Inhibition of LRRK2 kinase activity stimulates macroautophagy

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most important genetic contributors to Parkinson's disease. LRRK2 has been implicated in a number of cellular processes, including macroautophagy. To test whether LRRK2 has a role in regulating autophagy, a specific inhibitor of the kinase activity of LRRK2 was applied to human neuroglioma cells and downstream readouts of autophagy examined. The resulting data demonstrate that inhibition of LRRK2 kinase activity stimulates macroautophagy in the absence of any alteration in the translational targets of mTORC1, suggesting that LRRK2 regulates autophagic vesicle formation independent of canonical mTORC1 signaling. This study represents the first pharmacological dissection of the role LRRK2 plays in the autophagy/lysosomal pathway, emphasizing the importance of this pathway as a marker for LRRK2 physiological function. Moreover it highlights the need to dissect autophagy and lysosomal activities in the context of LRRK2 related pathologies with the final aim of understanding their aetiology and identifying specific target for disease modifying therapies in patients.

On the radius of centrality in evolving communication networks

In this article, we investigate how the choice of the attenuation factor in an extended version of Katz centrality influences the centrality of the nodes in evolving communication networks. For given snapshots of a network, observed over a period of time, recently developed communicability indices aim to identify the best broadcasters and listeners (receivers) in the network. Here we explore the attenuation factor constraint, in relation to the spectral radius (the largest eigenvalue) of the network at any point in time and its computation in the case of large networks. We compare three different communicability measures: standard, exponential, and relaxed (where the spectral radius bound on the attenuation factor is relaxed and the adjacency matrix is normalised, in order to maintain the convergence of the measure). Furthermore, using a vitality-based measure of both standard and relaxed communicability indices, we look at the ways of establishing the most important individuals for broadcasting and receiving of messages related to community bridging roles. We compare those measures with the scores produced by an iterative version of the PageRank algorithm and illustrate our findings with two examples of real-life evolving networks: the MIT reality mining data set, consisting of daily communications between 106 individuals over the period of one year, a UK Twitter mentions network, constructed from the direct \emph{tweets} between 12.4k individuals during one week, and a subset the Enron email data set.

Mark Casson: the Entrepreneur at 30 -continued relevance?

Mark Casson's The Entrepreneur: An Economic Theory (1982) has become one of the most influential books in the field of entrepreneurship. For the first time, this article outlines its origins and summarizes its main themes. The article goes on to show how Casson's subsequent research has closely followed the research agenda he set for himself in The Entrepreneur and illustrates the continuing challenge his work presents to entrepreneurship scholars. The article is based on an interview the authors conducted with Mark Casson on the thirtieth anniversary of the book's publication. Copyright © 2014 Strategic Management Society.

Multilevel research in the field of organizational behavior: an empirical look at 10 years of theory and research

During the last 30 years, significant debate has taken place regarding multilevel research. However, the extent to which multilevel research is overtly practiced remains to be examined. This article analyzes 10 years of organizational research within a multilevel framework (from 2001 to 2011). The goals of this article are (a) to understand what has been done, during this decade, in the field of organizational multilevel research and (b) to suggest new arenas of research for the next decade. A total of 132 articles were selected for analysis through ISI Web of Knowledge. Through a broad-based literature review, results suggest that there is equilibrium between the amount of empirical and conceptual papers regarding multilevel research, with most studies addressing the cross-level dynamics between teams and individuals. In addition, this study also found that the time still has little presence in organizational multilevel research. Implications, limitations, and future directions are addressed in the end. Organizations are made of interacting layers. That is, between layers (such as divisions, departments, teams, and individuals) there is often some degree of interdependence that leads to bottom-up and top-down influence mechanisms. Teams and organizations are contexts for the development of individual cognitions, attitudes, and behaviors (top-down effects; Kozlowski & Klein, 2000). Conversely, individual cognitions, attitudes, and behaviors can also influence the functioning and outcomes of teams and organizations (bottom-up effects; Arrow, McGrath, & Berdahl, 2000). One example is when the rewards system of one organization may influence employees’ intention to quit and the existence or absence of extra role behaviors. At the same time, many studies have showed the importance of bottom-up emergent processes that yield higher level phenomena (Bashshur, Hernández, & González-Romá, 2011; Katz-Navon & Erez, 2005; Marques-Quinteiro, Curral, Passos, & Lewis, in press). For example, the affectivity of individual employees may influence their team’s interactions and outcomes (Costa, Passos, & Bakker, 2012). Several authors agree that organizations must be understood as multilevel systems, meaning that adopting a multilevel perspective is fundamental to understand real-world phenomena (Kozlowski & Klein, 2000). However, whether this agreement is reflected in practicing multilevel research seems to be less clear. In fact, how much is known about the quantity and quality of multilevel research done in the last decade? The aim of this study is to compare what has been proposed theoretically, concerning the importance of multilevel research, with what has really been empirically studied and published. First, this article outlines a review of the multilevel theory, followed by what has been theoretically “put forward” by researchers. Second, this article presents what has really been “practiced” based on the results of a review of multilevel studies published from 2001 to 2011 in business and management journals. Finally, some barriers and challenges to true multilevel research are suggested. This study contributes to multilevel research as it describes the last 10 years of research. It quantitatively depicts the type of articles being written, and where we can find the majority of the publications on empirical and conceptual work related to multilevel thinking.

Pathogenic Parkinson’s disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation

LRRK2 is one of the most important genetic contributors to Parkinson’s disease (PD). Point mutations in this gene cause an autosomal dominant form of PD, but to date no cellular phenotype has been consis- tently linked with mutations in each of the functional domains (ROC, COR and Kinase) of the protein product of this gene. In this study, primary fibroblasts from individuals carrying pathogenic mutations in the three central domains of LRRK2 were assessed for alterations in the autophagy/lysosomal pathway using a combination of biochemical and cellular approaches. Mutations in all three domains resulted in alterations in markers for autophagy/lysosomal function compared to wild type cells. These data high- light the autophagy and lysosomal pathways as read outs for pathogenic LRRK2 function and as a marker for disease, and provide insight into the mechanisms linking LRRK2 function and mutations.

O6-carboxymethylguanine DNA adduct formation and lipid peroxidation upon in vitro gastrointestinal digestion of haem-rich meat

Scope Epidemiological and clinical studies have demonstrated that the consumption of red haem-rich meat may contribute to the risk of colorectal cancer. Two hypotheses have been put forward to explain this causal relationship, i.e. N-nitroso compound (NOC) formation and lipid peroxidation (LPO). Methods and Results In this study, the NOC-derived DNA adduct O6-carboxymethylguanine (O6-CMG) and the LPO product malondialdehyde (MDA) were measured in individual in vitro gastrointestinal digestions of meat types varying in haem content (beef, pork, chicken). While MDA formation peaked during the in vitro small intestinal digestion, alkylation and concomitant DNA adduct formation was observed in seven (out of 15) individual colonic digestions using separate faecal inocula. From those, two haem-rich meat digestions demonstrated a significantly higher O6-CMG formation (p < 0.05). MDA concentrations proved to be positively correlated (p < 0.0004) with haem content of digested meat. The addition of myoglobin, a haem-containing protein, to the digestive simulation showed a dose–response association with O6-CMG (p = 0.004) and MDA (p = 0.008) formation. Conclusion The results suggest the haem-iron involvement for both the LPO and NOC pathway during meat digestion. Moreover, results unambiguously demonstrate that DNA adduct formation is very prone to inter-individual variation, suggesting a person-dependent susceptibility to colorectal cancer development following haem-rich meat consumption.

The perceived impact of the National Health Service on personalised nutrition service delivery among the UK public

Personalised nutrition (PN) has the potential to reduce disease risk and optimise health and performance. Although previous research has shown good acceptance of the concept of PN in the UK, preferences regarding the delivery of a PN service (e.g. online v. face-to-face) are not fully understood. It is anticipated that the presence of a free at point of delivery healthcare system, the National Health Service (NHS), in the UK may have an impact on end-user preferences for deliverances. To determine this, supplementary analysis of qualitative data obtained from focus group discussions on PN service delivery, collected as part of the Food4Me project in the UK and Ireland, was undertaken. Irish data provided comparative analysis of a healthcare system that is not provided free of charge at the point of delivery to the entire population. Analyses were conducted using the 'framework approach' described by Rabiee (Focus-group interview and data analysis. Proc Nutr Soc 63, 655-660). There was a preference for services to be led by the government and delivered face-to-face, which was perceived to increase trust and transparency, and add value. Both countries associated paying for nutritional advice with increased commitment and motivation to follow guidelines. Contrary to Ireland, however, and despite the perceived benefit of paying, UK discussants still expected PN services to be delivered free of charge by the NHS. Consideration of this unique challenge of free healthcare that is embedded in the NHS culture will be crucial when introducing PN to the UK.

Ratings of age of acquisition of 299 words across 25 languages: is there a cross-linguistic order of words?

We present a new set of subjective age-of-acquisition (AoA) ratings for 299 words (158 nouns, 141 verbs) in 25 languages from five language families (Afro-Asiatic: Semitic languages; Altaic: one Turkic language: Indo-European: Baltic, Celtic, Germanic, Hellenic, Slavic, and Romance languages; Niger-Congo: one Bantu language; Uralic: Finnic and Ugric languages). Adult native speakers reported the age at which they had learned each word. We present a comparison of the AoA ratings across all languages by contrasting them in pairs. This comparison shows a consistency in the orders of ratings across the 25 languages. The data were then analyzed (1) to ascertain how the demographic characteristics of the participants influenced AoA estimations and (2) to assess differences caused by the exact form of the target question (when did you learn vs. when do children learn this word); (3) to compare the ratings obtained in our study to those of previous studies; and (4) to assess the validity of our study by comparison with quasi-objective AoA norms derived from the MacArthur–Bates Communicative Development Inventories (MB-CDI). All 299 words were judged as being acquired early (mostly before the age of 6 years). AoA ratings were associated with the raters’ social or language status, but not with the raters’ age or education. Parents reported words as being learned earlier, and bilinguals reported learning them later. Estimations of the age at which children learn the words revealed significantly lower ratings of AoA. Finally, comparisons with previous AoA and MB-CDI norms support the validity of the present estimations. Our AoA ratings are available for research or other purposes.

Regulation of cardiac myocyte cell death.

Cardiac myocyte death, whether through necrotic or apoptotic mechanisms, is a contributing factor to many cardiac pathologies. Although necrosis and apoptosis are the widely accepted forms of cell death, they may utilize the same cell death machinery. The environment within the cell probably dictates the final outcome, producing a spectrum of response between the two extremes. This review examines the probable mechanisms involved in myocyte death. Caspases, the generally accepted executioners of apoptosis, are significant in executing cardiac myocyte death, but other proteases (e.g., calpains, cathepsins) also promote cell death, and these are discussed. The two principal cell death pathways (death receptor- and mitochondrial-mediated) are described in relation to the emerging structural information for the principal proteins, and they are discussed relative to current understanding of myocyte cell death mechanisms. Whereas the mitochondrial pathway is probably a significant factor in myocyte death in both acute and chronic phases of myocardial diseases, the death receptor pathway may prove significant in the longer term. The Bcl-2 family of proteins are key regulators of the mitochondrial death pathway. These proteins are described and their possible functions are discussed. The commitment to cell death is also influenced by protein kinase cascades that are activated in the cell. Whereas certain pathways are cytoprotective (e.g., phosphatidylinositol 3'-kinase), the roles of other kinases are less clear. Since myocyte death is implicated in a number of cardiac pathologies, attenuation of the death pathways may prove important in ameliorating such disease states, and possible therapeutic strategies are explored.

Legitimacy

This chapter examines the importance of legitimacy for international organizations, and their efforts to legitimate themselves vis-à-vis different audiences. Legitimacy, which for decades barely featured in the scholarly analysis of international organizations, has since the late 1990s been an increasingly important lens through which the processes, practices, and structures of international organizations have been examined. The chapter makes three main arguments. First, it argues that in most international organizations the most important actors engaging in legitimation efforts are not the supranational bureaucracies, but member states. This has important implications for our understanding of the purposes of seeking legitimacy, and for the possible practices. Second, legitimacy and legitimation serve a range of purposes for these states, beyond achieving greater compliance with their decisions, which has been one of the key functional logics highlighted for legitimacy in the literature. Instead, legitimacy is frequently sought to exclude outsiders from the functional or territorial domains affected by an international organization’s authority, or to maintain external material and political support for existing arrangements. Third, one of the most prominent legitimation efforts, institutional reforms, often prioritizes form over function, signalling to important and powerful audiences to encourage their continued material and political support. To advance these arguments, the chapter is divided into four sections. The first develops the concept of legitimacy and its application to international organizations, and then asks why their legitimacy has become such an important intellectual and political concern in recent years. The second part will look in more detail at the legitimation practices of international organizations, focusing on who engages in these practices, who the key audiences are, and how legitimation claims are advanced. The third section will look in more detail at one of the most common forms of legitimation – institutional reform – through the lens of two such reforms in international organizations: efforts towards greater interoperability in NATO, and the establishment of the African Peace and Security Architecture in the African Union (AU). The chapter will conclude with some reflections of the contribution that a legitimacy perspective has made to our understanding of the practices of international organizations.

Amor intellectualis diaboli

An essay on love and liberty in the writings of Gillian Rose, Marquis de Sade, Max Horkheimer and Theodor W. Adorno, written in response to the following provocation: "Encore un effort. A banderole publicitaire carries the breathless descriptions of the new fashions for 1968, when anything goes and details place the accent on this or that part of the body and its adornment: a pair of shoes that come off in a struggle, for example, the heel of one snapped off; a striking checked shirt, with two buttons undone; a light-coloured trench coat (perfect for a May day); a blouson-style jacket that allows easy freedom of movement; place casual slacks worn with an ankle boot. Beauty is in the streets as fashion becomes democratic (or so say the houses of haute couture), while the philosopher of the boudoir extorts us once again to make an effort if we wish to be republicans. Here, to an assembled crowd of sensitive men and women, which petit-maitre or dangerous man of principles would suggest that the only moral system to reinforce political revolution is that of libertinage, the revenge of nature's course against the aberrations of society?"