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.

The impact of NTFP sales on rural households’ cash income in India’s dry deciduous forest

In recent years, researchers and policy makers have recognized that nontimber forest products (NTFPs) extracted from forests by rural people can make a significant contribution to their well-being and to the local economy. This study presents and discusses data that describe the contribution of NTFPs to cash income in the dry deciduous forests of Orissa and Jharkhand, India. In its focus on cash income, this study sheds light on how the sale of NTFPs and products that use NTFPs as inputs contribute to the rural economy. From analysis of a unique data set that was collected over the course of a year, the study finds that the contribution of NTFPs to cash income varies across ecological settings, seasons, income level, and caste. Such variation should inform where and when to apply NTFP forest access and management policies.

Antisense-induced myostatin exon skipping leads to muscle hypertrophy in mice following Octa‑guanidine morpholino oligomer treatment

Myostatin is a negative regulator of muscle mass, and several strategies are being developed to knockdown its expression to improve muscle-wasting conditions. Strategies using antimyostatin-blocking antibodies, inhibitory-binding partners, signal transduction blockers, and RNA interference system (RNAi)-based knockdown have yielded promising results and increased muscle mass in experimental animals. These approaches have, however, a number of disadvantages such as transient effects or adverse immune complications. We report here the use of antisense oligonucleotides (AOs) to manipulate myostatin pre-mRNA splicing and knockdown myostatin expression. Both 2’O-methyl phosphorothioate RNA (2’OMePS) and phosphorodiamidate morpholino oligomers (PMO) led to efficient exon skipping in vitro and in vivo and knockdown of myostatin at the transcript level. The substantial myostatin exon skipping observed after systemic injection of Vivo-PMO into normal mice led to a significant increase in soleus muscle mass as compared to the controls injected with normal saline suggesting that this approach could be feasible to ameliorate muscle-wasting pathologies.

Comparative genomics suggests that an ancestral polyploidy event leads to enhanced root nodule symbiosis in the Papilionoideae

Root nodule symbiosis (RNS) is one of the most efficient biological systems for nitrogen fixation and it occurs in 90% of genera in the Papilionoideae, the largest subfamily of legumes. Most papilionoid species show evidence of a polyploidy event occurred approximately 58 million years ago. Although polyploidy is considered to be an important evolutionary force in plants, the role of this papilionoid polyploidy event, especially its association with RNS, is not understood. In this study, we explored this role using an integrated comparative genomic approach and conducted gene expression comparisons and gene ontology enrichment analyses. The results show the following: (1) approximately a quarter of the papilionoid-polyploidy-derived duplicate genes are retained; (2) there is a striking divergence in the level of expression of gene duplicate pairs derived from the polyploidy event; and (3) the retained duplicates are frequently involved in the processes crucial for RNS establishment, such as symbiotic signalling, nodule organogenesis, rhizobial infection and nutrient exchange and transport. Thus, we conclude that the papilionoid polyploidy event might have further refined RNS and induced a more robust and enhanced symbiotic system. This conclusion partly explains the widespread occurrence of the Papilionoideae.

Modeling Coulombic failure of sea ice with leads

[1] Sea ice failure under low-confinement compression is modeled with a linear Coulombic criterion that can describe either fractural failure or frictional granular yield along slip lines. To study the effect of anisotropy we consider a simplified anisotropic sea ice model where the sea ice thickness depends on orientation. Accommodation of arbitrary deformation requires failure along at least two intersecting slip lines, which are determined by finding two maxima of the yield criterion. Due to the anisotropy these slip lines generally differ from the standard, Coulombic slip lines that are symmetrically positioned around the compression direction, and therefore different tractions along these slip lines give rise to a nonsymmetric stress tensor. We assume that the skewsymmetric part of this tensor is counterbalanced by an additional elastic stress in the sea ice field that suppresses floe spin. We consider the case of two leads initially formed in an isotropic ice cover under compression, and address the question of whether these leads will remain active or new slip lines will form under a rotation of the principal compression direction. Decoupled and coupled models of leads are considered and it is shown that for this particular case they both predict lead reactivation in almost the same way. The coupled model must, however, be used in determining the stress as the decoupled model does not resolve the stress asymmetry properly when failure occurs in one lead and at a new slip line.

Multinational subsidiary sales and performance in South East Asia

We extend the theory of the multinational enterprise (MNE) by exploring the concept of subsidiary-specific advantages (SSAs) as a driver for subsidiary performance. We investigate the relationship of host country-specific advantages (host CSAs) in the form of market attractiveness, SSAs and subsidiary sales as they affect subsidiary performance. From an original primary dataset of 101 British multinational (MNE) subsidiaries in six South East Asian countries, our analysis reveals three significant findings. First, host market attractiveness has a statistically positive impact on the performance of subsidiaries. Second, the three traditional SSAs of general management, marketing capabilities and invested capital enhance subsidiary performance. Third, we examine geographic direction and types of customers for subsidiary sales by following international accounting standards. We find that these subsidiaries generate on average 95 percent of total sales from the Asia Pacific region and 91 percent of total sales from external customers. Our findings have important research and managerial implications.

Roles of the non-medical prescribing leads within organisations across a Strategic Health Authority: perceived functions and factors supporting the role

Objectives Extending the roles of nurses, pharmacists and allied health professionals to include prescribing has been identified as one way of improving service provision. In the UK, over 50 000 non-medical healthcare professionals are now qualified to prescribe. Implementation of non-medical prescribing ( NMP) is crucial to realise the potential return on investment. The UK Department of Health recommends a NMP lead to be responsible for the implementation of NMP within organisations. The aim of this study was to explore the role of NMP leads in organisations across one Strategic Health Authority (SHA) and to inform future planning with regards to the criteria for those adopting this role, the scope of the role and factors enabling the successful execution of the role. Methods Thirty-nine NMP leads across one SHA were approached. Semi-structured telephone interviews were conducted. Issues explored included the perceived role of the NMP lead, safety and clinical governance procedures and facilitators to the role. Transcribed audiotapes were coded and analysed using thematic analytical techniques. Key findings In total, 27/39 (69.2%) NMP leads were interviewed. The findings highlight the key role that the NMP lead plays with regards to the support and development of NMP within National Health Service trusts. Processes used to appoint NMP leads lacked clarity and varied between trusts. Only two NMP leads had designated or protected time for their role. Strategic influence, operational management and clinical governance were identified as key functions. Factors that supported the role included organisational support, level of influence and dedicated time. Conclusion The NMP lead plays a significant role in the development and implementation of NMP. Clear national guidance is needed with regards to the functions of this role, the necessary attributes for individuals recruited into this post and the time that should be designated to it. This is important as prescribing is extended to include other groups of non-medical healthcare professionals.

nor-Mevaldic acid surrogates as selective antifungal agent leads against Botrytis cinerea. Enantioselective preparation of 4-hydroxy-6-(1-phenylethoxy)tetrahydro-2H-pyran-2-one

Solvent-free desymmetrisation of meso-dialdehyde 1 with chiral 1-phenylethan-1-ol, led to preparation of 4-silyloxy-6-alkyloxytetrahydro-2H-pyran-2-one (+)-3a with a 96:4 d.r. Deprotected lactone (+)-19a and the related racemic lactones 16a-18a present a lactone moiety resembling the natural substrate of HMG-CoA reductase and their antifungal properties have been evaluated against the phytopathogenic fungi Botrytis cinerea and Colletotrichum gloeosporioides. These compounds were selectively active against B. cinerea, while inactive against C. gloeosporioides.

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.

Differential interaction of estrogen receptor and thyroid hormone receptor isoforms on the rat oxytocin receptor promoter leads to differences in transcriptional regulation

Both the estrogen receptor (ER) and thyroid hormone receptor (TR) are members of the nuclear receptor superfamily. Two isoforms of the ER, alpha and beta, exist. The TRalpha and beta isoforms are products of two distinct genes that are further differentially spliced to give TRalpha1 and alpha2, TRbeta1 and beta2. The TRs have been shown to interfere with ER-mediated transcription from both the consensus estrogen response element (ERE) and the rat preproenkephalin (PPE) promoter, possibly by competing with ER binding to the ERE or by squelching coactivators essential for ER-mediated transcription. The rat oxytocin receptor (OTR) gene is thought to be involved in several facets of reproductive and affiliative behaviors. 17beta-Estradiol-bound ERs upregulate the OTR gene in the ventromedial hypothalamus, a region critical for the induction of lordosis behavior in several species. We investigated the effects of the ligand-binding TR isoforms on the ER-mediated transcription from a physiological promoter of a behaviorally relevant gene such as the OTR. Only ERalpha could induce the OTR gene in two cell lines tested, the CV-1 and the SK-N-BE2C neuroblastoma cell lines. ERbeta was incapable of inducing the gene in either cell line. ERalpha is therefore not equivalent to ERbeta on this physiological promoter. Indeed, in the neural cell line, ERbeta can inhibit ERalpha-mediated induction from the OTR promoter. While the TRalpha1 isoform inhibited ERalpha-mediated induction in the neural cell line, the TRbeta1 isoform stimulated induction, thus demonstrating isoform specificity in the interaction. The use of a DNA-binding mutant, the TR P box mutant, showed that inhibition of ERalpha-mediated induction of the rat OTR gene promoter by the TRalpha1 isoform does not require DNA-binding ability. SRC-1 overexpression relieved TRalpha1-mediated inhibition in both cell lines, suggesting that squelching for coactivators is an important molecular mechanism in TRalpha-mediated inhibition. Such interactions between TR and ER isoforms on the rat OTR promoter provide a mechanism to achieve neuroendocrine integration.