Adeno-associated virus-8-Mediated intravenous transfer of myostatin propeptide leads to systemic functional improvements of slow but not fast muscle

Myostatin is a member of the transformating growth factor-_ (TGF-_) superfamily of proteins and is produced almost exclusively in skeletal muscle tissue, where it is secreted and circulates as a serum protein. Myostatin acts as a negative regulator of muscle mass through the canonical SMAD2/3/4 signaling pathway. Naturally occurring myostatin mutants exhibit a ‘double muscling’ phenotype in which muscle mass is dramatically increased as a result of both hypertrophy and hyperplasia. Myostatin is naturally inhibited by its own propeptide; therefore, we assessed the impact of adeno associated virus-8 (AAV8) myostatin propeptide vectors when systemically introduced in MF-1 mice. We noted a significant systemic increase in muscle mass in both slow and fast muscle phenotypes, with no evidence of hyperplasia; however, the nuclei-to- cytoplasm ratio in all myofiber types was significantly reduced. An increase in muscle mass in slow (soleus) muscle led to an increase in force output; however, an increase in fast (extensor digitorum longus [EDL]) muscle mass did not increase force output. These results suggest that the use of gene therapeutic regimens of myostatin inhibition for age-related or disease-related muscle loss may have muscle-specific effects.

Chronic systemic therapy with low-dose morpholino oligomers ameliorates the pathology and normalizes locomotor behavior in mdx Mice

The administration of antisense oligonucleotides (AOs) to skip one or more exons in mutated forms of the DMD gene and so restore the reading frame of the transcript is one of the most promising approaches to treat Duchenne muscular dystrophy (DMD). At present, preclinical studies demonstrating the efficacy and safety of long-term AO administration have not been conducted. Furthermore, it is essential to determine the minimal effective dose and frequency of administration. In this study, two different low doses (LDs) of phosphorodiamidate morpholino oligomer (PMO) designed to skip the mutated exon 23 in the mdx dystrophic mouse were administered for up to 12 months. Mice treated for 50 weeks showed a substantial dose-related amelioration of the pathology, particularly in the diaphragm. Moreover, the generalized physical activity was profoundly enhanced compared to untreated mdx mice showing that widespread, albeit partial, dystrophin expression restores the normal activity in mdx mice. Our results show for the first time that a chronic long-term administration of LDs of unmodified PMO, equivalent to doses in use in DMD boys, is safe, significantly ameliorates the muscular dystrophic phenotype and improves the activity of dystrophin-deficient mice, thus encouraging the further clinical translation of this approach in humans.

Managing the duality of IHRM: unravelling the strategy and perceptions of key actors in South Korean MNCs

This research aims to extend our understanding of the duality between global integration and local responsiveness in multinational corporations (MNCs) by exploring the perceptions of corporate HR actors regarding the intra-organisational factors that alter the balance between these pressures. It examines the perceptions and actions of key actors in the context of two Korean MNCs. The study shows the importance attributed to a range of socio-procedural factors by corporate actors and which, therefore, inform the practical management of the dual forces, notably: HR expertise, social ties, trustworthy relationships and co-involvement in decision processes.

The relationship between well-being, future planning and intentions to utilise intervention programmes: what can be learned from homeless service users?

There has been an increasing interest in the impact of individual well-being on the attitudes and actions of people receiving services designed to offer support. If well-being factors are important in the uptake and success of service programmes it is important that the nature of the relationships involved is understood by service designers and implementers. As a contribution to understanding, this paper examines the impact of well-being on the uptake of intervention programmes for homeless people. From the literature on well-being a number of factors are identified that contribute towards overall well-being, which include personal efficacy and identity, but also more directly well-being can be viewed as personal or group/collective esteem. The impact of these factors on service use is assessed by means of two studies of homelessness service users, comparing the implementation of two research tools: a shortened and a fuller one. The conclusions are that the factors identified are related to service use. The higher the collective esteem – esteem drawn from identification with services and their users and providers – and the less that they feel isolated, the more benefits that homeless people will perceive with service use, and in turn the more likely they are to be motivated to use services. However, the most important factors in explaining service use are a real sense that it is appropriate to accept social support from others, a rejection of the social identity as homeless but a cultivation of being valued as part of a non-homeless community, and a positive perception of the impact of the service.

British national identity and the dilemmas of multiculturalism

Nationalism and multiculturalism are often perceived as polar opposites with the former viewed as the disease and the latter the cure. Contrary to this view, this article argues that a strong national identity, albeit of a particular kind, is prerequisite to a stable and functioning multicultural society. The article seeks to identify both the causes and the implications of the absence of an overarching, civic national identity in Britain, further to the goal of seeking a meaningful solution. It is our contention that the problem lies in the difficulty involved in reconciling current pressures on British identity with a coherent narrative of British history, especially its imperial past.

Structural spoilers or structural supports? Unionism and the strategic integration of HR functions

The strategic integration of the human resource (HR) function is regarded as crucial in the literature on (strategic) human resource management ((S)HRM). Evidence on the contextual or structural influences on this integration is, however, limited. The structural implications of unionism are particularly intriguing given the evolution of study of the employment relationship. Pluralism is typically seen as antithetical to SHRM, and unions as an impediment to the strategic integration of HR functions, but there are also suggestions in the literature that unionism might facilitate the strategic integration of HR. This paper deploys large-scale international survey evidence to examine the organization-level influence of unionism on this strategic integration, allowing for other established and plausible influences. The analysis reveals that exceptionally, where the organization-level role of unions is particularly contested, unionism does impede the strategic integration of HR. However, it is the predominance of the facilitation of the strategic integration of HR by unionism which is most remarkable.

Domestic cold pitched roofs in the UK: - effect of using different roof insulation materials

The type and thickness of insulation on the topside horizontal of cold pitched roofs has a significant role in controlling air movement, energy conservation and moisture transfer reduction through the ceiling to the loft (roof void) space. To investigate its importance, a numerical model using a HAM software package on a Matlab platform with a Simulink simulation tool has been developed using insitu measurements of airflows from the dwelling space through the ceiling to the loft of three houses of different configurations and loft space. Considering typical UK roof underlay (i.e. bituminous felt and a vapour permeable underlay), insitu measurements of the 3 houses were tested using a calibrated passive sampling technique. Using the measured airflows, the effect of air movement on three types of roof insulation (i.e. fibreglass, cellulose and foam) was modelled to investigate associated energy losses and moisture transport. The thickness of the insulation materials were varied but the ceiling airtightness and eaves gap size were kept constant. These instances were considered in order to visualize the effects of the changing parameters. In addition, two different roof underlays of varying resistances were considered and compared to access the influence of the underlay, if any, on energy conservation. The comparison of these insulation materials in relation to the other parameters showed that the type of insulation material and thickness, contributes significantly to energy conservation and moisture transfer reduction through the roof and hence of the building as a whole.

Professionalism and professional institutions in times of change

Professionalism and professional institutions have developed and changed very gradually in recent decades, such that there are conflicting and competing definitions of what it means to be a professional. The direction of travel is examined through an institutional lens in terms of current trends and practices that have transformed professional life. At first sight, the evolution of professionalism appears to be developing into a new professionalism that requires less of professional institutions and more of the institutions of societal governance, such as contracts and statutes. These transformations are explored with reference to the need for a sustainable urban environment, showing that despite a reduced role of professional institutions, certain aspects of professionalism remain crucially important, especially in those jurisdictions where societal governance is not well developed. With the growing sophistication of legislation, insurance and commerce, the emphasis of what it means to be a professional is evolving. One key aspect of professionalism that is not usually listed in most texts is role definition and how this provides a sense of identity. Professionalism remains a relevant and important concept, but the exigencies of a sustainable urban environment transcend the objectives of the professions and demand a broader, collaborative and participative agenda.

Peroxynitrite mediates disruption of Ca2+ homeostasis by carbon monoxide via Ca2+ ATPase degradation

CO stimulates formation of NO and reactive oxygen species which, via peroxynitrite formation, inhibit Ca(2+) extrusion via PMCA, leading to disruption of Ca(2+) signaling. We propose this contributes to the neurological damage associated with CO toxicity.

Modulation of ion channels by hydrogen sulfide

Increasing current awareness and understanding of the roles and mechanisms of action of ion channel regulation by H(2)S will open opportunities for therapeutic intervention with clear clinical benefits, and inform future therapies. In addition, more sensitive methods for detecting relevant physiological concentrations of H(2)S will allow for clarification of specific ion channel regulation with reference to physiological or pathophysiological settings.

The effects of explicit versus parameterized convection on the MJO in a large-domain high-resolution tropical case study. Part I: Characterization of large-scale organization and propagation

High-resolution simulations over a large tropical domain (∼20◦S–20◦N and 42◦E–180◦E) using both explicit and parameterized convection are analyzed and compared to observations during a 10-day case study of an active Madden-Julian Oscillation (MJO) event. The parameterized convection model simulations at both 40 km and 12 km grid spacing have a very weak MJO signal and little eastward propagation. A 4 km explicit convection simulation using Smagorinsky subgrid mixing in the vertical and horizontal dimensions exhibits the best MJO strength and propagation speed. 12 km explicit convection simulations also perform much better than the 12 km parameterized convection run, suggesting that the convection scheme, rather than horizontal resolution, is key for these MJO simulations. Interestingly, a 4 km explicit convection simulation using the conventional boundary layer scheme for vertical subgrid mixing (but still using Smagorinsky horizontal mixing) completely loses the large-scale MJO organization, showing that relatively high resolution with explicit convection does not guarantee a good MJO simulation. Models with a good MJO representation have a more realistic relationship between lower-free-tropospheric moisture and precipitation, supporting the idea that moisture-convection feedback is a key process for MJO propagation. There is also increased generation of available potential energy and conversion of that energy into kinetic energy in models with a more realistic MJO, which is related to larger zonal variance in convective heating and vertical velocity, larger zonal temperature variance around 200 hPa, and larger correlations between temperature and ascent (and between temperature and diabatic heating) between 500–400 hPa.

Coming to grips with 'abandoned arable' land in efforts to enhance communal grazing systems in the Eastern Cape province, South Africa

The communal lands of the Eastern Cape have been regarded as both tools and problems by policy-makers. In particular, communal lands are problematised as environmentally degraded, of suboptimum productivity and constraining economic development. The Eastern Cape Communal Lands Research Project was framed within this policy discourse with the aim of introducing legume-based pasture into ‘abandoned arable lands’. Initial results from community workshops show that the institutional arrangements for these arable lands vary widely and, with them, the capacity to utilise any new technology that may have application to them. Rather than simply draw on social capital, if a participatory research approach is to enhance the agency of the participating communites, it may need to contribute to social capital building and especially to create a dialogical space in which the matters being researched can be discussed meaningfully.

'A hideously difficult country': British propaganda to France in the early Cold War

This article examines British propaganda efforts in the early Cold War in the light of a developing relationship in which the senders' own strategies were to be modified and challenged.The article argues that initiatives to broadcast propaganda from Britain into France via the BBC operated within a broader and developing information policy context. Broadcasting from outside the country through the BBC was supplemented with attempts by British personnel stationed in France to embed positive messages directly within the contemporary French media. By 1950 however, the Britsih propaganda initiative seemed inappropriate and outmoded, taken over by the French themselves and by a British desire to prioritise countries outside Western Europe.

Establishing a reliable Jini infrastructure for parallel applications

Java is becoming an increasingly popular language for developing distributed and parallel scientific and engineering applications. Jini is a Java-based infrastructure developed by Sun that can allegedly provide all the services necessary to support distributed applications. It is the aim of this paper to explore and investigate the services and properties that Jini actually provides and match these against the needs of high performance distributed and parallel applications written in Java. The motivation for this work is the need to develop a distributed infrastructure to support an MPI-like interface to Java known as MPJ. In the first part of the paper we discuss the needs of MPJ, the parallel environment that we wish to support. In particular we look at aspects such as reliability and ease of use. We then move on to sketch out the Jini architecture and review the components and services that Jini provides. In the third part of the paper we critically explore a Jini infrastructure that could be used to support MPJ. Here we are particularly concerned with Jini's ability to support reliably a cocoon of MPJ processes executing in a heterogeneous envirnoment. In the final part of the paper we summarise our findings and report on future work being undertaken on Jini and MPJ.

Behavioral and spatial analysis of extraterritorial movements in red foxes (Vulpes vulpes)

Abstract: Movements away from the natal or home territory are important to many ecological processes, including gene flow, population regulation, and disease epidemiology, yet quantitative data on these behaviors are lacking. Red foxes exhibit 2 periods of extraterritorial movements: when an individual disperses and when males search neighboring territories for extrapair copulations during the breeding season. Using radiotracking data collected at 5-min interfix intervals, we compared movement parameters, including distance moved, speed of movement, and turning angles, of dispersal and reproductive movements to those made during normal territorial movements; the instantaneous separation distances of dispersing and extraterritorial movements to the movements of resident adults; and the frequency of locations of 95%, 60%, and 30% harmonic mean isopleths of adult fox home territories to randomly generated fox movements. Foxes making reproductive movements traveled farther than when undertaking other types of movement, and dispersal movements were straighter. Reproductive and dispersal movements were faster than territorial movements and also differed in intensity of search and thoroughness. Foxes making dispersal movements avoided direct contact with territorial adults and moved through peripheral areas of territories. The converse was true for reproductive movements. Although similar in some basic characteristics, dispersal and reproductive movements are fundamentally different both behaviorally and spatially and are likely to have different ultimate purposes and contrasting effects on spatial processes such as disease transmission