudes, including severe winters. The possibility of a link between Arctic change and mid-latitude weather has spurred research activities that reveal three potential dynamical pathways linking Arctic amplification to mid-latitude weather: changes in storm tracks, the jet stream, and planetary waves and their associated energy propagation. Through changes in these key atmospheric features, it is possible, in principle, for sea ice and snow cover to jointly influence mid-latitude weather. However, because of incomplete knowledge of how high-latitude climate change influences these phenomena, combined with sparse and short data records, and imperfect models, large uncer - tainties regarding the magnitude of such an influence remain. We conclude that improved process understanding, sustained and additional Arctic observations, and better coordinated modelling studies will be needed to advance our understanding of the influences on mid-latitude weather and extreme events.

Contribution of semi-arid ecosystems to interannual variability of the global carbon cycle

Abstract: The land and ocean act as a sink for fossil-fuel emissions, thereby slowing the rise of atmospheric carbon dioxide concentrations. Although the uptake of carbon by oceanic and terrestrial processes has kept pace with accelerating carbon dioxide emissions until now, atmospheric carbon dioxide concentrations exhibit a large variability on interannual timescales, considered to be driven primarily by terrestrial ecosystem processes dominated by tropical rainforests. We use a terrestrial biogeochemical model, atmospheric carbon dioxide inversion and global carbon budget accounting methods to investigate the evolution of the terrestrial carbon sink over the past 30 years, with a focus on the underlying mechanisms responsible for the exceptionally large land carbon sink reported in 2011 (ref. 2). Here we show that our three terrestrial carbon sink estimates are in good agreement and support the finding of a 2011 record land carbon sink. Surprisingly, we find that the global carbon sink anomaly was driven by growth of semi-arid vegetation in the Southern Hemisphere, with almost 60 per cent of carbon uptake attributed to Australian ecosystems, where prevalent La Nina conditions caused up to six consecutive seasons of increased precipitation. In addition, since 1981, a six per cent expansion of vegetation cover over Australia was associated with a fourfold increase in the sensitivity of continental net carbon uptake to precipitation. Our findings suggest that the higher turnover rates of carbon pools in semi-arid biomes are an increasingly important driver of global carbon cycle inter-annual variability and that tropical rainforests may become less relevant drivers in the future. More research is needed to identify to what extent the carbon stocks accumulated during wet years are vulnerable to rapid decomposition or loss through fire in subsequent years.

Effective Messages in Vaccine Promotion: A Randomized Trial

Abstract: OBJECTIVES: To test the effectiveness of messages designed to reduce vaccine misperceptions and increase vaccination rates for measles-mumps-rubella (MMR). METHODS: A Web-based nationally representative 2-wave survey experiment was conducted with 1759 parents age 18 years and older residing in the United States who have children in their household age 17 years or younger (conducted June–July 2011). Parents were randomly assigned to receive 1 of 4 interventions: (1) information explaining the lack of evidence that MMR causes autism from the Centers for Disease Control and Prevention; (2) textual information about the dangers of the diseases prevented by MMR from the Vaccine Information Statement; (3) images of children who have diseases prevented by the MMR vaccine; (4) a dramatic narrative about an infant who almost died of measles from a Centers for Disease Control and Prevention fact sheet; or to a control group. RESULTS: None of the interventions increased parental intent to vaccinate a future child. Refuting claims of an MMR/autism link successfully reduced misperceptions that vaccines cause autism but nonetheless decreased intent to vaccinate among parents who had the least favorable vaccine attitudes. In addition, images of sick children increased expressed belief in a vaccine/autism link and a dramatic narrative about an infant in danger increased self-reported belief in serious vaccine side effects. CONCLUSIONS: Current public health communications about vaccines may not be effective. For some parents, they may actually increase misperceptions or reduce vaccination intention. Attempts to increase concerns about communicable diseases or correct false claims about vaccines may be especially likely to be counterproductive. More study of pro-vaccine messaging is needed.

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

Abstract: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

Uncertainties in CMIP5 Climate Projections due to Carbon Cycle Feedbacks

Abstract: In the context of phase 5 of the Coupled Model Intercomparison Project, most climate simulations use prescribed atmospheric CO2 concentration and therefore do not interactively include the effect of carbon cycle feedbacks. However, the representative concentration pathway 8.5 (RCP8.5) scenario has additionally been run by earth system models with prescribed CO2 emissions. This paper analyzes the climate projections of 11 earth system models (ESMs) that performed both emission-driven and concentration-driven RCP8.5 simulations. When forced by RCP8.5 CO2 emissions, models simulate a large spread in atmospheric CO2; the simulated 2100 concentrations range between 795 and 1145 ppm. Seven out of the 11 ESMs simulate a larger CO2 (on average by 44 ppm, 985 ± 97 ppm by 2100) and hence higher radiative forcing (by 0.25 W m−2) when driven by CO2 emissions than for the concentration-driven scenarios (941 ppm). However, most of these models already overestimate the present-day CO2, with the present-day biase...

Plasmonic meta-atoms and metasurfaces

Abstract: Metamaterials enable the tailoring of properties like dielectric permittivity and magnetic permeability. Electromagnetic excitations of metamaterial constituents and their interactions are reviewed, as well as promising future directions. Despite the extraordinary degree of interest in optical metamaterials in recent years, the hoped-for devices and applications have, in large part, yet to emerge. It is becoming clear that the first generation of metamaterial-based devices will most probably arise from their two-dimensional equivalents — metasurfaces. In this Review, we describe recent progress in the area of metasurfaces formed from plasmonic meta-atoms. In particular, we approach the subject from the perspective of the fundamental excitations supported by the meta-atoms and the interactions between them. We also identify some areas ripe for future research and indicate likely avenues for future device development.

Best practices for use of stable isotope mixing models in food-web studies

Abstract: Stable isotope mixing models are increasingly used to quantify consumer diets, but may be misused and misinter- preted. We address major challenges to their effective application. Mixing models have increased rapidly in sophistication. Current models estimate probability distributions of source contributions, have user-friendly interfaces, and incorporate com- plexities such as variability in isotope signatures, discrimination factors, hierarchical variance structure, covariates, and con- centration dependence. For proper implementation of mixing models, we offer the following suggestions. First, mixing models can only be as good as the study and data. Studies should have clear questions, be informed by knowledge of the system, and have strong sampling designs to effectively characterize isotope variability of consumers and resources on proper spatio-temporal scales. Second, studies should use models appropriate for the question and recognize their assumptions and limitations. Decisions about source grouping or incorporation of concentration dependence can influence results. Third, studies should be careful about interpretation of model outputs. Mixing models generally estimate proportions of assimilated resources with substantial uncertainty distributions. Last, common sense, such as graphing data before analyzing, is essential to maximize usefulness of these tools. We hope these suggestions for effective implementation of stable isotope mixing models will aid continued development and application of this field.

Prevalence, Determinants and Patterns of Multimorbidity in Primary Care: A Systematic Review of Observational Studies

Abstract: Introduction Multimorbidity is a major concern in primary care. Nevertheless, evidence of prevalence and patterns of multimorbidity, and their determinants, are scarce. The aim of this study is to systematically review studies of the prevalence, patterns and determinants of multimorbidity in primary care. Methods Systematic review of literature published between 1961 and 2013 and indexed in Ovid (CINAHL, PsychINFO, Medline and Embase) and Web of Knowledge. Studies were selected according to eligibility criteria of addressing prevalence, determinants, and patterns of multimorbidity and using a pretested proforma in primary care. The quality and risk of bias were assessed using STROBE criteria. Two researchers assessed the eligibility of studies for inclusion (Kappa = 0.86). Results We identified 39 eligible publications describing studies that included a total of 70,057,611 patients in 12 countries. The number of health conditions analysed per study ranged from 5 to 335, with multimorbidity prevalence ranging from 12.9% to 95.1%. All studies observed a significant positive association between multimorbidity and age (odds ratio [OR], 1.26 to 227.46), and lower socioeconomic status (OR, 1.20 to 1.91). Positive associations with female gender and mental disorders were also observed. The most frequent patterns of multimorbidity included osteoarthritis together with cardiovascular and/or metabolic conditions. Conclusions Well-established determinants of multimorbidity include age, lower socioeconomic status and gender. The most prevalent conditions shape the patterns of multimorbidity. However, the limitations of the current evidence base means that further and better designed studies are needed to inform policy, research and clinical practice, with the goal of improving health-related quality of life for patients with multimorbidity. Standardization of the definition and assessment of multimorbidity is essential in order to better understand this phenomenon, and is a necessary immediate step.

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data

Abstract: The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Methane fluxes show consistent temperature dependence across microbial to ecosystem scales

Abstract: Methane (CH4) is an important greenhouse gas because it has 25 times the global warming potential of carbon dioxide (CO2) by mass over a century. Recent calculations suggest that atmospheric CH4 emissions have been responsible for approximately 20% of Earth's warming since pre-industrial times. Understanding how CH4 emissions from ecosystems will respond to expected increases in global temperature is therefore fundamental to predicting whether the carbon cycle will mitigate or accelerate climate change. Methanogenesis is the terminal step in the remineralization of organic matter and is carried out by strictly anaerobic Archaea. Like most other forms of metabolism, methanogenesis is temperature-dependent. However, it is not yet known how this physiological response combines with other biotic processes (for example, methanotrophy, substrate supply, microbial community composition) and abiotic processes (for example, water-table depth) to determine the temperature dependence of ecosystem-level CH4 emissions. It is also not known whether CH4 emissions at the ecosystem level have a fundamentally different temperature dependence than other key fluxes in the carbon cycle, such as photosynthesis and respiration. Here we use meta-analyses to show that seasonal variations in CH4 emissions from a wide range of ecosystems exhibit an average temperature dependence similar to that of CH4 production derived from pure cultures of methanogens and anaerobic microbial communities. This average temperature dependence (0.96 electron volts (eV)), which corresponds to a 57-fold increase between 0 and 30°C, is considerably higher than previously observed for respiration (approximately 0.65 eV) and photosynthesis (approximately 0.3 eV). As a result, we show that both the emission of CH4 and the ratio of CH4 to CO2 emissions increase markedly with seasonal increases in temperature. Our findings suggest that global warming may have a large impact on the relative contributions of CO2 and CH4 to total greenhouse gas emissions from aquatic ecosystems, terrestrial wetlands and rice paddies.

Exercise based rehabilitation for heart failure

Abstract: Background People with heart failure experience marked reductions in their exercise capacity, which has detrimental effects on their activities of daily living, health-related quality of life and ultimately their hospital admission rate and mortality. Study characteristics We searched the scientific literature for randomised controlled trials (experiments in which two or more interventions, possibly including a control intervention or no intervention, are compared by being randomly allocated to participants) looking at the effectiveness of exercise-based treatments compared with no exercise on heart failure in adults over 18 years of age. The inclusion criteria of this updated review were extended to consider not only HF due to reduced ejection fraction (HFREF or 'systolic HF') (ejection fraction is a measure of how well your heart is pumping), but also HF due to preserved ejection fraction (HFPEF or 'diastolic HF'). The search is current to January 2013. Key results We found 33 RCTs that included 4740 participants. The findings of this update are consistent with the previous (2010) version of this Cochrane review and show important benefits of exercise-based rehabilitation that include a reduction in the risk of hospital admissions due to HF and improvements in health-related quality of life compared with not undertaking exercise. There was a high level of variation across studies in health-related quality of life outcome. While the majority of evidence was for exercise-based rehabilitation in people with HFREF, this update did identify a broader evidence base that included higher risk (New York Heart Association class IV) and older people, people with HFPEF and more programmes conducted in a home-based setting. We found no evidence to suggest that exercise training programmes cause harm in terms of an increase in the risk of death in either the short or longer term. A small body of economic evidence was identified indicating exercise-based rehabilitation to be cost-effective. Further evidence is needed to understand the effect of exercise training in people with HFPEF better and the costs and effects of exclusively home-based exercise rehabilitation programmes.

Zeolitic imidazolate framework materials: recent progress in synthesis and applications

Abstract: Zeolitic imidazolate frameworks (ZIFs) represent a new and special class of metal organic frameworks comprised of imidazolate linkers and metal ions, with structures similar to conventional aluminosilicate zeolites Their intrinsic porous characteristics, abundant functionalities as well as exceptional thermal and chemical stabilities have led to a wide range of potential applications for various ZIF materials Explosive research activities ranging from synthesis approaches to attractive applications of ZIFs have emerged in this rapidly developing field in the past 5 years In this review, the development and recent progress towards different synthesis strategies to generate both powder and membrane/film-based ZIF materials are analysed and summarised Their attractive and potential applications in gas separation, catalysis, sensing and electronic devices, and drug delivery in the past years are discussed and reviewed In addition, the prospects and potential new development of ZIF materials are presented

Unravelling the structural and mechanistic basis of CRISPR-Cas systems.

Abstract: Bacteria and archaea have evolved sophisticated adaptive immune systems, known as CRISPR–Cas (clustered regularly interspaced short palindromic repeats–CRISPR-associated proteins) systems, which target and inactivate invading viruses and plasmids. Immunity is acquired by integrating short fragments of foreign DNA into CRISPR loci, and following transcription and processing of these loci, the CRISPR RNAs (crRNAs) guide the Cas proteins to complementary invading nucleic acid, which results in target interference. In this Review, we summarize the recent structural and biochemical insights that have been gained for the three major types of CRISPR–Cas systems, which together provide a detailed molecular understanding of the unique and conserved mechanisms of RNA-guided adaptive immunity in bacteria and archaea.

Persistent growth of CO2 emissions and implications for reaching climate targets

Abstract: Efforts to limit climate change below a given temperature level require that global emissions of CO2 cumulated over time remain below a limited quota. This quota varies depending on the temperature level, the desired probability of staying below this level and the contributions of other gases. In spite of this restriction, global emissions of CO2 from fossil fuel combustion and cement production have continued to grow by 2.5% per year on average over the past decade. Two thirds of the CO2 emission quota consistent with a 2 °C temperature limit has already been used, and the total quota will likely be exhausted in a further 30 years at the 2014 emissions rates. We show that CO2 emissions track the high end of the latest generation of emissions scenarios, due to lower than anticipated carbon intensity improvements of emerging economies and higher global gross domestic product growth. In the absence of more stringent mitigation, these trends are set to continue and further reduce the remaining quota until the onset of a potential new climate agreement in 2020. Breaking current emission trends in the short term is key to retaining credible climate targets within a rapidly diminishing emission quota.

An optoelectronic framework enabled by low-dimensional phase-change films

Abstract: The development of materials whose refractive index can be optically transformed as desired, such as chalcogenide-based phase-change materials, has revolutionized the media and data storage industries by providing inexpensive, high-speed, portable and reliable platforms able to store vast quantities of data. Phase-change materials switch between two solid states--amorphous and crystalline--in response to a stimulus, such as heat, with an associated change in the physical properties of the material, including optical absorption, electrical conductance and Young's modulus. The initial applications of these materials (particularly the germanium antimony tellurium alloy Ge2Sb2Te5) exploited the reversible change in their optical properties in rewritable optical data storage technologies. More recently, the change in their electrical conductivity has also been extensively studied in the development of non-volatile phase-change memories. Here we show that by combining the optical and electronic property modulation of such materials, display and data visualization applications that go beyond data storage can be created. Using extremely thin phase-change materials and transparent conductors, we demonstrate electrically induced stable colour changes in both reflective and semi-transparent modes. Further, we show how a pixelated approach can be used in displays on both rigid and flexible films. This optoelectronic framework using low-dimensional phase-change materials has many likely applications, such as ultrafast, entirely solid-state displays with nanometre-scale pixels, semi-transparent 'smart' glasses, 'smart' contact lenses and artificial retina devices.

Bacteria–phage coevolution as a driver of ecological and evolutionary processes in microbial communities

Abstract: Bacteria–phage coevolution, the reciprocal evolution between bacterial hosts and the phages that infect them, is an important driver of ecological and evolutionary processes in microbial communities. There is growing evidence from both laboratory and natural populations that coevolution can maintain phenotypic and genetic diversity, increase the rate of bacterial and phage evolution and divergence, affect community structure, and shape the evolution of ecologically relevant bacterial traits. Although the study of bacteria–phage coevolution is still in its infancy, with open questions regarding the specificity of the interaction, the gene networks of coevolving partners, and the relative importance of the coevolving interaction in complex communities and environments, there have recently been major advancements in the field. In this review, we sum up our current understanding of bacteria–phage coevolution both in the laboratory and in nature, discuss recent findings on both the coevolutionary process itself and the impact of coevolution on bacterial phenotype, diversity and interactions with other species (particularly their eukaryotic hosts), and outline future directions for the field.

Disease associations between honeybees and bumblebees as a threat to wild pollinators

Abstract: Emerging infectious diseases (EIDs) pose a risk to human welfare, both directly and indirectly, by affecting managed livestock and wildlife that provide valuable resources and ecosystem services, such as the pollination of crops. Honeybees (Apis mellifera), the prevailing managed insect crop pollinator, suffer from a range of emerging and exotic high-impact pathogens, and population maintenance requires active management by beekeepers to control them. Wild pollinators such as bumblebees (Bombus spp.) are in global decline, one cause of which may be pathogen spillover from managed pollinators like honeybees or commercial colonies of bumblebees. Here we use a combination of infection experiments and landscape-scale field data to show that honeybee EIDs are indeed widespread infectious agents within the pollinator assemblage. The prevalence of deformed wing virus (DWV) and the exotic parasite Nosema ceranae in honeybees and bumblebees is linked; as honeybees have higher DWV prevalence, and sympatric bumblebees and honeybees are infected by the same DWV strains, Apis is the likely source of at least one major EID in wild pollinators. Lessons learned from vertebrates highlight the need for increased pathogen control in managed bee species to maintain wild pollinators, as declines in native pollinators may be caused by interspecies pathogen transmission originating from managed pollinators.

Uptake and retention of microplastics by the shore crab Carcinus maenas.

Abstract: Microplastics, plastics particles <5 mm in length, are a widespread pollutant of the marine environment. Oral ingestion of microplastics has been reported for a wide range of marine biota, but uptake into the body by other routes has received less attention. Here, we test the hypothesis that the shore crab (Carcinus maenas) can take up microplastics through inspiration across the gills as well as ingestion of pre-exposed food (common mussel Mytilus edulis). We used fluorescently labeled polystyrene microspheres (8–10 μm) to show that ingested microspheres were retained within the body tissues of the crabs for up to 14 days following ingestion and up to 21 days following inspiration across the gill, with uptake significantly higher into the posterior versus anterior gills. Multiphoton imaging suggested that most microspheres were retained in the foregut after dietary exposure due to adherence to the hairlike setae and were found on the external surface of gills following aqueous exposure. Results were used...

On the ability to inhibit thought and action: general and special theories of an act of control.

Abstract: Response inhibition is an important act of control in many domains of psychology and neuroscience. It is often studied in a stop-signal task that requires subjects to inhibit an ongoing action in response to a stop signal. Performance in the stop-signal task is understood as a race between a go process that underlies the action and a stop process that inhibits the action. Responses are inhibited if the stop process finishes before the go process. The finishing time of the stop process is not directly observable; a mathematical model is required to estimate its duration. Logan and Cowan (1984) developed an independent race model that is widely used for this purpose. We present a general race model that extends the independent race model to account for the role of choice in go and stop processes, and a special race model that assumes each runner is a stochastic accumulator governed by a diffusion process. We apply the models to 2 data sets to test assumptions about selective influence of capacity limitations on drift rates and strategies on thresholds, which are largely confirmed. The model provides estimates of distributions of stop-signal response times, which previous models could not estimate. We discuss implications of viewing cognitive control as the result of a repertoire of acts of control tailored to different tasks and situations.

Evolutionary algorithms and other metaheuristics in water resources

Abstract: The development and application of evolutionary algorithms (EAs) and other metaheuristics for the optimisation of water resources systems has been an active research field for over two decades. Research to date has emphasized algorithmic improvements and individual applications in specific areas (e.g. model calibration, water distribution systems, groundwater management, river-basin planning and management, etc.). However, there has been limited synthesis between shared problem traits, common EA challenges, and needed advances across major applications. This paper clarifies the current status and future research directions for better solving key water resources problems using EAs. Advances in understanding fitness landscape properties and their effects on algorithm performance are critical. Future EA-based applications to real-world problems require a fundamental shift of focus towards improving problem formulations, understanding general theoretic frameworks for problem decompositions, major advances in EA computational efficiency, and most importantly aiding real decision-making in complex, uncertain application contexts.

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

Abstract: 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.

Temperature sensitivity of soil respiration rates enhanced by microbial community response

Abstract: Soils store about four times as much carbon as plant biomass, and soil microbial respiration releases about 60 petagrams of carbon per year to the atmosphere as carbon dioxide. Short-term experiments have shown that soil microbial respiration increases exponentially with temperature. This information has been incorporated into soil carbon and Earth-system models, which suggest that warming-induced increases in carbon dioxide release from soils represent an important positive feedback loop that could influence twenty-first-century climate change. The magnitude of this feedback remains uncertain, however, not least because the response of soil microbial communities to changing temperatures has the potential to either decrease or increase warming-induced carbon losses substantially. Here we collect soils from different ecosystems along a climate gradient from the Arctic to the Amazon and investigate how microbial community-level responses control the temperature sensitivity of soil respiration. We find that the microbial community-level response more often enhances than reduces the mid- to long-term (90 days) temperature sensitivity of respiration. Furthermore, the strongest enhancing responses were observed in soils with high carbon-to-nitrogen ratios and in soils from cold climatic regions. After 90 days, microbial community responses increased the temperature sensitivity of respiration in high-latitude soils by a factor of 1.4 compared to the instantaneous temperature response. This suggests that the substantial carbon stores in Arctic and boreal soils could be more vulnerable to climate warming than currently predicted.

Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease

Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and cognitive decline. We performed a cross-tissue analysis of methylomic variation in AD using samples from four independent human post-mortem brain cohorts. We identified a differentially methylated region in the ankyrin 1 (ANK1) gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as being substantially hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex), but not in the cerebellum, a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from three independent brain cohorts. This study represents, to the best of our knowledge, the first epigenome-wide association study of AD employing a sequential replication design across multiple tissues and highlights the power of this approach for identifying methylomic variation associated with complex disease.

Human Capital Theory: A Holistic Criticism

Abstract: Human capital theory has had a profound impact on a range of disciplines from economics to education and sociology. The theory has always been the subject of bitter criticisms from the very beginning, but it has comfortably survived and expanded its influence over other research disciplines. Not surprisingly, a considerable number of criticisms have been made as a reaction to this expansion. However, it seems that these criticisms are rather fragmented and disorganized. To bridge this gap and organize them in a systematic way, the present article takes a holistic approach and reviews human capital theory from four comprehensive perspectives focusing on the methodological, empirical, practical, and moral aspects of the theory.

Diabetes Prevention in the Real World: Effectiveness of Pragmatic Lifestyle Interventions for the Prevention of Type 2 Diabetes and of the Impact of Adherence to Guideline Recommendations: A Systematic Review and Meta-analysis

Abstract: OBJECTIVE To summarize the evidence on effectiveness of translational diabetes prevention programs, based on promoting lifestyle change to prevent type 2 diabetes in real-world settings and to examine whether adherence to international guideline recommendations is associated with effectiveness. RESEARCH DESIGN AND METHODS Bibliographic databases were searched up to July 2012. Included studies had a follow-up of ≥12 months and outcomes comparing change in body composition, glycemic control, or progression to diabetes. Lifestyle interventions aimed to translate evidence from previous efficacy trials of diabetes prevention into real-world intervention programs. Data were combined using random-effects meta-analysis and meta-regression considering the relationship between intervention effectiveness and adherence to guidelines. RESULTS Twenty-five studies met the inclusion criteria. The primary meta-analysis included 22 studies (24 study groups) with outcome data for weight loss at 12 months. The pooled result of the direct pairwise meta-analysis shows that lifestyle interventions resulted in a mean weight loss of 2.12 kg (95% CI -2.61 to -1.63; I(2) = 91.4%). Adherence to guidelines was significantly associated with a greater weight loss (an increase of 0.3 kg per point increase on a 12-point guideline-adherence scale). CONCLUSIONS Evidence suggests that pragmatic diabetes prevention programs are effective. Effectiveness varies substantially between programs but can be improved by maximizing guideline adherence. However, more research is needed to establish optimal strategies for maximizing both cost-effectiveness and longer-term maintenance of weight loss and diabetes prevention effects.

Global environmental change I A social turn for resilience

Abstract: Resilience is everywhere in contemporary debates about global environmental change. The application of resilience concepts to social and ecological systems and dilemmas has been roundly critiqued f...