The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch

The Raf-1 protein kinase is a major activator of the ERK MAPK pathway, which links signaling by a variety of cell surface receptors to the regulation of cell proliferation, survival, differentiation and migration. Signaling by Raf-1 is regulated by a complex and poorly understood interplay between phosphorylation events and protein-protein interactions. One important mode of Raf-1 regulation involves the phosphorylation-dependent binding of 14-3-3 proteins. Here, we have examined the mechanism whereby the C-terminal 14-3-3 binding site of Raf-1, S621, controls the activation of MEK-ERK signaling. We show that phosphorylation of S621 turns over rapidly and is enriched in the activated pool of endogenous Raf-1. The phosphorylation on this site can be mediated by Raf-1 itself but also by other kinase(s). Mutations that prevent the binding of 14-3-3 proteins to S621 render Raf-1 inactive by specifically disrupting its capacity to bind to ATP, and not by gross conformational alteration as indicated by intact MEK binding. Phosphorylation of S621 correlates with the inhibition of Raf-1 catalytic activity in vitro, but 14-3-3 proteins can completely reverse this inhibition. Our findings suggest that 14-3-3 proteins function as critical cofactors in Raf-1 activation, which induce and maintain the protein in a state that is competent for both ATP binding and MEK phosphorylation.

Statnote 14: the correlation of two variables (Pearson's 'r')

Pearson's correlation coefficient (‘r’) is one of the most widely used of all statistics. Nevertheless, care needs to be used in interpreting the results because with large numbers of observations, quite small values of ‘r’ become significant and the X variable may only account for a small proportion of the variance in Y. Hence, ‘r squared’ should always be calculated and included in a discussion of the significance of ‘r’. The use of ‘r’ also assumes that the data follow a bivariate normal distribution (see Statnote 17) and this assumption should be examined prior to the study. If the data do not conform to such a distribution, the use of a non-parametric correlation coefficient should be considered. A significant correlation should not be interpreted as indicating ‘causation’ especially in observational studies, in which the two variables may be correlated because of their mutual correlations with other confounding variables.

A consideration of modelling techniques that can be used to evaluate manufacturing strategies

Practising engineers frequently seek to understand what the effects of various manufacturing strategies will be on the performance of their production facilities. In this situation a computer model can help to provide insight and form predictions about future manufacturing system performance. Various types of modelling methods exist and each provide models that have distinct characteristics. This paper presents a review of popular modelling techniques and, based on the results of a structured experimental study, summarises their capabilities to support the evaluation of manufacturing strategies.

New studies in global IT and business service outsourcing:5th global scourcing workshop 2011, Courchevel, France, March 14-17, 2011, revised selected papers

This book contains 11 carefully revised and selected papers from the 5th Workshop on Global Sourcing, held in Courchevel, France, March 14-17, 2011. They have been gleaned from a vast empirical base brought together by leading researchers in information systems, strategic management, and operations. This volume is intended for use by students, academics, and practitioners interested in the outsourcing and offshoring of information technology and business processes. It offers a review of the key topics in outsourcing and offshoring, populated with practical frameworks that serve as a tool kit for students and managers. The topics discussed combine theoretical and practical insights, and they are extensively illustrated by case studies from client and vendor organizations. Last but not least, the book examines current and future trends in outsourcing and offshoring, paying particular attention to how innovation can be realized in global or outsourced software development environments.

Severe visual impairment due to diabetes mellitus:can this be influenced by community & hospital retinal screening and formal hospital diabetic annual review?

Purpose: Diabetes is a leading cause of visual impairment in working age population in the UK. This study looked at the causes of Severe Visual Impairment(SVI) in the patients attending diabetic eye clinic and influence on the rate of SVI, over a 12 year period, after introducing retinal screening programmes in the hospital and the community in 1993 (review in 1992, 1998 & 2004). Methods: Medical records of all the patients attending the diabetic eye clinic over a period of 5months(April to August) in 1992, 1998 and 2004 were reviewed. The data collected for each patient included age, sex, ethnic origin, diabetes (type,duration &treatment), the best corrected visual acuity (present and at time of presentation), type and duration of retinopathy and attendance record to both diabetic clinic and diabetic eye clinic. In this study, SVI is defined as a visual acuity of 6/36 or worse in at least one eye. Results: In 1992, of a total 245 patients, 58patients(23.6%) had SVI {38 (15.5% of total) due to diabetic retinopathy [31(12.6%) maculopathy, 2(0.8%) vitreous haemorrhage and 5(2%) retinal detachment] and 20(8.1%) due to non–diabetic retinopathy causes}. In 1998, of a total 297, 77patients(25.9%) had SVI {33(11.1% of total) due to diabetic retinopathy [19(6.4%) maculopathy, 9(3%) proliferative retinopathy, 8(2.7%) vitreous haemorrhage and 3(1%) retinal detachment]and 44(14.8%)due to non–diabetic retinopathy}. In 2004, of a total 471, 72patients(15.2%) had SVI{46(9.7%of total) due to diabetic retinopathy [37(7.8%) maculopathy, 1(0.2%) proliferative retinopathy, 6(1.8%) vitreous haemorrhage and 2(0.4%) retinal detachment]and 26(5.5%) due to non– diabetic retinopathy causes}. Conclusions: Introduction of formalised annual diabetic review including retinal screening and a community retinal screening programme has reduced the rate of severe visual impairment due to diabetic retinopathy, in patients attending diabetic eye clinic, from 15.5% in1992 to 9.7% in2004. Keywords: diabetic retinopathy