Stimulation of translation by human Unr requires cold shock domains 2 and 4, and correlates with poly(A) binding protein interaction

The RNA binding protein Unr, which contains five cold shock domains, has several specific roles in post-transcriptional control of gene expression. It can act as an activator or inhibitor of translation initiation, promote mRNA turnover, or stabilise mRNA. Its role depends on the mRNA and other proteins to which it binds, which includes cytoplasmic poly(A) binding protein 1 (PABP1). Since PABP1 binds to all polyadenylated mRNAs, and is involved in translation initiation by interaction with eukaryotic translation initiation factor 4G (eIF4G), we investigated whether Unr has a general role in translational control. We found that Unr strongly stimulates translation in vitro, and mutation of cold shock domains 2 or 4 inhibited its translation activity. The ability of Unr and its mutants to stimulate translation correlated with its ability to bind RNA, and to interact with PABP1. We found that Unr stimulated the binding of PABP1 to mRNA, and that Unr was required for the stable interaction of PABP1 and eIF4G in cells. siRNA-mediated knockdown of Unr reduced the overall level of cellular translation in cells, as well as that of cap-dependent and IRES-dependent reporters. These data describe a novel role for Unr in regulating cellular gene expression

How large should whales be?

The evolution and distribution of species body sizes for terrestrial mammals is well-explained by a macroevolutionary tradeoff between short-term selective advantages and long-term extinction risks from increased species body size, unfolding above the 2g minimum size induced by thermoregulation in air. Here, we consider whether this same tradeoff, formalized as a constrained convection-reaction-diffusion system, can also explain the sizes of fully aquatic mammals, which have not previously been considered. By replacing the terrestrial minimum with a pelagic one, at roughly 7000g, the terrestrial mammal tradeoff model accurately predicts, with no tunable parameters, the observed body masses of all extant cetacean species, including the 175,000,000g Blue Whale. This strong agreement between theory and data suggests that a universal macroevolutionary tradeoff governs body size evolution for all mammals, regardless of their habitat. The dramatic sizes of cetaceans can thus be attributed mainly to the increased convective heat loss is water, which shifts the species size distribution upward and pushes its right tail into ranges inaccessible to terrestrial mammals. Under this macroevolutionary tradeoff, the largest expected species occurs where the rate at which smaller-bodied species move up into large-bodied niches approximately equals the rate at which extinction removes them.Comment: 7 pages, 3 figures, 2 data table

Sex-biased parental care and sexual size dimorphism in a provisioning arthropod

The diverse selection pressures driving the evolution of sexual size dimorphism (SSD) have long been debated. While the balance between fecundity selection and sexual selection has received much attention, explanations based on sex-specific ecology have proven harder to test. In ectotherms, females are typically larger than males, and this is frequently thought to be because size constrains female fecundity more than it constrains male mating success. However, SSD could additionally reflect maternal care strategies. Under this hypothesis, females are relatively larger where reproduction requires greater maximum maternal effort – for example where mothers transport heavy provisions to nests. To test this hypothesis we focussed on digger wasps (Hymenoptera: Ammophilini), a relatively homogeneous group in which only females provision offspring. In some species, a single large prey item, up to 10 times the mother’s weight, must be carried to each burrow on foot; other species provide many small prey, each flown individually to the nest. We found more pronounced female-biased SSD in species where females carry single, heavy prey. More generally, SSD was negatively correlated with numbers of prey provided per offspring. Females provisioning multiple small items had longer wings and thoraxes, probably because smaller prey are carried in flight. Despite much theorising, few empirical studies have tested how sex-biased parental care can affect SSD. Our study reveals that such costs can be associated with the evolution of dimorphism, and this should be investigated in other clades where parental care costs differ between sexes and species

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

Ethnic minorities and prescription medication; concordance between self-reports and medical records

BACKGROUND: Ethnic differences in health care utilisation are frequently reported in research. Little is known about the concordance between different methods of data collection among ethnic minorities. The aim of this study was to examine to which extent ethnic differences between self-reported data and data based on electronic medical records (EMR) from general practitioners (GPs) might be a validity issue or reflect a lower compliance among minority groups. METHODS: A cross-sectional, national representative general practice study, using EMR data from 195 GPs. The study population consisted of Dutch, Turks, Surinamese, Antilleans and Morrocans. Self-reported data were collected through face-to-face interviews and could be linked to the EMR of GPs. The main outcome measures were the level of agreement between annual prescribing rate based on the EMRs of GPs and the self-reported receipt and use of prescriptions during the preceding 14 days. RESULTS: The pattern of ethnic differences in receipt and use of prescription medication depended on whether self-reported data or EMR data were used. Ethnic differences based on self-reports were not consistently reflected in EMR data. The percentage of agreement above chance between EMR data and self-reported receipt was in general relative low. CONCLUSION: Ethnic differences between self-reported data and EMR data might not be fully perceived as a cross-cultural validity issue. At least for Moroccans and Turks, compliance with the prescribed medication by the GP is suggested not to be optimal

The First Human Epitope Map of the Alphaviral E1 and E2 Proteins Reveals a New E2 Epitope with Significant Virus Neutralizing Activity

Although the murine immune response to Venezuelan equine encephalitis virus (VEEV) is well-characterized, little is known about the human antibody response to VEEV. In this study we used phage display technology to isolate a panel of 11 VEEV-specfic Fabs from two human donors. Seven E2-specific and four E1-specific Fabs were identified and mapped to five E2 epitopes and three E1 epitopes. Two neutralizing Fabs were isolated, E2-specific F5 and E1-specific L1A7, although the neutralizing capacity of L1A7 was 300-fold lower than F5. F5 Fab was expressed as a complete IgG1 molecule, F5 native (n) IgG. Neutralization-escape VEEV variants for F5 nIgG were isolated and their structural genes were sequenced to determine the theoretical binding site of F5. Based on this sequence analysis as well as the ability of F5 to neutralize four neutralization-escape variants of anti-VEEV murine monoclonal antibodies (mapped to E2 amino acids 182–207), a unique neutralization domain on E2 was identified and mapped to E2 amino acids 115–119

Improved Interpretation of Mercury Intrusion and Soil Water Retention Percolation Characteristics by Inverse Modelling and Void Cluster Analysis

This work addresses two continuing fallacies in the interpretation of percolation characteristics of porous solids. The first is that the first derivative (slope) of the intrusion characteristic of the non-wetting fluid or drainage characteristic of the wetting fluid corresponds to the void size distribution, and the second is that the sizes of all voids can be measured. The fallacies are illustrated with the aid of the PoreXpert® inversemodelling package.Anewvoid analysis method is then described, which is an add-on to the inverse modelling package and addresses the second fallacy. It is applied to three widely contrasting and challenging porous media. The first comprises two fine-grain graphites for use in the next-generation nuclear reactors. Their larger void sizes were measured by mercury intrusion, and the smallest by using a grand canonical Monte Carlo interpretation of surface area measurement down to nanometre scale. The second application is to the mercury intrusion of a series of mixtures of ground calcium carbonate with powdered microporous calcium carbonate known as functionalised calcium carbonate (FCC). The third is the water retention/drainage characteristic of a soil sample which undergoes naturally occurring hydrophilic/hydrophobic transitions. The first-derivative approximation is shown to be reasonable in the interpretation of the mercury intrusion porosimetry of the two graphites, which differ only at low mercury intrusion pressures, but false for FCC and the transiently hydrophobic soil. The findings are supported by other experimental characterisations, in particular electron and atomic force microscopy

Chronic widespread bodily pain is increased among individuals with history of fracture:findings from UK Biobank

Acknowledgments This work was supported by grants from the Medical Research Council, British Heart Foundation, Arthritis Research UK, National Osteoporosis Society, International Osteoporosis Foundation, NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, and NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. This research has been conducted using the UK Biobank Resource. Compliance with ethical standards.Peer reviewedPublisher PD