The Role of Cellular Senescence in Werner Syndrome: Toward Therapeutic Intervention in Human Premature Aging

Werner syndrome (WS) is a premature aging disorder used as a model of normal human aging. WS individuals have several characteristics of normal aging, such as cataracts, hair graying, and skin aging, but manifest these at an early age. Additionally, WS individuals have high levels of inflammatory diseases, such as atherosclerosis and type 2 diabetes. The in vivo aging in WS is associated with accelerated aging of fibroblasts in culture. The cause of the accelerated senescence is not understood, but may be due to the genomic instability that is a hallmark of WS. Genome instability results in activation of stress kinases, such as p38, and the p38-specific inhibitor SB203580, prevents the accelerated senescence seen in WS fibroblasts. However, oxidative damage plays a role, as low oxygen conditions and antioxidant treatment revert some of the accelerated senescence phenotype. The effects of oxidative stress appear to be suppressible by SB203580; however, it does not appear to be transduced by p38. As SB203580 is known to inhibit other kinases in addition to p38, this suggests that more than one kinase pathway is involved. The recent development of p38 inhibitors with different binding properties, specificities, and oral bioavailability, and of new potent and selective inhibitors of JNK and MK2, will make it possible to dissect the roles of various kinase pathways in the accelerated senescence of WS cells. If this accelerated senescence is reflective of WS aging in vivo, these kinase inhibitors may well form the basis of antiaging therapies for individuals with WS

D Meson Elliptic Flow In Noncentral Pb-pb Collisions At √s Nn=2.76 Tev

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Analysis of chip formation mechanisms and modelling of slabber process

During the primary transformation in wood industry, logs are faced with conical rough milling cutters commonly named slabber or canter heads. Chips produced consist of raw materials for pulp paper and particleboard industries. The process efficiency of these industries partly comes from particle size distribution. However, chips formation is greatly dependent on milling conditions and material variability. Thus, this study aims at better understanding and predicting chips production in wood milling. The different mechanisms of their formation are studied through orthogonal cutting experiments at high cutting speed for beech and Douglas fir. Within these conditions, ejection of free water inside wood can be observed during fragmentation, particularly on beech. As previously seen in quasi-static experiments, chip thickness is proportional to the nominal cut thickness. Moreover, the grain orientation has a great influence on the cutting mechanisms, so as the nominal cut and the grows rings widths. This chip fragmentation study finally allows the improvement of the cutting conditions in rough milling. In order to optimize machine design as well as cutting geometry, a geometrical model of a generic slabber head is developed. This model allows the study of the effective cutting kinematics, the log-cutting edges interactions and the effective wood grain direction during cutting. This paper describes the great influence of the carriage position on cutting conditions. The results obtained here can be directly used by milling machine manufacturers.Allocation Spécifique Normalie