99 research outputs found

    Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia

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    Background: Cachexia, a multifactorial syndrome affecting more than 50% of patients with advanced cancer and responsible for ~20% of cancer-associated deaths, is still a poorly understood process without a standard cure available. Skeletal muscle atrophy caused by systemic inflammation is a major clinical feature of cachexia, leading to weight loss, dampening patients' quality of life, and reducing patients' response to anticancer therapy. RAGE (receptor for advanced glycation end-products) is a multiligand receptor of the immunoglobulin superfamily and a mediator of muscle regeneration, inflammation, and cancer. Methods: By using murine models consisting in the injection of colon 26 murine adenocarcinoma (C26-ADK) or Lewis lung carcinoma (LLC) cells in BALB/c and C57BL/6 or Ager−/− (RAGE-null) mice, respectively, we investigated the involvement of RAGE signalling in the main features of cancer cachexia, including the inflammatory state. In vitro experiments were performed using myotubes derived from C2C12 myoblasts or primary myoblasts isolated from C57BL/6 wild type and Ager−/− mice treated with the RAGE ligand, S100B (S100 calcium-binding protein B), TNF (tumor necrosis factor)α±IFN (interferon) γ, and tumour cell- or masses-conditioned media to analyse hallmarks of muscle atrophy. Finally, muscles of wild type and Ager−/− mice were injected with TNFα/IFNγ or S100B in a tumour-free environment. Results: We demonstrate that RAGE is determinant to activate signalling pathways leading to muscle protein degradation in the presence of proinflammatory cytokines and/or tumour-derived cachexia-inducing factors. We identify the RAGE ligand, S100B, as a novel factor able to induce muscle atrophy per se via a p38 MAPK (p38 mitogen-activated protein kinase)/myogenin axis and STAT3 (signal transducer and activator of transcription 3)-dependent MyoD (myoblast determination protein 1) degradation. Lastly, we found that in cancer conditions, an increase in serum levels of tumour-derived S100B and HMGB1 (high mobility group box 1) occurs leading to chronic activation/overexpression of RAGE, which induces hallmarks of cancer cachexia (i.e. muscle wasting, systemic inflammation, and release of tumour-derived pro-cachectic factors). Absence of RAGE in mice translates into reduced serum levels of cachexia-inducing factors, delayed loss of muscle mass and strength, reduced tumour progression, and increased survival. Conclusions: RAGE is a molecular determinant in inducing the hallmarks of cancer cachexia, and molecular targeting of RAGE might represent a therapeutic strategy to prevent or counteract the cachectic syndrome

    The association between age at first calving and survival of first lactation heifers within dairy herds

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    The objective of this research was to evaluate the survival rate of primiparous heifers within a large sample of herds across the UK and specifically to assess the association between age at first calving (AFC) on their survival. Data from 437 herds was re-structured for analysis. Descriptive statistics were calculated, and a multilevel logistic regression model used to explore factors associated with the risk of first lactation culling. Potential explanatory variables included AFC, herd size, culling rate within the whole herd, calving season, herd mean 305d yield and herd mean calving interval. The mean within-herd culling rate for the primiparous heifers was 15.9%. The mean within-herd AFC was 29.6 months, with 35.9% of heifers having an AFC greater than 30 months of age. Multivariable analysis revealed a negative association between survival rate of primiparous heifers and increasing AFC, and also associations with herd culling rate in older cows and calving season. This study highlights the importance of AFC for survival of primiparous heifers, as well the need to address heifer wastage in herds with high culling rates

    Inlet Flow Control and Prediction Technologies for Embedded Propulsion Systems

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    Fail-safe, hybrid, flow control (HFC) is a promising technology for meeting high-speed cruise efficiency, low-noise signature, and reduced fuel-burn goals for future, Hybrid-Wing-Body (HWB) aircraft with embedded engines. This report details the development of HFC technology that enables improved inlet performance in HWB vehicles with highly integrated inlets and embedded engines without adversely affecting vehicle performance. In addition, new test techniques for evaluating Boundary-Layer-Ingesting (BLI)-inlet flow-control technologies developed and demonstrated through this program are documented, including the ability to generate a BLI-like inlet-entrance flow in a direct-connect, wind-tunnel facility, as well as, the use of D-optimal, statistically designed experiments to optimize test efficiency and enable interpretation of results. Validated improvements in numerical analysis tools and methods accomplished through this program are also documented, including Reynolds-Averaged Navier-Stokes CFD simulations of steady-state flow physics for baseline, BLI-inlet diffuser flow, as well as, that created by flow-control devices. Finally, numerical methods were employed in a ground-breaking attempt to directly simulate dynamic distortion. The advances in inlet technologies and prediction tools will help to meet and exceed "N+2" project goals for future HWB aircraft

    Effect of family relatedness on characteristics of estimated IBD probabilities in relation to precision of QTL estimates

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    <p>Abstract</p> <p>Background</p> <p>A random QTL effects model uses a function of probabilities that two alleles in the same or in different animals at a particular genomic position are identical by descent (IBD). Estimates of such IBD probabilities and therefore, modeling and estimating QTL variances, depend on marker polymorphism, strength of linkage and linkage disequilibrium of markers and QTL, and the relatedness of animals in the pedigree. The effect of relatedness of animals in a pedigree on IBD probabilities and their characteristics was examined in a simulation study.</p> <p>Results</p> <p>The study based on nine multi-generational family structures, similar to a pedigree structure of a real dairy population, distinguished by an increased level of inbreeding from zero to 28% across the studied population. Highest inbreeding level in the pedigree, connected with highest relatedness, was accompanied by highest IBD probabilities of two alleles at the same locus, and by lower relative variation coefficients. Profiles of correlation coefficients of IBD probabilities along the marked chromosomal segment with those at the true QTL position were steepest when the inbreeding coefficient in the pedigree was highest. Precision of estimated QTL location increased with increasing inbreeding and pedigree relatedness. A method to assess the optimum level of inbreeding for QTL detection is proposed, depending on population parameters.</p> <p>Conclusions</p> <p>An increased overall relationship in a QTL mapping design has positive effects on precision of QTL position estimates. But the relationship of inbreeding level and the capacity for QTL detection depending on the recombination rate of QTL and adjacent informative marker is not linear.</p

    Mechanical vibrations of magnetically levitated viscoelastic droplets

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    The mechanical vibrations of magnetically levitated droplets were investigated using a simple optical deflection technique. Droplets of water and a water-based solution of poly(acrylamide-co-acrylic acid) were levitated in the bore of a superconducting magnet and perturbed with a short puff of air. Centre of mass and surface vibrations were monitored using laser light refracted through the droplet, focussed on to the end of an optical fiber and detected using a photodiode. Time dependent variations in the voltage generated by the photodiode were Fourier transformed to obtain the frequency and spectral width of the drops' mechanical resonances. A simple theory of drop vibration was developed to extract the rheological properties of the droplets from these quantities. The resulting values of G' and G" that were extracted were found to be in good agreement with values obtained using conventional rheology techniques

    Snowmass White Paper: Prospects of CP-violation measurements with the Higgs boson at future experiments

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    The search for CP violation in interactions of the Higgs boson with either fermions or bosons provides attractive reference measurements in the Particle Physics Community Planning Exercise (a.k.a. "Snowmass"). Benchmark measurements of CP violation provide a limited and well-defined set of parameters that could be tested at the proton, electron-positron, photon, and muon colliders, and compared to those achieved through study of virtual effects in electric dipole moment measurements. We review the current status of these CP-sensitive studies and provide projections to future measurements.Comment: Snowmass White Paper. 23 pages, 6 figure
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