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Despite the need for more effective drug treatments to address muscle atrophy and disease, physiologically accurate in vitro screening models and higher information content preclinical assays that aid in the discovery and development of novel therapies are lacking. To this end, MyoScreen was developed: a robust and versatile high-throughput high-content screening (HT/HCS) platform that integrates a physiologically and pharmacologically relevant micropatterned human primary skeletal muscle model with a panel of pertinent phenotypic and functional assays. MyoScreen myotubes form aligned, striated myofibers, and they show nerve-independent accumulation of acetylcholine receptors (AChRs), excitation–contraction coupling (ECC) properties characteristic of adult skeletal muscle and contraction in response to chemical stimulation. Reproducibility and sensitivity of the fully automated MyoScreen platform are highlighted in assays that quantitatively measure myogenesis, hypertrophy and atrophy, AChR clusterization, and intracellular calcium release dynamics, as well as integrating contractility data. A primary screen of 2560 compounds to identify stimulators of myofiber regeneration and repair, followed by further biological characterization of two hits, validates MyoScreen for the discovery and testing of novel therapeutics. MyoScreen is an improvement of current in vitro muscle models, enabling a more predictive screening strategy for preclinical selection of the most efficacious new chemical entities earlier in the discovery pipeline process.

Despite the need for more effective drug treatments to address muscle atrophy and disease, physiologically accurate in vitro screening models and higher information content preclinical assays that aid in the discovery and development of novel therapies are lacking. To this end, MyoScreen was developed: a robust and versatile high-throughput high-content screening (HT/HCS) platform that integrates a physiologically and pharmacologically relevant micropatterned human primary skeletal muscle model with a panel of pertinent phenotypic and functional assays. MyoScreen myotubes form aligned, striated myofibers, and they show nerve-independent accumulation of acetylcholine receptors (AChRs), excitation–contraction coupling (ECC) properties characteristic of adult skeletal muscle and contraction in response to chemical stimulation. Reproducibility and sensitivity of the fully automated MyoScreen platform are highlighted in assays that quantitatively measure myogenesis, hypertrophy and atrophy, AChR clusterization, and intracellular calcium release dynamics, as well as integrating contractility data. A primary screen of 2560 compounds to identify stimulators of myofiber regeneration and repair, followed by further biological characterization of two hits, validates MyoScreen for the discovery and testing of novel therapeutics. MyoScreen is an improvement of current in vitro muscle models, enabling a more predictive screening strategy for preclinical selection of the most efficacious new chemical entities earlier in the discovery pipeline process.

Decreased expression of neuronal genes such as brain‐derived neurotrophic factor (BDNF) is associated with several neurological disorders. One molecular mechanism associated with Huntington disease (HD) is a discrete increase in the nuclear activity of the transcriptional repressor REST/NRSF binding to repressor element‐1 (RE1) sequences. High‐throughput screening of a library of 6,984 compounds with luciferase‐assay measuring REST activity in neural derivatives of human embryonic stem cells led to identify two benzoimidazole‐5‐carboxamide derivatives that inhibited REST silencing in a RE1‐dependent manner. The most potent compound, X5050, targeted REST degradation, but neither REST expression, RNA splicing nor binding to RE1 sequence. Differential transcriptomic analysis revealed the upregulation of neuronal genes targeted by REST in wild‐type neural cells treated with X5050. This activity was confirmed in neural cells produced from human induced pluripotent stem cells derived from a HD patient. Acute intraventricular delivery of X5050 increased the expressions of BDNF and several other REST‐regulated genes in the prefrontal cortex of mice with quinolinate‐induced striatal lesions. This study demonstrates that the use of pluripotent stem cell derivatives can represent a crucial step toward the identification of pharmacological compounds with therapeutic potential in neurological affections involving decreased expression of neuronal genes associated to increased REST activity, such as Huntington disease. StemCells2013;31:1816‐1828

Le codage centralisé du PMSI est effectué par 29 techniciens d'information médicale (TIM). En 2019, une démarche de réorganisation a été instaurée avec trois objectifs : assurer la continuité du codage, améliorer la qualité du codage et la qualité de vie au travail.

In this paper we report on the structural and magnetic properties of GeMn layers grown on Ge(001). We show that for the optimized Mn concentration (6%) and for optimized growth temperature (close to 130 °C), GeMn samples exhibit a high Curie temperature (higher than 400 K) and Anomalous Hall Effect up to room temperature. Our GeMn layers grown at low temperature (70 °C to 130 °C) are composed of vertical Mn-rich nano-colums. Samples grown at temperatures higher than 130 °C contain GeMn nanoclusters. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The major bioturbation features in an oligotrophic canyon, macrobenthic assemblage and biogenic structures have been studied simultaneously at a station of 1000 m depth in the channel of Toulon Canyon. Two different techniques of quantifying biogenic structures have been employed: X-rays of the sediment column and photographs of the sea floor. In this deep environment, a macrobenthic community dominated by 64.4% of subsurface deposit feeders provides slow bioturbation with intensity proportional to low macrobenthos density (13.1 ± 5.6 individuals dm− Z. Subsurface feeding appears to be the best feeding strategy as there are numerous turbidite deposits observed in this canyon. Burrow records in the sediment column due to macrobenthos are very scarce. Sediment mixing processes do not exceed 3 cm as 85% of the macrobenthos is encountered in the top 3 em. From photographs of the sediment surface, the density of biogenic features induced by megabenthos is estimated to be 3.3 ± 1.1 structures m−2. Organisms responsible for the more frequently encountered biogenic structures, groups of six, nine or 12 holes, are identified as the Thalassinidean shrimpsCalocaris macandreae. In the Toulon Canyon, the relatively low biological mixing associated with low sedimentation rates provide good maintenance of biogenic structures at the sediment surface. The density of biogenic structures at the sediment-water interface is inversely proportional to macrobenthos abundance which is in agreement with Kitchell's hypothesis. This canyon represents an inverse example to the Atlantic Ocean where macrobenthos is more abundant and biogenic structure density is smaller.