The role of deubiquitinating enzymes in apoptosis

It has become apparent that ubiquitination plays a critical role in cell survival and cell death. In addition, deubiquitinating enzymes (DUBs) have been determined to be highly important regulators of these processes. Cells can be subjected to various stresses and respond in a variety of different ways ranging from activation of survival pathways to the promotion of cell death, which eventually eliminates damaged cells. The regulatory mechanisms of apoptosis depend on the balanced action between ubiquitination and deubiquitination systems. There is a growing recognition that DUBs play essential roles in regulating several binding partners to modulate the process of apoptosis. Thus, the interplay between the timing of DUB activity and the specificity of ubiquitin attachment and removal from its substrates during apoptosis is important to ensure cellular homeostasis. This review discusses the role of a few ubiquitin-specific DUBs that are involved in either promoting or suppressing the process of apoptosis.     

Resveratrol improves health and survival of mice on a high-calorie diet

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.     

BVAR as a category management tool: An illustration and comparison with alternative techniques

Category management—a relatively new function in marketing—involves large-scale, real-time forecasting of multiple data series in complex environments. In this paper, we illustrate how Bayesian Vector Auto regression (BVAR) fulfils the category manager's decision-support requirements by providing accurate forecasts of a category's state variables (prices, volumes and advertising levels), incorporating management interventions (merchandising events such as end-aisle displays), and revealing competitive dynamics through impulse response analyses. Using 124 weeks of point-of-sale scanner data comprising 31 variables for four brands, we compare the out-of-sample forecasts from BVAR to forecasts from exponential smoothing, univariate and multivariate Box-Jenkins transfer function analyses, and multivariate ARMA models. Theil U's indicate that BVAR forecasts are superior to those from alternate approaches. In large-scale forecasting applications, BVAR's ease of identification and parsimonious use of degrees of freedom are particularly valuable.     

Atomistic mechanisms governing elastic limit and incipient plasticity in crystals

Nanometre-scale contact experiments and simulations demonstrate the potential to probe incipient plasticity--the onset of permanent deformation--in crystals. Such studies also point to the need for an understanding of the mechanisms governing defect nucleation in a broad range of fields and applications. Here we present a fundamental framework for describing incipient plasticity that combines results of atomistic and finite-element modelling, theoretical concepts of structural stability at finite strain, and experimental analysis. We quantify two key features of the nucleation and subsequent evolution of defects. A position-sensitive criterion based on elastic stability determines the location and character of homogeneously nucleated defects. We validate this stability criterion at both the atomistic and the continuum levels. We then propose a detailed interpretation of the experimentally observed sequence of displacement bursts to elucidate the role of secondary defect sources operating locally at stress levels considerably smaller than the ideal strength required for homogeneous nucleation. These findings provide a self-consistent explanation of the discontinuous elastic plastic response in nanoindentation measurements, and a guide to fundamental studies across many disciplines that seek to quantify and predict the initiation and early stages of plasticity.     

Nanoindentation. Simulation of defect nucleation in a crystal

Nanoindentation is the penetration of a surface to nanometre depths using an indenting device. It can be simulated using the Bragg bubble-raft model, in which a close-packed array of soap bubbles corresponds to the equilibrium positions of atoms in a crystalline solid. Here we show that homogeneous defect nucleation occurs within a crystal when its surface roughness is comparable to the radius of the indenter tip, and that the depth of the nucleation site below the surface is proportional to the half-width of the contact. Our results may explain the unusually high local stress required for defect nucleation in nano-indented face-centred cubic crystals.