Fluctuating viscoelasticity based on a finite number of dumbbells

Two alternative routes are taken to derive, on the basis of the dynamics of a finite number of dumbbells, viscoelasticity in terms of a conformation tensor with fluctuations. The first route is a direct approach using stochastic calculus only, and it serves as a benchmark for the second route, which is guided by thermodynamic principles. In the latter, the Helmholtz free energy and a generalized relaxation tensor play a key role. It is shown that the results of the two routes agree only if a finite-size contribution to the Helmholtz free energy of the conformation tensor is taken into account. Using statistical mechanics, this finite-size contribution is derived explicitly in this paper for a large class of models; this contribution is non-zero whenever the number of dumbbells in the volume of observation is finite. It is noted that the generalized relaxation tensor for the conformation tensor does not need any finite-size correction

Correcting pervasive errors in RNA crystallography through enumerative structure prediction

Three-dimensional RNA models fitted into crystallographic density maps exhibit pervasive conformational ambiguities, geometric errors and steric clashes. To address these problems, we present enumerative real-space refinement assisted by electron density under Rosetta (ERRASER), coupled to Python-based hierarchical environment for integrated 'xtallography' (PHENIX) diffraction-based refinement. On 24 data sets, ERRASER automatically corrects the majority of MolProbity-assessed errors, improves the average Rfree factor, resolves functionally important discrepancies in noncanonical structure and refines low-resolution models to better match higher-resolution models

Protection against severe infant lower respiratory tract infections by immune training: mechanistic studies

BACKGROUND: Results from recent clinical studies suggest potential efficacy of immune training (IT)-based approaches for protection against severe lower respiratory tract infections in infants, but underlying mechanisms are unclear. OBJECTIVE: We used systems-level analyses to elucidate IT mechanisms in infants in a clinical trial setting. METHODS: Pre- and posttreatment peripheral blood mononuclear cells from a placebo-controlled trial in which winter treatment with the IT agent OM85 reduced infant respiratory infection frequency and/or duration were stimulated for 24 hours with the virus/bacteria mimics polyinosinic:polycytidylic acid/lipopolysaccharide. Transcriptomic profiling via RNA sequencing, pathway and upstream regulator analyses, and systems-level gene coexpression network analyses were used sequentially to elucidate and compare responses in treatment and placebo groups. RESULTS: In contrast to subtle changes in antivirus-associated polyinosinic:polycytidylic acid response profiles, the bacterial lipopolysaccharide-triggered gene coexpression network responses exhibited OM85 treatment-associated upregulation of IFN signaling. This was accompanied by network rewiring resulting in increased coordination of TLR4 expression with IFN pathway-associated genes (especially master regulator IRF7); segregation of TNF and IFN-γ (which potentially synergize to exaggerate inflammatory sequelae) into separate expression modules; and reduced size/complexity of the main proinflammatory network module (containing, eg, IL-1,IL-6, and CCL3). Finally, we observed a reduced capacity for lipopolysaccharide-induced inflammatory cytokine (eg, IL-6 and TNF) production in the OM85 group. CONCLUSION: These changes are consistent with treatment-induced enhancement of bacterial pathogen detection/clearance capabilities concomitant with enhanced capacity to regulate ensuing inflammatory response intensity and duration. We posit that IT agents exemplified by OM85 potentially protect against severe lower respiratory tract infections in infants principally by effects on innate immune responses targeting the bacterial components of the mixed respiratory viral/bacterial infections that are characteristic of this age group

Description of Hymenolepis microstoma (Nottingham strain): a classical tapeworm model for research in the genomic era

<p>Abstract</p> <p>Background</p> <p><it>Hymenolepis microstoma </it>(Dujardin, 1845) Blanchard, 1891, the mouse bile duct tapeworm, is a rodent/beetle-hosted laboratory model that has been used in research and teaching since its domestication in the 1950s. Recent characterization of its genome has prompted us to describe the specific strain that underpins these data, anchoring its identity and bringing the 150+ year-old original description up-to-date.</p> <p>Results</p> <p>Morphometric and ultrastructural analyses were carried out on laboratory-reared specimens of the 'Nottingham' strain of <it>Hymenolepis microstoma </it>used for genome characterization. A contemporary description of the species is provided including detailed illustration of adult anatomy and elucidation of its taxonomy and the history of the specific laboratory isolate.</p> <p>Conclusions</p> <p>Our work acts to anchor the specific strain from which the <it>H. microstoma </it>genome has been characterized and provides an anatomical reference for researchers needing to employ a model tapeworm system that enables easy access to all stages of the life cycle. We review its classification, life history and development, and briefly discuss the genome and other model systems being employed at the beginning of a genomic era in cestodology.</p

A statistical toolbox for metagenomics: assessing functional diversity in microbial communities

<p>Abstract</p> <p>Background</p> <p>The 99% of bacteria in the environment that are recalcitrant to culturing have spurred the development of metagenomics, a culture-independent approach to sample and characterize microbial genomes. Massive datasets of metagenomic sequences have been accumulated, but analysis of these sequences has focused primarily on the descriptive comparison of the relative abundance of proteins that belong to specific functional categories. More robust statistical methods are needed to make inferences from metagenomic data. In this study, we developed and applied a suite of tools to describe and compare the richness, membership, and structure of microbial communities using peptide fragment sequences extracted from metagenomic sequence data.</p> <p>Results</p> <p>Application of these tools to acid mine drainage, soil, and whale fall metagenomic sequence collections revealed groups of peptide fragments with a relatively high abundance and no known function. When combined with analysis of 16S rRNA gene fragments from the same communities these tools enabled us to demonstrate that although there was no overlap in the types of 16S rRNA gene sequence observed, there was a core collection of operational protein families that was shared among the three environments.</p> <p>Conclusion</p> <p>The results of comparisons between the three habitats were surprising considering the relatively low overlap of membership and the distinctively different characteristics of the three habitats. These tools will facilitate the use of metagenomics to pursue statistically sound genome-based ecological analyses.</p

PCB pollution continues to impact populations of orcas and other dolphins in European waters

Organochlorine (OC) pesticides and the more persistent polychlorinated biphenyls (PCBs) have well-established dose-dependent toxicities to birds, fish and mammals in experimental studies, but the actual impact of OC pollutants on European marine top predators remains unknown. Here we show that several cetacean species have very high mean blubber PCB concentrations likely to cause population declines and suppress population recovery. In a large pan-European meta-analysis of stranded (n = 929) or biopsied (n = 152) cetaceans, three out of four species:- striped dolphins (SDs), bottlenose dolphins (BNDs) and killer whales (KWs) had mean PCB levels that markedly exceeded all known marine mammal PCB toxicity thresholds. Some locations (e.g. western Mediterranean Sea, south-west Iberian Peninsula) are global PCB "hotspots" for marine mammals. Blubber PCB concentrations initially declined following a mid-1980s EU ban, but have since stabilised in UK harbour porpoises and SDs in the western Mediterranean Sea. Some small or declining populations of BNDs and KWs in the NE Atlantic were associated with low recruitment, consistent with PCB-induced reproductive toxicity. Despite regulations and mitigation measures to reduce PCB pollution, their biomagnification in marine food webs continues to cause severe impacts among cetacean top predators in European seas

Maternal Psychosocial Stress during Pregnancy and Placenta Weight: Evidence from a National Cohort Study

To study in a large-scale cohort with prospective data the associations between psychosocial stress during pregnancy and placenta weight at birth. Animal data suggest that the placenta is involved in stress-related fetal programming.; We defined a priori two types of psychosocial stress during pregnancy, life stress (perceived burdens in major areas of life) and emotional symptoms (e.g. anxiety). We estimated the associations of maternal stress during pregnancy with placenta weight at birth, controlled for length of gestation, by predicting gestational age- and sex-specific z-scores of placenta weight through multiple regression analysis, adjusted for potential confounders (N?=?78,017 singleton pregnancies). Life stress (per increase in stress score by 1, range: 0-18) during pregnancy was associated with increased placenta weight at birth (z-score, reported in 10(-3); B, 14.33; CI, 10.12-18.54). In contrast, emotional symptoms during pregnancy were not associated with placenta weight at birth.; Maternal life stress but not emotional symptoms during pregnancy was associated with increased placenta weight at birth; yet, the association-estimate was rather small. Our results may contribute to a better understanding of the role of the placenta in the regulation of intrauterine processes in response to maternal stress

Elabela/Toddler is an Endogenous Agonist of the Apelin APJ Receptor in the Adult Cardiovascular System, and Exogenous Administration of the Peptide Compensates for the Downregulation of its Expression in Pulmonary Arterial Hypertension

BACKGROUND: -Elabela/Toddler (ELA) is a critical cardiac developmental peptide that acts through the G protein-coupled apelin receptor, despite lack of sequence similarity to the established ligand apelin. Our aim was to investigate the receptor pharmacology, expression pattern and in vivo function of ELA peptides in the adult cardiovascular system, to seek evidence for alteration in pulmonary arterial hypertension (PAH) in which apelin signaling is down-regulated, and to demonstrate attenuation of PAH severity with exogenous administration of ELA in a rat model. METHODS: -In silico docking analysis, competition binding experiments and down-stream assays were used to characterize ELA receptor binding in human heart and signaling in cells expressing the apelin receptor. ELA expression in human cardiovascular tissues and plasma was determined using RT-qPCR, dual-labelling immunofluorescent staining and immunoassays. Acute cardiac effects of ELA-32 and [Pyr(1)]apelin-13 were assessed by magnet resonance imaging and cardiac catheterization in anesthetized rats. Cardiopulmonary human and rat tissues from PAH patients and monocrotaline (MCT) and Sugen/hypoxia exposed rats were used to show changes in ELA expression in PAH. The effect of ELA treatment on cardiopulmonary remodeling in PAH was investigated in the MCT rat model. RESULTS: -ELA competed for binding of apelin in human heart with overlap for the two peptides indicated by in silico modeling. ELA activated G protein- and Β-arrestin-dependent pathways. We detected ELA expression in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, cardiac output and elicited vasodilatation in rat in vivo ELA expression was reduced in cardiopulmonary tissues from PAH patients and PAH rat models, respectively. ELA treatment significantly attenuated elevation of right ventricular systolic pressure and right ventricular hypertrophy and pulmonary vascular remodeling in MCT exposed rats. CONCLUSIONS: -These results show ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin, is down-regulated in human disease and rodent PAH models and exogenous peptide can reduce the severity of cardiopulmonary remodeling and function in PAH in rats. This study provides additional proof of principle that an apelin receptor agonist may be of therapeutic use in PAH in man.Supported by the Wellcome Trust 107715/Z/15/Z and Programme in Metabolic and Cardiovascular Disease 096822/Z/11/Z, Medical Research Council MC_PC_14116, British Heart Foundation PS/02/001, PG/05/127/19872, FS/14/59/31282 and in part by the National Institute for Health Research Cambridge Biomedical Research Centre and the Pulmonary Hypertension Association UK

phenix.mr_rosetta: molecular replacement and model rebuilding with Phenix and Rosetta.

The combination of algorithms from the structure-modeling field with those of crystallographic structure determination can broaden the range of templates that are useful for structure determination by the method of molecular replacement. Automated tools in phenix.mr_rosetta simplify the application of these combined approaches by integrating Phenix crystallographic algorithms and Rosetta structure-modeling algorithms and by systematically generating and evaluating models with a combination of these methods. The phenix.mr_rosetta algorithms can be used to automatically determine challenging structures. The approaches used in phenix.mr_rosetta are described along with examples that show roles that structure-modeling can play in molecular replacement