Differential sensitivity of Src-family kinases to activation by SH3 domain displacement

Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo. © 2014 Moroco et al

Obesity prevention: a proposed framework for translating evidence into action

Obesity as a major public health and economic problem has risen to the top of policy and programme agendas in many countries, with prevention of childhood obesity providing a particularly compelling mandate for action. There is widespread agreement that action is needed urgently, that it should be comprehensive and sustained, and that it should be evidence-based. While policy and programme funding decisions are inevitably subject to a variety of historical, social, and political influences, a framework for defining their evidence base is needed. This paper describes the development of an evidence-based, decision-making framework that is particularly relevant to obesity prevention. Building upon existing work within the fields of public health and health promotion, the Prevention Group of the International Obesity Task Force (IOTF) developed a set of key issues and evidence requirements for obesity prevention. These were presented and discussed at an IOTF workshop in April 2004 and were then further developed into a practical framework. The framework is defined by five key policy andprogramme issues that form the basis of the framework. These are: (i) building a case for action on obesity; (ii) identifying contributing factors and points of intervention; (iii) defining the opportunities for action; (iv)evaluating potential interventions; and (v) selecting a portfolio of specific policies, programmes, and actions. Each issue has a different set of evidence requirements and analytical outputs to support policy and programme decision-making. Issue 4 was identified as currently the most problematic because of the relative lack of efficacy and effectiveness studies. Compared with clinical decision-making where the evidence base is dominated by randomized controlled trials with high internal validity, the evidence base for obesity prevention needs many different types of evidence and often needs the informed opinions of stakeholders to ensure external validity and contextual relevance

Female-biased dispersal and non-random gene flow of MC1R variants do not result in a migration load in barn owls.

Non-random gene flow is a widely neglected force in evolution and ecology. This genotype-dependent dispersal is difficult to assess, yet can impact the genetic variation of natural populations and their fitness. In this work, we demonstrate a high immigration rate of barn owls (Tyto alba) inside a Swiss population surveyed during 15 years. Using ten microsatellite loci as an indirect method to characterize dispersal, two-third of the genetic tests failed to detect a female-biased dispersal, and Monte Carlo simulations confirmed a low statistical power to detect sex-biased dispersal in case of high dispersal rate of both sexes. The capture-recapture data revealed a female-biased dispersal associated with an excess of heterozygote for the melanocortin-1 receptor gene (MC1R), which is responsible for their ventral rufous coloration. Thus, female homozygotes for the MC1R <sub>WHITE</sub> allele might be negatively selected during dispersal. Despite the higher immigration of females that are heterozygote at MC1R, non-random gene flow should not lead to a migration load regarding this gene because we did not detect an effect of MC1R on survival and reproductive success in our local population. The present study highlights the usefulness of using multiple methods to correctly decrypt dispersal and gene flow. Moreover, despite theoretical expectations, we show that non-random dispersal of particular genotypes does not necessarily lead to migration load in recipient populations