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.

Branded lives:the production and consumption of meaning at work

'Branded Lives explodes the myth that a brand must, or even can stand for one unified, easily communicated message. While warning of the dangers of managing to preserve this myth, the book also celebrates the plurality of brand meanings generated by those employed to serve both the brand and the customer. I recommend reading this book in its entirety. If you are like me, your reading will bring a refreshing fullness to the experience of brands and branding and many new insights.' - Mary Jo Hatch, University of Virginia, US. © Matthew J. Brannan, Elizabeth Parsons and Vincenza Priola 2011. All rights reserved.

Improper use of formative endogenous variables

Researchers often develop and test conceptual models containing formative variables. In many cases, these formative variables are specified as being endogenous. This article provides a clarification of formative variable theory, distinguishing between the formative latent variable and the formative composite variable. When an endogenous latent variable relies on formative indicators for measurement, empirical studies can say nothing about the relationship between exogenous variables and the endogenous formative latent variable: conclusions can only be drawn regarding the exogenous variables' relationships with a composite variable. The authors also show the dangers associated with developing theory about antecedents to endogenous formative variables at the (aggregate) formative latent variable level. Modeling relationships with endogenous formative variables at the (disaggregate) indicator level informs richer theory development, and encourages more precise empirical testing. When antecedents' relationships with endogenous formative variables are modeled at the formative latent variable level rather than the formative indicator level, theory construction can verge on the superficial, and empirical findings can be ambiguous in substantive meaning.

An exploration of the absence of corporate social reporting (CSR) in Bangladesh

This paper aims to broaden the present CSR literature by examining the absence of CSR within the context of a developing country. This is an area which to date is relatively under researched in comparison to the more widely studied presence of CSR within developed Western countries. For this purpose, 23 semi-structured interviews were undertaken with senior corporate managers in Bangladesh. The findings suggest that the main reasons for non-disclosure include lack of legal requirements and lack of knowledge/awareness. The other reasons mentioned are lack of resources, poor performance and fear of bad publicity and inherent dangers in additional disclosures. The paper has raised some serious public policy concerns by exploring the underlying motives for absence of CSR in general and some eco-justice issues in particular (e.g. child labour, equal opportunities and poverty alleviation). These significant issues require careful consideration by the policy makers at the national, regional and international levels.

Regulating audit beyond the crisis:a critical discussion of the EU green paper

With the European Commission making global leadership claims in the field of audit regulation, the content of its 2010 Green Paper on ‘Audit Policy: Lessons from the Crisis’ warrants careful scrutiny. Important issues raised in the Green Paper include regulatory oversight, competition in the audit market, the dangers of having very few firms with the capacity to audit global transnational corporations, professional judgement, innovative audit practices and, last but not least, social responsibility. This article analyses the principal perspectives and assumptions underpinning the construction of the Green Paper. The aims are threefold: to enhance understanding of the contemporary regulatory mindset of the European Commission, contribute to policy debate and inspire future research.

An exploration into measurement consistency on coordinate measuring machines

In high precision industry, the measurement of geometry is often performed using coordinate measuring machines (CMMs). Measurements on CMMs can occur at many places within a long and global supply chain. In this context it is a challenge to control consistency, so that measurements are applied with appropriate levels of rigour and achieve comparable results, wherever and whenever they are performed. In this paper, a framework is outlined in which consistency is controlled through measurement strategy, such as the number and location of measurement points. The framework is put to action in a case study, demonstrating the usefulness of the approach and highlighting the dangers of imposing rigid measurement strategies across the supply chain, even if linked to standardised manufacturing processes. Potential mitigations, and the requirements for future research, are outlined.

Privacy and the City:user identification and location semantics in location-based social networks

With the advent of GPS enabled smartphones, an increasing number of users is actively sharing their location through a variety of applications and services. Along with the continuing growth of Location-Based Social Networks (LBSNs), security experts have increasingly warned the public of the dangers of exposing sensitive information such as personal location data. Most importantly, in addition to the geographical coordinates of the user’s location, LBSNs allow easy access to an additional set of characteristics of that location, such as the venue type or popularity. In this paper, we investigate the role of location semantics in the identification of LBSN users. We simulate a scenario in which the attacker’s goal is to reveal the identity of a set of LBSN users by observing their check-in activity. We then propose to answer the following question: what are the types of venues that a malicious user has to monitor to maximize the probability of success? Conversely, when should a user decide whether to make his/her check-in to a location public or not? We perform our study on more than 1 million check-ins distributed over 17 urban regions of the United States. Our analysis shows that different types of venues display different discriminative power in terms of user identity, with most of the venues in the “Residence” category providing the highest re-identification success across the urban regions. Interestingly, we also find that users with a high entropy of their check-ins distribution are not necessarily the hardest to identify, suggesting that it is the collective behaviour of the users’ population that determines the complexity of the identification task, rather than the individual behaviour.

It's the way you check-in:identifying users in location-based social networks

In recent years, the rapid spread of smartphones has led to the increasing popularity of Location-Based Social Networks (LBSNs). Although a number of research studies and articles in the press have shown the dangers of exposing personal location data, the inherent nature of LBSNs encourages users to publish information about their current location (i.e., their check-ins). The same is true for the majority of the most popular social networking websites, which offer the possibility of associating the current location of users to their posts and photos. Moreover, some LBSNs, such as Foursquare, let users tag their friends in their check-ins, thus potentially releasing location information of individuals that have no control over the published data. This raises additional privacy concerns for the management of location information in LBSNs. In this paper we propose and evaluate a series of techniques for the identification of users from their check-in data. More specifically, we first present two strategies according to which users are characterized by the spatio-temporal trajectory emerging from their check-ins over time and the frequency of visit to specific locations, respectively. In addition to these approaches, we also propose a hybrid strategy that is able to exploit both types of information. It is worth noting that these techniques can be applied to a more general class of problems where locations and social links of individuals are available in a given dataset. We evaluate our techniques by means of three real-world LBSNs datasets, demonstrating that a very limited amount of data points is sufficient to identify a user with a high degree of accuracy. For instance, we show that in some datasets we are able to classify more than 80% of the users correctly.

The impact of statin use on fetal development:a meta-analysis

INTRODUCTION: Statin use inadvertently during pregnancy and proposed use of statins for the treatment of preeclampsia, led us to question the evidence behind their current contraindicated status. Several studies have evaluated the relationship between statin use in pregnancy with fetal outcome but their results have not been quantitatively assessed by meta-analysis. Our objective was to undertake a systematic review of all published clinical evidence to assess the effects of statin use in pregnancy on subsequent fetal wellbeing. METHODS: A comprehensive search strategy was performed of all electronic databases and the Merck reporting database for studies published from 1966 to 2014. Two reviewers independently screened citations and undertook study quality assessment and data extraction. We obtained summary estimates of adverse fetal events that were classified as potentially fatal, clinically significant morbidity or minor adverse event. We identified 602 titles and reviewed 30 articles for inclusion and exclusion criteria. Meta-analysis was performed on seven studies (3 cohort, 3 case-series and 1 case-control). RESULTS: Of the 922 cases of statin exposure in pregnancy, 27 exposures were associated with lethal or clinically significant fetal morbidity and 10 with minor adverse events. Statin exposure was limited to the first trimester in all but two cases. The pooled rate of lethal or clinically significant fetal abnormalities in pregnant women exposed to statins was 0.01 (95% CI 0.00-0.04), less than the European rate of 0.026 (95% CI 2.54- 2.57)EUROCAT. The rate of fetal abnormality for simvastatin was 0.03 (95% CI 0.00-0.08), atorvostatin 0.11 (95% CI 0.00-0.52), pravastatin 0.01 (95% CI 0.00-0.2) and lovastatin use 0.04 (95% CI 0.00-0.28). Systems based anomalies were also calculated, congenital heart disease was 0.8 (95% CI 0.02-0.12) compared with the background rate of 0.79 (95% CI 0.78- 0.80). CONCLUSIONS: The published data suggests that statins may not be teratogenic when given inadvertently during pregnancy and prospective studies such as The StAmP Trial may provide more data