16 research outputs found

    The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity

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    The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including Îł-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor ÎČ-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished ÎČ-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing Îł-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD. © 2014 Tourette et al

    Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators

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    Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys¼ electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0–3 vs. 4–6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95–100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest

    A Roadmap for HEP Software and Computing R&D for the 2020s

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    Particle physics has an ambitious and broad experimental programme for the coming decades. This programme requires large investments in detector hardware, either to build new facilities and experiments, or to upgrade existing ones. Similarly, it requires commensurate investment in the R&D of software to acquire, manage, process, and analyse the shear amounts of data to be recorded. In planning for the HL-LHC in particular, it is critical that all of the collaborating stakeholders agree on the software goals and priorities, and that the efforts complement each other. In this spirit, this white paper describes the R&D activities required to prepare for this software upgrade.Peer reviewe

    Potato Ingestion as an Effective Race Fuel Alternative to Improve Cycling Performance in Trained Cyclists

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    Carbohydrate (CHO) ingestion is an established strategy to improve endurance performance. Race fuels should not only sustain performance, but also be readily digested and absorbed and replenish electrolytes. Potatoes are a cost-effective option that fulfills these criteria; however, their impact on endurance performance remains unexamined. PURPOSE: Compare the effects of potato purée (POT) ingestion during endurance cycling on subsequent performance versus commercial CHO gel (GEL) or a control (water, CTL). METHODS: Twelve trained cyclists (31±9y; 71±8kg; VO2max: 61±9mL/kg/min) consumed a standardized breakfast then performed a 2h cycling challenge (60-85%VO2max) followed by a time trial (6kJ/kg body mass) while consuming POT, GEL, or CTL in a randomized-crossover design. POT, GEL and CTL were administered with U-[13C6]glucose for an indirect estimate of gastric emptying rate. Repeated blood samples were collected. RESULTS: Time trial performance significantly improved (P=0.03) with POT (33.0±4.5min) and GEL (33.0±4.2min) versus CTL condition (39.5±7.9min); while POT and GEL conditions (P=1.00) had no difference. Post-challenge, blood glucose concentrations were lower (P0.05). CONCLUSION: Potatoes served as a viable alternative to commercial gels by sustaining performance and blood glucose concentrations during endurance cycling events in trained cyclists
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