SUMO-2 and PIAS1 modulate insoluble mutant Huntingtin protein accumulation

A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression

Effects of prolonged and acute muscle pain on the force control strategy during isometric contractions

Musculoskeletal pain is associated with multiple adaptions in movement control. This study aimed to determine whether changes in movement control acquired during acute pain are maintained over days of pain exposure. On day 0, the extensor carpi radialis brevis muscle of healthy participants was injected with nerve growth factor (NGF) to induce persistent movement-evoked pain (n\ua0=\ua013) or isotonic saline as a control (n\ua0=\ua013). On day 2, short-lasting pain was induced by injection of hypertonic saline into extensor carpi radialis brevis muscles of all participants. Three-dimensional force components were recorded during submaximal isometric wrist extensions on day 0, day 4, and before, during, and after saline-induced pain on day 2. Standard deviation (variation of task-related force) and total excursion of center of pressure (variation of force direction) were assessed. Maximal movement-evoked pain was 3.3\ua0±\ua0.4 (0–10 numeric scale) in the NGF-group on day 2 whereas maximum saline-induced pain was 6.8\ua0±\ua0.3\ua0cm (10-cm visual analog scale). The difference in centroid position of force direction relative to day 0 was greater in the NGF group than in the control group (P\ua

Switchable Scheduling for Runtime Adaptation of Optimization

International audienceParallel applications used to be executed alone until their termination on partitions of supercomputers: a very static environment for very static applications. The recent shift to multicore architectures for desktop and embedded systems as well as the emergence of cloud computing is raising the problem of the impact of the execution context on performance. The number of criteria to take into account for that pur-pose is significant: architecture, system, workload, dynamic parameters, etc. Finding the best optimization for every context at compile time is clearly out of reach. Dynamic optimization is the natural solution, but it is often costly in execution time and may offset the optimization it is en-abling. In this paper, we present a static-dynamic compiler optimization technique that generates loop-based programs with dynamic auto-tuning capabilities with very low overhead. Our strategy introduces switchable scheduling, a family of program transformations that allows to switch between optimized versions while always processing useful computation. We present both the technique to generate self-adaptive programs based on switchable scheduling and experimental evidence of their ability to sustain high-performance in a dynamic environment

Unifying Thread-Level Speculation and Transactional Memory ⋆

Abstract. The motivation of this work is to ask whether Transactional Memory (TM) and Thread-Level Speculation (TLS), two prominent concurrency paradigms usually considered separately, can be combined into a hybrid approach that extracts untapped parallelism and speed-up from common programs. We show that the answer is positive by describing an algorithm, called TLSTM, that leverages an existing TM with TLS capabilities. We also show that our approach is able to achieve up to a 48 % increase in throughput over the base TM, on read dominated workloads of long transactions in a multi-threaded application.