ECOdrug: A database connecting drugs and conservation of their targets across species

This is the author accepted manuscriptPharmaceuticals are designed to interact with specific molecular targets in humans and these targets generally have orthologs in other species. This provides opportunities for the drug discovery community to use alternative model species for drug development. It also means, however, there is potential for mode of action related effects in non-target wildlife species as many pharmaceuticals reach the environment through patient use and manufacturing wastes. Acquiring insight in drug target ortholog predictions across species and taxonomic groups has proven difficult because of the lack of an optimal strategy and because necessary information is spread across multiple and diverse sources and platforms. We introduce a new research platform tool, ECOdrug, that reliably connects drugs to their protein targets across divergent species. It harmonizes ortholog predictions from multiple sources via a simple user interface underpinning critical applications for a wide range of studies in pharmacology, ecotoxicology and comparative evolutionary biology. ECOdrug can be used to identify species with drug targets and identify drugs that interact with those targets. As such, it can be applied to support intelligent targeted drug safety testing by ensuring appropriate and relevant species are selected in ecological risk assessments. ECOdrug is freely accessible and available at: Http://www.ecodrug.org.Innovative Medicines Initiative Joint Undertaking under Intelligent Assessment of PharmaceuticalsEuropean Union’s Seventh Framework ProgrammeAstraZenecaNC3Rs funded projec

Combined Effects of Thrombosis Pathway Gene Variants Predict Cardiovascular Events

The genetic background of complex diseases is proposed to consist of several low-penetrance risk loci. Addressing this complexity likely requires both large sample size and simultaneous analysis of different predisposing variants. We investigated the role of four thrombosis genes: coagulation factor V (F5), intercellular adhesion molecule 1 (ICAM1), protein C (PROC), and thrombomodulin (THBD) in cardiovascular diseases. Single allelic gene variants and their pair-wise combinations were analyzed in two independently sampled population cohorts from Finland. From among 14,140 FINRISK participants (FINRISK-92, n = 5,999 and FINRISK-97, n = 8,141), we selected for genotyping a sample of 2,222, including 528 incident cardiovascular disease (CVD) cases and random subcohorts totaling 786. To cover all known common haplotypes (>10%), 54 single nucleotide polymorphisms (SNPs) were genotyped. Classification-tree analysis identified 11 SNPs that were further analyzed in Cox's proportional hazard model as single variants and pair-wise combinations. Multiple testing was controlled by use of two independent cohorts and with false-discovery rate. Several CVD risk variants were identified: In women, the combination of F5 rs7542281 × THBD rs1042580, together with three single F5 SNPs, was associated with CVD events. Among men, PROC rs1041296, when combined with either ICAM1 rs5030341 or F5 rs2269648, was associated with total mortality. As a single variant, PROC rs1401296, together with the F5 Leiden mutation, was associated with ischemic stroke events. Our strategy to combine the classification-tree analysis with more traditional genetic models was successful in identifying SNPs—acting either in combination or as single variants—predisposing to CVD, and produced consistent results in two independent cohorts. These results suggest that variants in these four thrombosis genes contribute to arterial cardiovascular events at population level

Photon capture cones and embedding diagrams of the Ernst spacetime

The differences between the character of the Schwarzschild and Ernst spacetimes are illustrated by comparing the photon capture cones, and the embedding diagrams of the $t=\mathrm{const}$ sections of the equatorial planes of both the ordinary and optical reference geometry of these spacetimes. The non-flat asymptotic character of the Ernst spacetime reflects itself in two manifest facts: the escape photon cones correspond to purely outward radial direction, and the embedding diagrams of both the ordinary and optical geometry shrink to zero radius asymptotically. Using the properties of the embedding diagrams, regions of these spacetimes which could have similar character are estimated, and it is argued that they can exist for the Ernst spacetimes with a sufficiently low strength of the magnetic field.Comment: 12 pages, 7 figure

Comprehensive screening of genomic and metagenomic data reveals a large diversity of tetracycline resistance genes

Tetracyclines are broad-spectrum antibiotics used to prevent or treat a variety of bacterial infections. Resistance is often mediated through mobile resistance genes, which encode one of the three main mechanisms: active efflux, ribosomal target protection or enzymatic degradation. In the last few decades, a large number of new tetracycline-resistance genes have been discovered in clinical settings. These genes are hypothesized to originate from environmental and commensal bacteria, but the diversity of tetracycline-resistance determinants that have not yet been mobilized into pathogens is unknown. In this study, we aimed to characterize the potential tetracycline resistome by screening genomic and metagenomic data for novel resistance genes. By using probabilistic models, we predicted 1254 unique putative tetracycline resistance genes, representing 195 gene families (<70 % amino acid sequence identity), whereof 164 families had not been described previously. Out of 17 predicted genes selected for experimental verification, 7 induced a resistance phenotype in an Escherichia coli host. Several of the predicted genes were located on mobile genetic elements or in regions that indicated mobility, suggesting that they easily can be shared between bacteria. Furthermore, phylogenetic analysis indicated several events of horizontal gene transfer between bacterial phyla. Our results also suggested that acquired efflux pumps originate from proteobacterial species, while ribosomal protection genes have been mobilized from Firmicutes and Actinobacteria. This study significantly expands the knowledge of known and putatively novel tetracycline resistance genes, their mobility and evolutionary history. The study also provides insights into the unknown resistome and genes that may be encountered in clinical settings in the future

Pregnancy related back pain, is it related to aerobic fitness? A longitudinal cohort study

<p>Abstract</p> <p>Background</p> <p>Low back pain with onset during pregnancy is common and approximately one out of three women have disabling pain. The pathogenesis of the pain condition is uncertain and there is no information on the role of physical fitness. Whether poorer physical conditioning is a cause or effect of back pain is also disputed and information from prospective studies needed.</p> <p>Methods</p> <p>A cohort of pregnant women, recruited from maternal health care centers in central Sweden, were examined regarding estimated peak oxygen uptake by cycle ergometer test in early pregnancy, reported physical activity prior to pregnancy, basic characteristics, back pain during pregnancy and back pain postpartum.</p> <p>Results</p> <p>Back pain during the current pregnancy was reported by nearly 80% of the women. At the postpartum appointment this prevalence was 40%. No association was displayed between estimated peak oxygen uptake and incidence of back pain during and after pregnancy, adjusted for physical activity, back pain before present pregnancy, previous deliveries, age and weight. A significant inverse association was found between estimated peak oxygen uptake and back pain intensity during pregnancy and a direct association post partum, in a fully adjusted multiple linear regression analysis.</p> <p>Conclusions</p> <p>Estimated peak oxygen uptake and reported physical activity in early pregnancy displayed no influence on the onset of subsequent back pain during or after pregnancy, where the time sequence support the hypothesis that poorer physical deconditioning is not a cause but a consequence of the back pain condition. The mechanism for the attenuating effect of increased oxygen uptake on back pain intensity is uncertain.</p

Gait in Pregnancy-related Pelvic girdle Pain: amplitudes, timing, and coordination of horizontal trunk rotations

Walking is impaired in Pregnancy-related Pelvic girdle Pain (PPP). Walking velocity is reduced, and in postpartum PPP relative phase between horizontal pelvis and thorax rotations was found to be lower at higher velocities, and rotational amplitudes tended to be larger. While attempting to confirm these findings for PPP during pregnancy, we wanted to identify underlying mechanisms. We compared gait kinematics of 12 healthy pregnant women and 12 pregnant women with PPP, focusing on the amplitudes of transverse segmental rotations, the timing and relative phase of these rotations, and the amplitude of spinal rotations. In PPP during pregnancy walking velocity was lower than in controls, and negatively correlated with fear of movement. While patients’ rotational amplitudes were larger, with large inter-individual differences, spinal rotations did not differ between groups. In the patients, peak thorax rotation occurred earlier in the stride cycle at higher velocities, and relative phase was lower. The earlier results on postpartum PPP were confirmed for PPP during pregnancy. Spinal rotations remained unaffected, while at higher velocities the peak of thorax rotations occurred earlier in the stride cycle. The latter change may serve to avoid excessive spine rotations caused by the larger segmental rotations

METAREP: JCVI metagenomics reports—an open source tool for high-performance comparative metagenomics

Summary: JCVI Metagenomics Reports (METAREP) is a Web 2.0 application designed to help scientists analyze and compare annotated metagenomics datasets. It utilizes Solr/Lucene, a high-performance scalable search engine, to quickly query large data collections. Furthermore, users can use its SQL-like query syntax to filter and refine datasets. METAREP provides graphical summaries for top taxonomic and functional classifications as well as a GO, NCBI Taxonomy and KEGG Pathway Browser. Users can compare absolute and relative counts of multiple datasets at various functional and taxonomic levels. Advanced comparative features comprise statistical tests as well as multidimensional scaling, heatmap and hierarchical clustering plots. Summaries can be exported as tab-delimited files, publication quality plots in PDF format. A data management layer allows collaborative data analysis and result sharing

Investigating the impact of poverty on colonization and infection with drug-resistant organisms in humans: a systematic review

Background Poverty increases the risk of contracting infectious diseases and therefore exposure to antibiotics. Yet there is lacking evidence on the relationship between income and non-income dimensions of poverty and antimicrobial resistance. Investigating such relationship would strengthen antimicrobial stewardship interventions. Methods A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Ovid, MEDLINE, EMBASE, Scopus, CINAHL, PsychINFO, EBSCO, HMIC, and Web of Science databases were searched in October 2016. Prospective and retrospective studies reporting on income or non-income dimensions of poverty and their influence on colonisation or infection with antimicrobial-resistant organisms were retrieved. Study quality was assessed with the Integrated quality criteria for review of multiple study designs (ICROMS) tool. Results Nineteen articles were reviewed. Crowding and homelessness were associated with antimicrobial resistance in community and hospital patients. In high-income countries, low income was associated with Streptococcus pneumoniae and Acinetobacter baumannii resistance and a seven-fold higher infection rate. In low-income countries the findings on this relation were contradictory. Lack of education was linked to resistant S. pneumoniae and Escherichia coli. Two papers explored the relation between water and sanitation and antimicrobial resistance in low-income settings. Conclusions Despite methodological limitations, the results suggest that addressing social determinants of poverty worldwide remains a crucial yet neglected step towards preventing antimicrobial resistance

Particle detectors, geodesic motion, and the equivalence principle

It is shown that quantum particle detectors are not reliable probes of spacetime structure. In particular, they fail to distinguish between inertial and non-inertial motion in a general spacetime. To prove this, we consider detectors undergoing circular motion in an arbitrary static spherically symmetric spacetime, and give a necessary and sufficient condition for the response function to vanish when the field is in the static vacuum state. By examining two particular cases, we show that there is no relation, in general, between the vanishing of the response function and the fact that the detector motion is, or is not, geodesic. In static asymptotically flat spacetimes, however, all rotating detectors are excited in the static vacuum. Thus, in this particular case the static vacuum appears to be associated with a non-rotating frame. The implications of these results for the equivalence principle are considered. In particular, we discuss how to properly formulate the principle for particle detectors, and show that it is satisfied.Comment: 14 pages. Revised version, with corrections; added two references. Accepted for publication in Class. Quantum Gra