Using molecular mechanics to predict bulk material properties of fibronectin fibers

The structural proteins of the extracellular matrix (ECM) form fibers with finely tuned mechanical properties matched to the time scales of cell traction forces. Several proteins such as fibronectin (Fn) and fibrin undergo molecular conformational changes that extend the proteins and are believed to be a major contributor to the extensibility of bulk fibers. The dynamics of these conformational changes have been thoroughly explored since the advent of single molecule force spectroscopy and molecular dynamics simulations but remarkably, these data have not been rigorously applied to the understanding of the time dependent mechanics of bulk ECM fibers. Using measurements of protein density within fibers, we have examined the influence of dynamic molecular conformational changes and the intermolecular arrangement of Fn within fibers on the bulk mechanical properties of Fn fibers. Fibers were simulated as molecular strands with architectures that promote either equal or disparate molecular loading under conditions of constant extension rate. Measurements of protein concentration within micron scale fibers using deep ultraviolet transmission microscopy allowed the simulations to be scaled appropriately for comparison to in vitro measurements of fiber mechanics as well as providing estimates of fiber porosity and water content, suggesting Fn fibers are approximately 75% solute. Comparing the properties predicted by single molecule measurements to in vitro measurements of Fn fibers showed that domain unfolding is sufficient to predict the high extensibility and nonlinear stiffness of Fn fibers with surprising accuracy, with disparately loaded fibers providing the best fit to experiment. This work shows the promise of this microstructural modeling approach for understanding Fn fiber properties, which is generally applicable to other ECM fibers, and could be further expanded to tissue scale by incorporating these simulated fibers into three dimensional network models

The relative roles of CO2 and palaeogeography in determining Late Miocene climate: results from a terrestrial model-data comparison

The Late Miocene (∼11.6–5.3 Ma) palaeorecord provides evidence for a warmer and wetter climate than that of today and there is uncertainty in the palaeo-CO2 record of at least 150 ppmv. We present results from fully coupled atmosphere-ocean-vegetation simulations for the Late Miocene that examine the relative roles of palaeogeography (topography and ice sheet geometry) and CO2 concentration in the determination of Late Miocene climate through comprehensive terrestrial model-data comparisons. Assuming that the data accurately reflects the Late Miocene climate, and that the Late Miocene palaeogeographic reconstruction used in the model is robust, then results indicate that the proxy-derived precipitation differences between the Late Miocene and modern can be largely accounted for by the palaeogeographic changes alone. However, the proxy-derived temperatures differences between the Late Miocene and modern can only begin to be accounted for if we assume a palaeo-CO2 concentration towards the higher end of the range of estimates

Chemical NOx budget in the upper troposphere over the tropical South Pacific

The chemical NOx budget in the upper troposphere over the tropical South Pacific is analyzed using aircraft measurements made at 6-12 km altitude in September 1996 during the Global Tropospheric Experiment (GTE) Pacific Exploratory Mission (PEM) Tropics A campaign. Chemical loss and production rates of NOx along the aircraft flight tracks are calculated with a photochemical model constrained by observations. Calculations using a standard chemical mechanism show a large missing source for NOx; chemical loss exceeds chemical production by a factor of 2.4 on average. Similar or greater NOx budget imbalances have been reported in analyses of data from previous field studies. Ammonium aerosol concentrations in PEM-Tropics A generally exceeded sulfate on a charge equivalent basis, and relative humidities were low (median 25% relative to ice). This implies that the aerosol could be dry in which case N2O5 hydrolysis would be suppressed as a sink for NOx. Suppression of N2O5 hydrolysis and adoption of new measurements of the reaction rate constants for NO2 + OH + M and HNO3 + OH reduces the median chemical imbalance in the NOx budget for PEM-Tropics A from 2.4 to 1.9. The remaining imbalance cannot be easily explained from known chemistry or long-range transport of primary NOx and may imply a major gap in our understanding of the chemical cycling of NOx in the free troposphere. Copyright 2000 by the American Geophysical Union

Activation workers’ perceptions of their long-term unemployed clients’ attitudes towards employment

The Work Programme’s use of severe social security benefit sanctions reflects British coalition ministers’ belief that many people on out-of-work benefits do not want a job. While a substantial empirical literature has repeatedly demonstrated that in fact unemployed benefit claimants possess the same work values as the employed and that the vast majority want paid work, it has ignored some conservative authors’ pleas to consider the views and experiences of people who work with the unemployed. Forty employees of agencies contracted to help unemployed people into employment were interviewed in summer 2011. Respondents had spent an estimated combined total of 147,000 hours in the presence of people who have claimed Jobseeker’s Allowance (JSA) for over six months. Most said that between a quarter and half of their present clients did not want employment. This finding does not contradict existing research, given that most JSA claimants re-enter employment within six months. However, all forty agreed that many others remained unemployed because they were choosy in the jobs they were willing to undertake, and,most strikingly, respondents overwhelmingly endorsed the view that a ‘dependency culture’ exists in households and neighbourhoods that have experienced joblessness for several generations

Disentangling the roles of late Miocene palaeogeography and vegetation:Implications for climate sensitivity

The impact of rising CO2 on future climate remains uncertain but the evidence for high CO2 in the palaeorecord suggests that past climates could provide a potentially quantifiable indication of climate in a high-CO2 world. One such past time period is the late Miocene (11.6-5.3Ma), for which CO2 reconstructions indicate higher levels than those of preindustrial, and similar to the present atmospheric level (~400ppm). The late Miocene palaeorecord suggests a much warmer and wetter Northern Hemisphere than preindustrial. However, vegetation feedbacks are an important component of the climate system and vegetation distribution reconstructions from the palaeorecord have been shown to be very different to the present vegetation distribution. We examine the roles that different vegetation and palaeogeography play in climate sensitivity for the late Miocene and consider the implications for potential future climate change. To do this we use coupled atmosphere-ocean-vegetation simulations of late Miocene and potential modern climates forced by three different CO2 concentrations with vegetation perturbation experiments and make quantitative comparisons to the palaeorecord. Optimal regions to target late Miocene palaeodata acquisition for the purposes of informing about future climate include North America, northern Africa, Australia, Paraguay and southern Brazil, and northeastern Asia. These regions are those which the model results predict to be most sensitive to CO2 forcing, but where the local temperature response to CO2 forcing is similar between the simulated potential modern and late Miocene climates. The model results suggest that climate sensitivity to CO2 forcing is directly affected by the palaeogeographic configuration and that the inferred climate sensitivity for doubled CO2 is 0.5-0.8°C higher for the late Miocene than we might expect for future climate because of differences in synergy. The greater land mass at high northern latitudes during the late Miocene and the differences in vegetation distribution predictions that result, combined with differences in ocean circulation and the effect of sea ice, make the late Miocene boundary conditions more sensitive to CO2 forcing than the modern boundary conditions.</p

Autoantibodies Produced at the Site of Tissue Damage Provide Evidence of Humoral Autoimmunity in Inclusion Body Myositis

Inclusion body myositis (IBM) belongs to a group of muscle diseases known as the inflammatory myopathies. The presence of antibody-secreting plasma cells in IBM muscle implicates the humoral immune response in this disease. However, whether the humoral immune response actively contributes to IBM pathology has not been established. We sought to investigate whether the humoral immune response in IBM both in the periphery and at the site of tissue damage was directed towards self-antigens. Peripheral autoantibodies present in IBM serum but not control serum recognized self-antigens in both muscle tissue and human-derived cell lines. To study the humoral immune response at the site of tissue damage in IBM patients, we isolated single plasma cells directly from IBM-derived muscle tissue sections and from these cells, reconstructed a series of recombinant immunoglobulins (rIgG). These rIgG, each representing a single muscle-associated plasma cell, were examined for reactivity to self-antigens. Both, flow cytometry and immunoblotting revealed that these rIgG recognized antigens expressed by cell lines and in muscle tissue homogenates. Using a mass spectrometry-based approach, Desmin, a major intermediate filament protein, expressed abundantly in muscle tissue, was identified as the target of one IBM muscle-derived rIgG. Collectively, these data support the view that IBM includes a humoral immune response in both the periphery and at the site of tissue damage that is directed towards self-antigens

Effect of plyometric training on handspring vault performance and functional power in youth female gymnasts

This study aimed to determine the effect of plyometric training (PT) when added to habitual gymnastic training (HT) on handspring vault (HV) performance variables. Twenty youth female competitive gymnasts (Age: 12.5 ± 1.67 y) volunteered to participate and were randomly assigned to two independent groups. The experimental plyometric training group (PTG) undertook a six-week plyometric program, involving two additional 45 min PT sessions a week, alongside their HT, while the control group (CG) performed regular HT only. Videography was used (120 Hz) in the sagittal plane to record both groups performing three HVs for both the baseline and post-intervention trials. Furthermore, participants completed a countermovement jump test (CMJ) to assess the effect of PT on functional power. Through the use of Quintic biomechanics software, significant improvements (P < 0.05) were found for the PTG for run-up velocity, take-off velocity, hurdle to board distance, board contact time, table contact time and post-flight time and CMJ height. However, there were no significant improvements on pre-flight time, shoulder angle or hip angle on the vault for the PTG. The CG demonstrated no improvement for all HV measures. A sport-specific PT intervention improved handspring vault performance measures and functional power when added to the habitual training of youth female gymnasts. The additional two hours plyometric training seemingly improved the power generating capacity of movement-specific musculature, which consequently improved aspects of vaulting performance. Future research is required to examine the whether the improvements are as a consequence of the additional volume of sprinting and jumping activities, as a result of the specific PT method or a combination of these factors

Statistical Properties of Turbulence: An Overview

We present an introductory overview of several challenging problems in the statistical characterisation of turbulence. We provide examples from fluid turbulence in three and two dimensions, from the turbulent advection of passive scalars, turbulence in the one-dimensional Burgers equation, and fluid turbulence in the presence of polymer additives.Comment: 34 pages, 31 figure