Skeletal muscle as an experimental model of choice to study tissue aging and rejuvenation.

Skeletal muscle is among the most age-sensitive tissues in mammal organisms. Significant changes in its resident stem cells (i.e., satellite cells, SCs), differentiated cells (i.e., myofibers), and extracellular matrix cause a decline in tissue homeostasis, function, and regenerative capacity. Based on the conservation of aging across tissues and taking advantage of the relatively well-characterization of the myofibers and associated SCs, skeletal muscle emerged as an experimental system to study the decline in function and maintenance of old tissues and to explore rejuvenation strategies. In this review, we summarize the approaches for understanding the aging process and for assaying the success of rejuvenation that use skeletal muscle as the experimental system of choice. We further discuss (and exemplify with studies of skeletal muscle) how conflicting results might be due to variations in the techniques of stem cell isolation, differences in the assays of functional rejuvenation, or deciding on the numbers of replicates and experimental cohorts

Determination of greenhouse gas sources and sinks in Swiss arable soils under organic and non-organic management

Agricultural practices contribute considerably to emissions of greenhouse gases (GHG). Knowledge on the impact of organic (ORG) compared to non-organic (NON-ORG) farming on soil-derived nitrous oxide (N2O) and methane (CH4) emissions is still limited. We conducted a literature search on measured soil GHG fluxes under ORG and NON-ORG from farming system comparisons and performed a meta-analysis. Based on 12 studies covering annual measurements, it appeared that area-scaled N2O emissions are with 14% significantly lower under ORG. However, yield-scaled N2O emissions are only 9% higher for ORG. Emissions from NON-ORG soils seemed to be influenced mainly by total N inputs, whereas for ORG other soil characteristics seemed to be more important because N2O from organic N fertilisers emits decoupled from the inputs. Furthermore, we observed a 12% higher CH4 uptake for arable soils under ORG

The aminopeptidase inhibitor CHR-2863 is an orally bioavailable inhibitor of murine malaria

Malaria remains a significant risk in many areas of the world, with resistance to the current antimalarial pharmacopeia an everincreasing problem. The M1 alanine aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) are believed to play a role in the terminal stages of digestion of host hemoglobin and thereby generate a pool of free amino acids that are essential for parasite growth and development. Here, we show that an orally bioavailable aminopeptidase inhibitor, CHR-2863, is efficacious against murine malaria

Civic republican social justice and the case of state grammar schools in England

The aim of this paper is to consider the ways in which civic republican theory can provide a meaningful and useful account of social justice, one that is which holds resonance for educational debates. Recognising the need for educationalists interested in civic republicanism to pay greater attention to ideas of justice – and in particular social justice as it concerns relationships between citizens (citizen to citizen, group to group or citizen to group) – it is argued that a form of civic republicanism committed to freedom as non-domination is capable of providing a substantive model for analysing social (in)justice within educational arenas. After positioning the contribution offered here within existing educational literature on civic republicanism, salient elements of social justice as freedom as non-domination are identified. On this basis, debates concerning the existence and potential expansion of state (public) grammar schools in England are considered in relation to the account of republican social justice as non-domination. It is argued that from this republican position grammar schools (1) represent an arbitrary domination of the interests of those less well off by those with greater material and cultural capital and (2) in doing so lead to advantages for some at the expense of others. Though the focus of the paper is on grammar schools in England, it is suggested that republican justice may be a useful frame for considering similar educational cases in England and elsewhere

A Plasmodium falciparum S33 proline aminopeptidase is associated with changes in erythrocyte deformability

Infection with the apicomplexan parasite Plasmodium falciparum is a major cause of morbidity and mortality worldwide. One of the Striking features of this parasite is its ability to remodel and decrease the deformability of host red blood cells, a process that contributes to disease. To further understand the virulence of Pf we investigated the biochemistry and function of a putative Pf S33 proline aminopeptidase (PJPAP). Unlike other P. falciparum aminopeptidases, PJPAP contains a predicted protein export element that is non-syntenic with other human infecting Plasmodium species. Characterization of PJPAP demonstrated that it is exported into the host red blood cell and that it is a prolyl aminopeptidase with a preference for N-terminal proline substrates. In addition genetic deletion of this exopeptidase was shown to lead to an increase in the deformability of parasite-infected red cells and in reduced adherence to the endothelial cell receptor CD36 under flow conditions. Our studies suggest that PJPAP plays a role in the rigidification and adhesion of infected red blood cells to endothelial surface receptors, a role that may make this protein a novel target for anti-disease interventions strategies. (C) 2016 Elsevier Inc. All rights reserved

The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially “druggable” point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340

JBrowse: a dynamic web platform for genome visualization and analysis

BACKGROUND: JBrowse is a fast and full-featured genome browser built with JavaScript and HTML5. It is easily embedded into websites or apps but can also be served as a standalone web page. RESULTS: Overall improvements to speed and scalability are accompanied by specific enhancements that support complex interactive queries on large track sets. Analysis functions can readily be added using the plugin framework; most visual aspects of tracks can also be customized, along with clicks, mouseovers, menus, and popup boxes. JBrowse can also be used to browse local annotation files offline and to generate high-resolution figures for publication. CONCLUSIONS: JBrowse is a mature web application suitable for genome visualization and analysis

Mechanically assisted electrochemical degradation of alumina-TiC composites

Alumina-TiC composite material is a tough ceramic composite with excellent hardness, wear resistance and oxidation resistance in dry and high-temperature conditions. In aqueous conditions, however, it is likely to be electrochemically active facilitating charge transfer processes due to the conductive nature of TiC. For application as an orthopedic biomaterial, it is crucial to assess the electrochemical behavior of this composite, especially under a combined mechanical and electrochemical environment. In this study, we examined the mechanically assisted electrochemical performance of alumina-TiC composite in an aqueous environment. The spontaneous electrochemical response to brushing abrasion was measured. Changes in the magnitude of electrochemical current with abrasion test conditions and possible causal relationship to the alteration in surface morphology were examined. Results showed that the alumina matrix underwent abrasive wear with evidence of microploughing and grain boundary damage. Chemical analysis revealed TiO2 formation in the abraded region, indicating oxidation of the conductive TiC domain. Furthermore, wear debris from alumina abrasion appeared to affect reaction kinetics at the composite-electrolyte interface. From this work, we established that the composite undergoes abrasion assisted electrochemical degradation even in gentle abrasive conditions and the severity of degradation is related to temperature and conditions of test environment

GLOBAL SIMULATIONS OF PROTOPLANETARY DISKS WITH OHMIC RESISTIVITY AND AMBIPOLAR DIFFUSION

Protoplanetary disks are believed to accrete onto their central T Tauri star because of magnetic stresses. Recently published shearing box simulations indicate that Ohmic resistivity, ambipolar diffusion and the Hall effect all play important roles in disk evolution. In the presence of a vertical magnetic field, the disk remains laminar between 1-5au, and a magnetocentrifugal disk wind forms that provides an important mechanism for removing angular momentum. Questions remain, however, about the establishment of a true physical wind solution in the shearing box simulations because of the symmetries inherent in the local approximation. We present global MHD simulations of protoplanetary disks that include Ohmic resistivity and ambipolar diffusion, where the time-dependent gas-phase electron and ion fractions are computed under FUV and X-ray ionization with a simplified recombination chemistry. Our results show that the disk remains laminar, and that a physical wind solution arises naturally in global disk models. The wind is sufficiently efficient to explain the observed accretion rates. Furthermore, the ionization fraction at intermediate disk heights is large enough for magneto-rotational channel modes to grow and subsequently develop into belts of horizontal field. Depending on the ionization fraction, these can remain quasi-global, or break-up into discrete islands of coherent field polarity. The disk models we present here show a dramatic departure from our earlier models including Ohmic resistivity only. It will be important to examine how the Hall effect modifies the evolution, and to explore the influence this has on the observational appearance of such systems, and on planet formation and migration.Comment: 18 pages, 12 figures, accepted for publication in Ap

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy