ProFunc: a server for predicting protein function from 3D structure

ProFunc () is a web server for predicting the likely function of proteins whose 3D structure is known but whose function is not. Users submit the coordinates of their structure to the server in PDB format. ProFunc makes use of both existing and novel methods to analyse the protein's sequence and structure identifying functional motifs or close relationships to functionally characterized proteins. A summary of the analyses provides an at-a-glance view of what each of the different methods has found. More detailed results are available on separate pages. Often where one method has failed to find anything useful another may be more forthcoming. The server is likely to be of most use in structural genomics where a large proportion of the proteins whose structures are solved are of hypothetical proteins of unknown function. However, it may also find use in a comparative analysis of members of large protein families. It provides a convenient compendium of sequence and structural information that often hold vital functional clues to be followed up experimentally

Cardiovascular mortality and oral antidiabetic drugs: protocol for a systematic review and network meta-analysis

Introduction Cardiovascular diseases are the leading cause of morbidity and mortality among individuals with diabetes. Despite the beneficial effects of antidiabetic drugs (ADDs) in terms of lowering haemoglobin A1c, several ADDs have been shown to increase the risk of cardiovascular events. Given the high prevalence of cardiovascular disease among individuals with diabetes, it is important to weigh the benefits of ADDs against their cardiovascular safety. Therefore, the objective of the current study is to conduct a systematic review with network meta-analysis to compare the effects of different oral pharmacological classes of ADDs on cardiovascular safety. Methods and analysis Randomised clinical trials (RCTs) and observational studies published in English up to 31 January 2017, and which include direct and/or indirect evidence, will be included. Studies will be retrieved by searching four electronic databases and cross-referencing. Dual selection and abstraction of data will occur. The primary outcome will be cardiovascular mortality. Secondary outcomes will include all-cause mortality, new event of acute myocardial infarction, stroke (haemorrhagic and ischaemic), hospitalisation for acute coronary syndrome and urgent revascularisation procedures. Risk of bias will be assessed using the Cochrane Risk of Bias assessment instrument for RCTs and the Strengthening the Reporting of Observational Studies in Epidemiology instrument for observational studies. Network meta-analysis will be performed using multivariate random-effects meta-regression models. The surface under the cumulative ranking curve will be used to provide a hierarchy of ADDs that increase cardiovascular mortality. Dissemination The results of this study will be presented at a professional conference and submitted to a peer-reviewed journal. PROSPERO registration number CRD42017051220

Mapping the Constrained Coding Regions in the human genome to their corresponding proteins

Constrained Coding Regions (CCRs) in the human genome have been derived from DNA sequencing data of large cohorts of healthy control populations, available in the Genome Aggregation Database (gnomAD) [1]. They identify regions depleted of protein-changing variants and thus identify segments of the genome that have been constrained during human evolution. By mapping these DNA-defined regions from genomic coordinates onto the corresponding protein positions and combining this information with protein annotations, we have explored the distribution of CCRs and compared their co-occurrence with different protein functional features, previously annotated at the amino acid level in public databases. As expected, our results reveal that functional amino acids involved in interactions with DNA/RNA, protein-protein contacts and catalytic sites are the protein features most likely to be highly constrained for variation in the control population. More surprisingly, we also found that linear motifs, linear interacting peptides (LIPs), disorder-order transitions upon binding with other protein partners and liquid-liquid phase separating (LLPS) regions are also strongly associated with high constraint for variability. We also compared intra-species constraints in the human CCRs with inter-species conservation and functional residues to explore how such CCRs may contribute to the analysis of protein variants. As has been previously observed, CCRs are only weakly correlated with conservation, suggesting that intraspecies constraints complement interspecies conservation and can provide more information to interpret variant effects

The Host Galaxy and Central Engine of the Dwarf AGN POX 52

We present new multi-wavelength observations of the dwarf Seyfert 1 galaxy POX 52 in order to investigate the properties of the host galaxy and the active nucleus, and to examine the mass of its black hole, previously estimated to be ~ 10^5 M_sun. Hubble Space Telescope ACS/HRC images show that the host galaxy has a dwarf elliptical morphology (M_I = -18.4 mag, Sersic index n = 4.3) with no detected disk component or spiral structure, confirming previous results from ground-based imaging. X-ray observations from both Chandra and XMM show strong (factor of 2) variability over timescales as short as 500 s, as well as a dramatic decrease in the absorbing column density over a 9 month period. We attribute this change to a partial covering absorber, with a 94% covering fraction and N_H = 58^{+8.4}_{-9.2} * 10^21 cm^-2, that moved out of the line of sight in between the XMM and Chandra observations. Combining these data with observations from the VLA, Spitzer, and archival data from 2MASS and GALEX, we examine the spectral energy distribution (SED) of the active nucleus. Its shape is broadly similar to typical radio-quiet quasar SEDs, despite the very low bolometric luminosity of L_bol = 1.3 * 10^43 ergs/s. Finally, we compare black hole mass estimators including methods based on X-ray variability, and optical scaling relations using the broad H-beta line width and AGN continuum luminosity, finding a range of black hole mass from all methods to be M_bh = (2.2-4.2) * 10^5 M_sun, with an Eddington ratio of L_bol/L_edd = 0.2-0.5.Comment: 19 pages, 16 figures, accepted for publication in Ap

Exercise in the treatment of youth substance use disorders: Review and recommendations

Substance use disorders among youth represent a significant public health concern. It is well established that regular exercise provides important physical and mental health benefits; however, evidence for the role of exercise as an adjunct component within substance use disorder treatment is scarce. In this review, we identify factors associated with the development and persistence of substance use disorders among youth, identify current treatment modalities, and present evidence to support the efficacy of incorporating exercise participation during rehabilitation. We also provide a series of recommendations for future research that explores the feasibility and effectiveness of exercise participation as a complement to substance use disorder treatment among youth

The Spring 1985 high precision baseline test of the JPL GPS-based geodetic system

The Spring 1985 High Precision Baseline Test (HPBT) was conducted. The HPBT was designed to meet a number of objectives. Foremost among these was the demonstration of a level of accuracy of 1 to 2:10 to the 7th power, or better, for baselines ranging in length up to several hundred kilometers. These objectives were all met with a high degree of success, with respect to the demonstration of system accuracy in particular. The results from six baselines ranging in length from 70 to 729 km were examined for repeatability and, in the case of three baselines, were compared to results from colocated VLBI systems. Repeatability was found to be 5:10 to the 8th power (RMS) for the north baseline coordinate, independent of baseline length, while for the east coordinate RMS repeatability was found to be larger than this by factors of 2 to 4. The GPS-based results were found to be in agreement with those from colocated VLBI measurements, when corrected for the physical separations of the VLBI and CPG antennas, at the level of 1 to 2:10 to the 7th power in all coordinates, independent of baseline length. The results for baseline repeatability are consistent with the current GPA error budget, but the GPS-VLBI intercomparisons disagree at a somewhat larger level than expected. It is hypothesized that these differences may result from errors in the local survey measurements used to correct for the separations of the GPS and VLBI antenna reference centers

Interleukin‐5 drives glycolysis and reactive oxygen species‐dependent citric acid cycling by eosinophils

Introduction Eosinophils have been long implicated in antiparasite immunity and allergic diseases and, more recently, in regulating adipose tissue homeostasis. The metabolic processes that govern eosinophils, particularly upon activation, are unknown. Methods Peripheral blood eosinophils were isolated for the analysis of metabolic processes using extracellular flux analysis and individual metabolites by stable isotope tracer analysis coupled to gas chromatography‐mass spectrometry following treatment with IL‐3, IL‐5 or granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Eosinophil metabolism was elucidated using pharmacological inhibitors. Results Human eosinophils engage a largely glycolytic metabolism but also employ mitochondrial metabolism. Cytokine stimulation generates citric acid cycle (TCA) intermediates from both glucose and glutamine revealing this previously unknown role for mitochondria upon eosinophil activation. We further show that the metabolic programme driven by IL‐5 is dependent on the STAT5/PI3K/Akt signalling axis and that nicotinamide adenine dinucleotide phosphate oxidase (NOX)‐dependent ROS production might be a driver of mitochondrial metabolism upon eosinophil activation. Conclusion We demonstrate for the first time that eosinophils are capable of metabolic plasticity, evidenced by increased glucose‐derived lactate production upon ROS inhibition. Collectively, this study reveals a role for both glycolysis and mitochondrial metabolism in cytokine‐stimulated eosinophils. Selective targeting of eosinophil metabolism may be of therapeutic benefit in eosinophil‐mediated diseases and regulation of tissue homeostasis

Human populations in the world's mountains: Spatio-temporal patterns and potential controls.

Changing climate and human demographics in the world's mountains will have increasingly profound environmental and societal consequences across all elevations. Quantifying current human populations in and near mountains is crucial to ensure that any interventions in these complex social-ecological systems are appropriately resourced, and that valuable ecosystems are effectively protected. However, comprehensive and reproducible analyses on this subject are lacking. Here, we develop and implement an open workflow to quantify the sensitivity of mountain population estimates over recent decades, both globally and for several sets of relevant reporting regions, to alternative input dataset combinations. Relationships between mean population density and several potential environmental covariates are also explored across elevational bands within individual mountain regions (i.e. "sub-mountain range scale"). Globally, mountain population estimates vary greatly-from 0.344 billion (31%) in 2015. A more detailed analysis using one of the population datasets (GHS-POP) revealed that in ∼35% of mountain sub-regions, population increased at least twofold over the 40-year period 1975-2015. The urban proportion of the total mountain population in 2015 ranged from 6% to 39%, depending on the combination of population and urban extent datasets used. At sub-mountain range scale, population density was found to be more strongly associated with climatic than with topographic and protected-area variables, and these relationships appear to have strengthened slightly over time. Such insights may contribute to improved predictions of future mountain population distributions under scenarios of future climatic and demographic change. Overall, our work emphasizes that irrespective of data choices, substantial human populations are likely to be directly affected by-and themselves affect-mountainous environmental and ecological change. It thereby further underlines the urgency with which the multitudinous challenges concerning the interactions between mountain climate and human societies under change must be tackled

Inferring Mycobacterium bovis transmission between cattle and badgers using isolates from the Randomised Badger Culling Trial.

Mycobacterium bovis (M. bovis) is a causative agent of bovine tuberculosis, a significant source of morbidity and mortality in the global cattle industry. The Randomised Badger Culling Trial was a field experiment carried out between 1998 and 2005 in the South West of England. As part of this trial, M. bovis isolates were collected from contemporaneous and overlapping populations of badgers and cattle within ten defined trial areas. We combined whole genome sequences from 1,442 isolates with location and cattle movement data, identifying transmission clusters and inferred rates and routes of transmission of M. bovis. Most trial areas contained a single transmission cluster that had been established shortly before sampling, often contemporaneous with the expansion of bovine tuberculosis in the 1980s. The estimated rate of transmission from badger to cattle was approximately two times higher than from cattle to badger, and the rate of within-species transmission considerably exceeded these for both species. We identified long distance transmission events linked to cattle movement, recurrence of herd breakdown by infection within the same transmission clusters and superspreader events driven by cattle but not badgers. Overall, our data suggests that the transmission clusters in different parts of South West England that are still evident today were established by long-distance seeding events involving cattle movement, not by recrudescence from a long-established wildlife reservoir. Clusters are maintained primarily by within-species transmission, with less frequent spill-over both from badger to cattle and cattle to badger