Transgenic Overexpression of LARGE Induces alpha-Dystroglycan Hyperglycosylation in Skeletal and Cardiac Muscle

Background: LARGE is one of seven putative or demonstrated glycosyltransferase enzymes defective in a common group of muscular dystrophies with reduced glycosylation of alpha-dystroglycan. Overexpression of LARGE induces hyperglycosylation of alpha-dystroglycan in both wild type and in cells from dystroglycanopathy patients, irrespective of their primary gene defect, restoring functional glycosylation. Viral delivery of LARGE to skeletal muscle in animal models of dystroglycanopathy has identical effects in vivo, suggesting that the restoration of functional glycosylation could have therapeutic applications in these disorders. Pharmacological strategies to upregulate Large expression are also being explored.Methodology/Principal Findings: In order to asses the safety and efficacy of long term LARGE over-expression in vivo, we have generated four mouse lines expressing a human LARGE transgene. On observation, LARGE transgenic mice were indistinguishable from the wild type littermates. Tissue analysis from young mice of all four lines showed a variable pattern of transgene expression: highest in skeletal and cardiac muscles, and lower in brain, kidney and liver. Transgene expression in striated muscles correlated with alpha-dystroglycan hyperglycosylation, as determined by immunoreactivity to antibody IIH6 and increased laminin binding on an overlay assay. Other components of the dystroglycan complex and extracellular matrix ligands were normally expressed, and general muscle histology was indistinguishable from wild type controls. Further detailed muscle physiological analysis demonstrated a loss of force in response to eccentric exercise in the older, but not in the younger mice, suggesting this deficit developed over time. However this remained a subclinical feature as no pathology was observed in older mice in any muscles including the diaphragm, which is sensitive to mechanical load-induced damage.Conclusions/Significance: This work shows that potential therapies in the dystroglycanopathies based on LARGE upregulation and alpha-dystroglycan hyperglycosylation in muscle should be safe

From pyramid to pointed egg? A 20-year perspective on poverty, prosperity and rural transformation in Tanzania

This article analyses patterns of poverty, prosperity and rural transformation in Tanzania through longitudinal research examining livelihoods and asset change in a twenty-year period. We argue that some current measures of rural transformation are inadequate for capturing forms of change that matter to rural Africans. We consider in detail some of the processes that lie behind such change in selected locations in Morogoro region, noting the importance of improvements that are taking place through smallholder agriculture. In concluding, the article discusses the implications of these findings for agricultural policy, while also cautioning about the blindness of our methods to other forms of poverty

Towards a synthesized critique of neoliberal biodiversity conservation

During the last three decades, the arena of biodiversity conservation has largely aligned itself with the globally dominant political ideology of neoliberalism and associated governmentalities. Schemes such as payments for ecological services are promoted to reach the multiple ‘wins’ so desired: improved biodiversity conservation, economic development, (international) cooperation and poverty alleviation, amongst others. While critical scholarship with respect to understanding the linkages between neoliberalism, capitalism and the environment has a long tradition, a synthesized critique of neoliberal conservation - the ideology (and related practices) that the salvation of nature requires capitalist expansion - remains lacking. This paper aims to provide such a critique. We commence with the assertion that there has been a conflation between ‘economics’ and neoliberal ideology in conservation thinking and implementation. As a result, we argue, it becomes easier to distinguish the main problems that neoliberal win-win models pose for biodiversity conservation. These are framed around three points: the stimulation of contradictions; appropriation and misrepresentation and the disciplining of dissent. Inspired by Bruno Latour’s recent ‘compositionist manifesto’, the conclusion outlines some ideas for moving beyond critique

Prenatal muscle development in a mouse model for the secondary dystroglycanopathies

The defective glycosylation of α-dystroglycan is associated with a group of muscular dystrophies that are collectively referred to as the secondary dystroglycanopathies. Mutations in the gene encoding fukutin-related protein (FKRP) are one of the most common causes of secondary dystroglycanopathy in the UK and are associated with a wide spectrum of disease. Whilst central nervous system involvement has a prenatal onset, no studies have addressed prenatal muscle development in any of the mouse models for this group of diseases. In view of the pivotal role of α-dystroglycan in early basement membrane formation, we sought to determine if the muscle formation was altered in a mouse model of FKRP-related dystrophy

Comparing and contrasting threat assessments of plant species at the global and sub-global level

Evidence-based assessments of extinction risk are established tools used to inform the conservation of plant species, and form the basis of key targets within the framework of the Global Strategy for Plant Conservation (GSPC). An overall picture of plants threat assessments is challenging due to the use of a variety of methodologies and range in scope from global to subnational. In this study, we quantify the state of progress in assessing the extinction risk of all land plants, determine the key geographic and taxonomic gaps with respect to our understanding of plant extinction risk, and evaluate the impact of different sources and methodologies on the utility of plant assessments. To this end, we have analyzed a cleaned dataset compiled from IUCN Red List of Threatened Species and Regional Red Lists. We reveal that there are assessments available for 89,810 distinct species or 25% of all accepted land plant species. However unlike with other major organismal lineages the bulk of the plant species assessments are derived from Regional Red Lists, and not the Global IUCN Red List. We demonstrate that this bias towards regional assessments results in distinct taxonomic and geographic strengths and weaknesses, and we identify substantial taxonomic and geographic gaps in the assessment coverage. With species that have been assessed in common at both global and regional levels, we explore the implications of combining threat assessments from different sources. We find that half of global and regional assessments do not agree on the exact category of extinction risk for a species. Regional assessments assign a higher risk of extinction; or underestimate extinction risk with almost equal frequency. We conclude with recommended interventions, but support the suggestion that all threat assessments should be pooled to provide more data and broaden the scope of threat assessments for monitoring progress towards GSPC targets

Local people and conservation officials’ perceptions on relationships and conflicts in South African protected areas

Protected areas (PAs) are often conflict-ridden, but conflict resolution mechanisms are often constrained by little appreciation of the perceptions of the principal agents (PA managers and local communities) about such conflicts. Getting local people’s support in PA management efforts is considered important for achieving conservation and livelihood goals. Using data from 13 nature reserves in South Africa, this study explores the perceptions of reserve managers and local communities about their relationships and the existence and underlying causes of conflicts. The findings showed sharp contrasts in perceptions between reserve managers and local communities. Reserve managers generally perceived that there were no conflicts with local communities and that their relationship with them was positive while local communities thought otherwise, claiming conflicts were centred around restricted access to PAs, lack of benefits from PAs and communication problems. These findings have profound implications for conservation, especially considering the importance of getting local people’s support in PA management