Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth

Laminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that mutations may impair skeletal muscle growth. Using human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, we observe impaired myogenic fusion with disorganized cadherin/β catenin adhesion complexes. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective fusion of activated MuSCs, defective protein synthesis and defective remodeling of the neuromuscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the yes-associated protein (YAP). We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely related but less severe EDMD models. In conclusion, combining studies in vitro, in vivo, and patient samples, we find that LMNA-CMD mutations interfere with mechanosignaling pathways in skeletal muscle, implicating A-type lamins in the regulation of skeletal muscle growth.     

Concurrent bisimulations in Petri nets

Summary After various attempts, an equivalence relation is defined for labelled Petri nets, on the base of the concurrency semantics of net theory. This relation, called Fully Concurrent bisimulation and abbreviated FC-bisimulation, preserves the level of concurrency of visible operations and, under some conditions, allows to enforce injective labelling on them. Refinements of a visible operation are also defined and we show that, under some conditions, they preserve FC-bisimulation.Research partly supported by ESPRIT Basic Research Action, project 3148: DEMON     

Site‐Specific Labelling of Native Mammalian Proteins for Single‐Molecule FRET Measurements

Human cells are complex entities in which molecular recognition and selection are critical for cellular processes often driven by structural changes and dynamic interactions. Biomolecules appear in different chemical states, and modifications, such as phosphorylation, affect their function. Hence, using proteins in their chemically native state in biochemical and biophysical assays is essential. Single‐molecule FRET measurements allow exploration of the structure, function and dynamics of biomolecules but cannot be fully exploited for the human proteome, as a method for the site‐specific coupling of organic dyes into native, non‐recombinant mammalian proteins is lacking. We address this issue showing the site‐specific engineering of fluorescent dyes into human proteins on the basis of bioorthogonal reactions. We show the applicability of the method to study functional and post‐translationally modified proteins on the single‐molecule level, among them the hitherto inaccessible human Argonaute 2.     

A sensitivity analysis method aimed at enhancing the metaheuristics for continuous optimization

An efficient covering of the search space is an important issue when dealing with metaheuristics. Sensitivity analysis methods aim at evaluating the influence of each variable of a problem on a model (i.e. objective function) response. Such methods provide knowledge on the function behavior and would be suitable for guiding metaheuristics. To evaluate correctly the dimensions influences, usual sensitivity analysis methods need a lot of evaluations of the objective function or are constrained with an experimental design. In this paper, we propose a new method, with a low computational cost, which can be used into metaheuristics to improve their search process. This method is based on two global sensitivity analysis methods: the linear correlation coefficient technique and Morris’ method. We propose to transform the global study of a non linear model into a local study of quasi-linear sub-parts of the model, in order to evaluate the global influence of each input variable on the model. This sensitivity analysis method will use evaluations of the objective function done by the metaheuristic to compute a weight of each variable. Then, the metaheuristic will generate new solutions choosing dimensions to offset, according to these weights. The tests done on usual benchmark functions of sensitivity analysis and continuous optimization (CEC 2013) reveal two issues. Firstly, our sensitivity analysis method provides good results, it correctly ranks each dimension’s influence. Secondly, integrating a sensitivity analysis method into a metaheuristic (here, Differential Evolution and ABC with modification rate) improves its results.     

Nonlinear output‐feedback control of torsional vibrations in drilling systems

This paper considers the design of a nonlinear observer‐based output‐feedback controller for oil‐field drill‐string systems aiming to eliminate (torsional) stick–slip oscillations. Such vibrations decrease the performance and reliability of drilling systems and can ultimately lead to system failure. Current industrial controllers regularly fail to eliminate stick–slip vibrations under increasingly challenging operating conditions caused by the tendency towards drilling deeper and inclined wells, where multiple vibrational modes play a role in the occurrence of stick–slip vibrations. As a basis for controller synthesis, a multi‐modal model of the torsional drill‐string dynamics for a real rig is employed, and a bit–rock interaction model with severe velocity‐weakening effect is used. The proposed model‐based controller design methodology consists of a state‐feedback controller and a (nonlinear) observer. Conditions, guaranteeing asymptotic stability of the desired equilibrium, corresponding to nominal drilling operation, are presented. The proposed control strategy has a significant advantage over existing vibration control systems as it can effectively cope with multiple modes of torsional vibration. Case study results using the proposed control strategy show that stick–slip oscillations can indeed be eliminated in realistic drilling scenarios in which industrial controllers fail to do so. Moreover, key robustness aspects of the control system involving the robustness against uncertainties in the bit–rock interaction and changing operational conditions are evidenced. Copyright © 2017 John Wiley & Sons, Ltd.     

Formation and Stability of β-Quartz Solid-Solution Phase in the Li-Si-Al-O-N System

The development of crystalline phases in lithium oxynitride glass-ceramics was examined, with particular emphasis placed on the effect of the nitrogen source (AlN or Si₃N₄) on the formation and stability of a β-quartz solid-solution ( ss ) phase. Oxynitride glasses derived from the Li-Si-Al-O-N system were heat-treated at temperatures up to 1200°C to yield glass-ceramics in which β-quartz( ss ) and β-spodumene( ss ) of approximate composition Li₂OAl₂O₃4SiO₂ formed as major phases and in which X-phase (Si₃Al₆O₁₂N₂) and silicon oxynitride (Si₂N₂O) were present as minor phases. The nitrogen-containing β-quartz( ss ) phase that was prepared with AlN was stable at 1200°C; however, the use of Si₃N₄ as the nitrogen source was significantly less effective in promoting such thermal stabilization. Lattice parameter measurements revealed that AlN and Si₃N₄ had different effects on the crystalline structures, and it was proposed that the enhanced thermal stability of the β-quartz( ss ) phase that was prepared with AlN was due to both the replacement of oxygen by nitrogen and the positioning of excess Al³⁺ ions into interstitial sites within the β-quartz( ss ) crystal lattice.     

A global NDVI and EVI reference data set for land-surface phenology using 13 years of daily SPOT-VEGETATION observations

Time series of vegetation indices (VIs) obtained by remote sensing are widely used to study phenology on regional and global scales. The aim of the study is to design a method and to produce a reference data set describing the seasonal and inter-annual variability of the land-surface phenology on a global scale. Specific constraints are inherent in the design of such a global reference data set: (1) the high diversity of vegetation types and the heterogeneous conditions of observation, (2) a near-daily resolution is needed to follow the rapid changes in phenology, (3) the time series used to depict the baseline vegetation cycle must be long enough to be representative of the current vegetation dynamic and encompass anomalies, and (4) a spatial resolution consistent with a land-cover-specific analysis should be privileged. This study focuses on the SPOT (Satellite Pour l’Observation de la Terre)-VEGETATION sensor and its 13-year time series of reflectance values. Five steps addressing the noise and the missing data in the reflectance time series were selected to process the daily multispectral reflectance observations. The final product provides, for every pixel, three profiles for 52 × 7-day periods: a mean, a median, and a standard deviation profile. The mean and median profiles represent the reference seasonal pattern for variation of the vegetation at a specific location whereas the standard deviation profile expresses the inter-annual variability of VIs. A quality flag at the pixel level demonstrated that the reference data set can be considered as a reliable representation of the vegetation phenology in most parts of the Earth.     

Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation

Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4⁺ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.     

Anomalous Resistance Hysteresis in Oxide ReRAM: Oxygen Evolution and Reincorporation Revealed by In Situ TEM

The control and rational design of redox‐based memristive devices, which are highly attractive candidates for next‐generation nonvolatile memory and logic applications, is complicated by competing and poorly understood switching mechanisms, which can result in two coexisting resistance hystereses that have opposite voltage polarity. These competing processes can be defined as regular and anomalous resistive switching. Despite significant characterization efforts, the complex nanoscale redox processes that drive anomalous resistive switching and their implications for current transport remain poorly understood. Here, lateral and vertical mapping of O vacancy concentrations is used during the operation of such devices in situ in an aberration corrected transmission electron microscope to explain the anomalous switching mechanism. It is found that an increase (decrease) in the overall O vacancy concentration within the device after positive (negative) biasing of the Schottky‐type electrode is associated with the electrocatalytic release and reincorporation of oxygen at the electrode/oxide interface and is responsible for the resistance change. This fundamental insight presents a novel perspective on resistive switching processes and opens up new technological opportunities for the implementation of memristive devices, as anomalous switching can now be suppressed selectively or used deliberately to achieve the desirable so‐called deep Reset.