Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Nationalised large-scale mining, trade unions and community representation: perspectives from Northern Madagascar

This article critically explores the nature and purpose of relationships and inter-dependencies between stakeholders in the context of a parastatal chromite mining company in the Betsiboka Region of Northern Madagascar. An examination of the institutional arrangements at the interface between the mining company and local communities identified power hierarchies and dependencies in the context of a dominant paternalistic environment. The interactions, inter alia, limited social cohesion and intensified the fragility and weakness of community representation, which was further influenced by ethnic hierarchies between the varied community groups; namely, indigenous communities and migrants to the area from different ethnic groups. Moreover, dependencies and nepotism, which may exist at all institutional levels, can create civil society stakeholder representatives who are unrepresentative of the society they are intended to represent. Similarly, a lack of horizontal and vertical trust and reciprocity inherent in Malagasy society engenders a culture of low expectations regarding transparency and accountability, which further catalyses a cycle of nepotism and elite rent-seeking behaviour. On the other hand, leaders retain power with minimal vertical delegation or decentralisation of authority among levels of government and limit opportunities to benefit the elite, perpetuating rent-seeking behaviour within the privileged minority. Within the union movement, pluralism and the associated politicisation of individual unions restricts solidarity, which impacts on the movement’s capacity to act as a cohesive body of opinion and opposition. Nevertheless, the unions’ drive to improve their social capital has increased expectations of transparency and accountability, resulting in demands for greater engagement in decision-making processes.

Targeting Staphylococcus aureus quorum sensing with non-peptidic small molecule inhibitors

A series of 3-oxo-C12-HSL, tetramic acid and tetronic acid analogues was synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were non-competitive inhibitors of the auto-inducing peptide (AIP)-activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17 which reduced nasal cell colonization and arthritis in a murine infection model.

The climate change–infectious disease nexus: is it time for climate change syndemics?

Conceptualizing climate as a distinct variable limits our understanding of the synergies and interactions between climate change and the range of abiotic and biotic factors, which influence animal health. Frameworks such as eco-epidemiology and the epi-systems approach, while more holistic, view climate and climate change as one of many discreet drivers of disease. Here, I argue for a new paradigmatic framework: climate-change syndemics. Climate-change syndemics begins from the assumption that climate change is one of many potential influences on infectious disease processes, but crucially is unlikely to act independently or in isolation; and as such, it is the inter-relationship between factors that take primacy in explorations of infectious disease and climate change. Equally importantly, as climate change will impact a wide range of diseases, the frame of analysis is at the collective rather than individual level (for both human and animal infectious disease) across populations.

Climate change and infectious disease: time for a new normal?

At present, there is a clarion call for action on climate change across the global health landscape. At the recent WHO-sponsored conference on health and climate (held in Geneva, Switzerland, on Aug 27–29, 2014) and the UN Climate Summit (New York, USA, on Sept 23, 2014), participants were encouraged to act decisively to change the current trajectory of climate disruption. Health inequalities, including those related to infectious diseases, have now been pushed to centre stage. This approach represents a step-change in thinking. But as we are urged toward collective action, is it time to rethink our approach to research, especially in relation to climate change and infectious disease?

A mechanism of internal decadal atlantic ocean variability in a high-resolution coupled climate model

The North Atlantic Ocean subpolar gyre (NA SPG) is an important region for initialising decadal climate forecasts. Climate model simulations and palaeo climate reconstructions have indicated that this region could also exhibit large, internally generated variability on decadal timescales. Understanding these modes of variability, their consistency across models, and the conditions in which they exist, is clearly important for improving the skill of decadal predictions — particularly when these predictions are made with the same underlying climate models. Here we describe and analyse a mode of internal variability in the NA SPG in a state-of-the-art, high resolution, coupled climate model. This mode has a period of 17 years and explains 15–30% of the annual variance in related ocean indices. It arises due to the advection of heat content anomalies around the NA SPG. Anomalous circulation drives the variability in the southern half of the NA SPG, whilst mean circulation and anomalous temperatures are important in the northern half. A negative feedback between Labrador Sea temperatures/densities and those in the North Atlantic Current is identified, which allows for the phase reversal. The atmosphere is found to act as a positive feedback on to this mode via the North Atlantic Oscillation which itself exhibits a spectral peak at 17 years. Decadal ocean density changes associated with this mode are driven by variations in temperature, rather than salinity — a point which models often disagree on and which we suggest may affect the veracity of the underlying assumptions of anomaly-assimilating decadal prediction methodologies.

Psychological contracts and independent sales contractors: an examination of the predictors of contractor-level outcomes

Over the past decade, the independent sales contractor (ISC) has emerged as both an important distribution channel and a management challenge. This study makes two contributions to this evolving field. First, it explores the interrelations of the psychological contract with sales performance, voluntary turnover and organisational advocacy of ISCs, which have hitherto been largely unexplored. Second, it examines differences between high- and low-performing sales contractors on these linkages, due to findings in the literature that a small number of sales contractors often achieve a majority of sales. Based on survey data as well as 7 years of contractor-level data related to sales performance and voluntary turnover (n = 189), results indicate that psychological contract fulfilment and perceived dependency are important determinants of subsequent sales performance, voluntary turnover and organisational advocacy, with significant differences reported between high- and low-performing ISCs. A notable finding pertinent for sales managers responsible for managing ISCs is that high-performing sales contractors are motivated by psychological contract fulfilment and a low perception of dependency, while low-performing sales contractors are more likely to act as advocates for the firm due to perceived dependency, but may concurrently engage in organisational advocacy as a means to leave the firm.

Molecular targets of cannabidiol in neurological disorders

Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD’s beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular phar- macology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD’s relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeu- tics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent with modulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug’s action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD’s effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD’s therapeutic mechanism of action.

Expression of the receptor tyrosine kinase ephb2 on dendritic cells is modulated by toll-like receptor ligation but is not required for t cell activation

The Eph receptor tyrosine kinases interact with their ephrin ligands on adjacent cells to facilitate contact-dependent cell communication. Ephrin B ligands are expressed on T cells and have been suggested to act as co-stimulatory molecules during T cell activation. There are no detailed reports of the expression and modulation of EphB receptors on dendritic cells, the main antigen presenting cells that interact with T cells. Here we show that mouse splenic dendritic cells (DC) and bone-marrow derived DCs (BMDC) express EphB2, a member of the EphB family. EphB2 expression is modulated by ligation of TLR4 and TLR9 and also by interaction with ephrin B ligands. Co-localization of EphB2 with MHC-II is also consistent with a potential role in T cell activation. However, BMDCs derived from EphB2 deficient mice were able to present antigen in the context of MHC-II and produce T cell activating cytokines to the same extent as intact DCs. Collectively our data suggest that EphB2 may contribute to DC responses, but that EphB2 is not required for T cell activation. This result may have arisen because DCs express other members of the EphB receptor family, EphB3, EphB4 and EphB6, all of which can interact with ephrin B ligands, or because EphB2 may be playing a role in another aspect of DC biology such as migration.

Investigation of institutional investors’ responsible investment practices in UK

The focus of Corporate Governance is shifting from the role of directors to active ownership. Based on their fiduciary duty to other shareholders, it is believed that institutional investors have an important role to play in this regard. However, the Pension Funds and the Sovereign Wealth Organisations are not driven by the same set of objectives. In addition, Environmental Social and Governance (ESG) issues in investment decision-making are now becoming more important and they are capable of becoming the mainstream in the future. However, there are widespread variations in perception of fiduciary responsibilities, ESG issues appraisal, as well as the strategies adopted by institutional investors on shareholder engagement as responsible investors. Responsible Investment market is largely driven by institutional investors and they are expected to continue to lead the way. This research work investigates the role of the main asset owners and their advisors in responsible investment practices in the UK. It adopts a qualitative approach using semi-structured interviews, questionnaire and meetings observations. Gathered data is analysed using grounded theory and the findings highlight the perception of the various investor groups to corporate governance. The research work contributes to the body of knowledge by assessing the corporate governance perspectives of the various classes of institutional investors which may have practical implications for other countries.

No country for honest men: political philosophers and real politics

There are limits on the duty to tell the truth. Sometimes, because of the undesirable consequences of honesty, we are morally required not to reveal certain truths and can even be required to lie. In this article, we explore the implications of this uncontroversial claim for the practice of political philosophers. We argue that, given the consequences of misunderstandings and misrepresentations that might occur, political philosophers will sometimes be under a moral duty not to disseminate their research and, in highly exceptional cases, have a moral duty to lie outright.

Reasonable adjustments for disabled pupils: what support do parents want for their child?

Schools in England (as elsewhere in Europe) have a duty to promote equality for disabled people and make reasonable adjustments for disabled children. There is, however, a degree of uncertainty about how well-placed parents are addressed to use the legislation to ensure their child’s needs. This paper presents data drawn from a national questionnaire designed for schools to use to identify their disabled pupils and examines, in detail, parental responses to a question on the kinds of support their child finds helpful in offsetting any difficulties they experience. It illustrates the complex and varied nature of the ‘reasonable adjustments’ that are required and an overriding sense that need to be underpinned by the values of a responsive child-centred approach, one that recognises that parents’ knowledge and understanding of their child are important. Schools need to have in place the two-way communication process that supports them in ‘knowing’ about the visible and invisible challenges that pupils with difficulties and disabilities face in participating in school life.

Какую поддержку хотят родители для своих детей с ОВЗ

Schools in England (as elsewhere in Europe) have a duty to promote equality for disabled people and make reasonable adjustments for disabled children. This paper presents data drawn from a national questionnairedesigned for schools to use to identify their disabled pupils and examines in detail parental responses to a question on the kinds of support their child finds helpful in offsetting any difficulties they experience. It illustrates the complex and varied nature of the reasonable adjustments required and an overriding sense these need to be underpinned by the values of a responsive child centred approach, one that reflects parents’ knowledge and understanding of their child. Schools need to have in place the two way communication process that supports them in “knowing” about the visible and invisible challenges that disabled pupils face in participating in school life

The brand likeability scale: an exploratory study of likeability in firm-level brands

We develop a new measurement scale to assess consumers’ brand likeability in firm-level brands. We present brand likeability as a multidimensional construct. In the context of service experience purchases, we find that increased likeability in brands results in: (1) greater amount of positive association; (2) increased interaction interest; (3) more personified quality; and (4) increased brand contentment. The four-dimensional multiple-item scale demonstrates good psychometric properties, showing strong evidence of reliability as well as convergent, discriminant and nomological validity. Our findings reveal that brand likeability is positively associated with satisfaction and positive word of mouth. The scale extends existing branding research, providing brand managers with a metric so that likeability can be managed strategically. It addresses the need for firms to act more likeably in an interaction-dominated economy. Focusing on likeability acts as a differentiator and encourages likeable brand personality traits. We present theoretical implications and future research directions on the holistic brand likeability concept.

Collective financing among Chinese entrepreneurs and department store retailing in China

Chinese entrepreneurship in department store retailing differed from that seen in other emerging economies before 1940. Rather than the leading examples of the format being owned by advanced economy firms, in China a small group of Cantonese entrepreneurs established what became known as the ‘Big Four’ department stores in Shanghai. By 1940 the ‘Big Four’ department stores were among the most famous stores in China, and among the biggest businesses in China. None of these Chinese entrepreneurs had any prior experience in department store retailing. Rather this article explains how their success in department store retailing was dependent on a business model that enabled these Chinese entrepreneurs to act as informal investment bankers (or ‘shadow’ banks) for the thousands of overseas Chinese wanting to invest surplus savings in mainland China, so creating large indigenous business groups.