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Emergence of drug-resistant bacteria represents a high, unmet medical need, and discovery of new antibacterials acting on new bacterial targets is strongly needed. ATP synthase has been validated as an antibacterial target in Mycobacterium tuberculosis, where its activity can be specifically blocked by the diarylquinoline TMC207. However, potency of TMC207 is restricted to mycobacteria with little or no effect on the growth of other Gram-positive or Gram-negative bacteria. Here, we identify diarylquinolines with activity against key Gram-positive pathogens, significantly extending the antibacterial spectrum of the diarylquinoline class of drugs. These compounds inhibited growth of Staphylococcus aureus in planktonic state as well as in metabolically resting bacteria grown in a biofilm culture. Furthermore, time-kill experiments showed that the selected hits are rapidly bactericidal. Drug-resistant mutations were mapped to the ATP synthase enzyme, and biochemical analysis as well as drug-target interaction studies reveal ATP synthase as a target for these compounds. Moreover, knockdown of the ATP synthase expression strongly suppressed growth of S. aureus, revealing a crucial role of this target in bacterial growth and metabolism. Our data represent a proof of principle for using the diarylquinoline class of antibacterials in key Gram-positive pathogens. Our results suggest that broadening the antibacterial spectrum for this chemical class is possible without drifting off from the target. Development of the diarylquinolines class may represent a promising strategy for combating Gram-positive pathogens. Copyright © 2012, American Society for Microbiology. All Rights Reserved.

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Colloque avec actes et comité de lecture. Internationale.; International audience; A theoretical modeling framework is proposed to follow shape and residual stress evolutions of layered flexible display structures with respect to coating deposition process, ambient temperature and relative humidity conditions. In the presented simplified version of this model, the mechanical equilibrium equations of elastic layers is coupled with transient mass transfer equations for the predictions of temperature and moisture content inside the structure. To calibrate this model, the behaviors of nanometric silicon nitride barrier layers on polyimide substrates were investigated. Then experimental measurements of the deflection dynamics of samples subjected to isothermal relative humidity jumps were compared with simulation results by considering different cases of boundary conditions. It is concluded that accurate simulations require accounting for the dependence of the water concentration-dependent diffusion coefficient.

A theoretical modeling framework is proposed to follow shape and residual stress evolutions of layered flexible display structures with respect to deposition, ambient temperature and relative humidity conditions. This model couples the mechanical equilibrium equations of elastic layers with transient heat and mass transfer equations for the predictions of temperature and moisture content inside the structure. Experimental data have been used to calibrate this model. For that purpose, nanometric silicon nitride barrier layers on polyimide substrates were investigated. The thermo-hygro-mechanical behavior of individual materials, including the water diffusion and sorption properties of polyimide were measured. Simulation results were then compared with experimental measurements of the curvature dynamics of samples subjected to isothermal relative humidity jumps. It is concluded that accurate simulations require accounting for the dependence of the water concentration-dependent diffusion coefficient.

Genetic studies recently unraveled the genetic cause of sclerosteosis, a rare skeletal dysplasia characterized by a generalized increase in bone mass. Different loss-of-function mutations were identified in SOST, a gene with no homology to any known gene. This SOST gene is also involved in the pathogenesis of van Buchem disease, a disorder closely resembling sclerosteosis, since a 52-kb deletion located downstream of SOST is found in patients diagnosed with this condition. Molecular studies showed a very restricted expression pattern of SOST and its gene product, sclerostin, with areas in the bone tissue, more precisely in cells of the osteoblast lineage, being the major sites of expression. Sclerostin is a secreted protein with a cysteine knot motif. In vitro studies demonstrated that sclerostin acts as a modulator of BMP signaling by binding to different members of the BMP growth factor family and acting on downstream BMP signal transduction events. The important function of sclerostin in bone metabolism has also been proven in vivo by the osteopenic phenotype of transgenic mice overexpressing SOST in bone. The identification of sclerostin as an important protein in bone metabolism opens new perspectives for the development of anabolic therapeutics to prevent and treat osteoporosis.

Flexible displays form complex structures joining together multiple layers of very various materials: metal or plastic flexible substrate, barrier and encapsulation layers, thin-films of transistor and optoelectronic devices. Residual stresses are inherent to these structures. In the case of inorganic layers deposited from a vapour phase onto a polymer substrate, these stresses comprise a so-called intrinsic contribution, which arises during the deposition, and thermal and hygroscopic contributions, which arise during temperature or relative humidity variations due to the different physical properties of materials. These residual stresses hinder to control the geometrical dimensions of the produced structures and are also at the origin of cracking and delaminating phenomena. Thus it is crucial to predict their development and to follow their evolution in order to optimize the production and the lifespan of these structures. For that purpose, our objective is to propose a numerical modelling framework of finite element type that makes possible to follow the geometrical evolution of multilayer composite structures with respect to the deposition conditions and the external conditions of temperature and relative humidity. In this study, we used bilayer samples formed with a nanometric silicon nitride layer, developed to protect organic light-emitting devices from ingression of oxygen and moisture, deposited on a polyimide foil. First experimental results obtained for the thermomechanical behaviours of the different materials, and for the diffusion and sorption properties for water of the polyimide substrate, are presented. Then these data are implemented in a non-linear numerical model coupling a quasi-static mechanical balance equation with some transient equations for the water concentration and for the temperature of the structure. Simulation results are finally compared with some experimental results, where the evolution of the curvature of bilayer samples subjected to thermal ramps, and/or to relative humidity jumps, was recorded. This study concludes that an accurate simulation needs to take into account the dependence of the water diffusion coefficient on the concentration, as well as on the transient evolutions of temperature and water concentration, whose time-scales are very different.