Temporal and Tissue Specific Regulation of RP-Associated Splicing Factor Genes PRPF3, PRPF31 and PRPC8—Implications in the Pathogenesis of RP

Genetic mutations in several ubiquitously expressed RNA splicing genes such as PRPF3, PRP31 and PRPC8, have been found to cause retina-specific diseases in humans. To understand this intriguing phenomenon, most studies have been focused on testing two major hypotheses. One hypothesis assumes that these mutations interrupt retina-specific interactions that are important for RNA splicing, implying that there are specific components in the retina interacting with these splicing factors. The second hypothesis suggests that these mutations have only a mild effect on the protein function and thus affect only the metabolically highly active cells such as retinal photoreceptors.We examined the second hypothesis using the PRPF3 gene as an example. We analyzed the spatial and temporal expression of the PRPF3 gene in mice and found that it is highly expressed in retinal cells relative to other tissues and its expression is developmentally regulated. In addition, we also found that PRP31 and PRPC8 as well as snRNAs are highly expressed in retinal cells.Our data suggest that the retina requires a relatively high level of RNA splicing activity for optimal tissue-specific physiological function. Because the RP18 mutation has neither a debilitating nor acute effect on protein function, we suggest that retinal degeneration is the accumulative effect of decades of suboptimal RNA splicing due to the mildly impaired protein

Tourism Partnerships in Protected Areas: Exploring Contributions to Sustainability

Partnerships between natural-area managers and the tourism industry have been suggested to contribute to sustainability in protected areas. This article explores how important sustainability outcomes of partnerships are to their members, how well they are realised and the features of partnerships leading to their achievement. In 21 case studies in Australia, interviews (n = 97) and surveys (n = 100) showed that of 14 sustainability outcomes, improved understanding of protected areas values and improved biodiversity conservation were the most important. Other highly ranked outcomes were greater respect for culture, heritage, and/or traditions; improved quality of environmental conditions; social benefits to local communities; and improved economic viability of the protected area. Scores for satisfaction with outcomes were, like those for importance, all high but were less than those for importance for the majority, with improvement in quality of environmental conditions showing the largest gap. The satisfaction score exceeded that for importance only for increased competitiveness of the protected area as a tourist destination. “Brown” aspects of sustainability, i.e., decreased waste or energy use, were among the lowest-scoring outcomes for both importance and satisfaction. The most important factor enabling sustainability outcomes was provision of benefits to partnership members. Others were increased financial support, inclusiveness, supportive organisational and administrative arrangements, direct involvement of decision makers, partnership maturity, creation of new relationships, decreased conflict, and stimulation of innovation. Improving sustainability outcomes, therefore, requires maintaining these partnership attributes and also increasing emphasis on reducing waste and resource use

The destabilistion of human GCAP1 by a proline to leucine mutation might cause cone-rod dystrophy

Guanylate cyclase activating protein-1 (GCAP1) is required for activation of retinal guanylate cyclase-1 (RetGC1), which is essential for recovery of photoreceptor cells to the dark state. In this paper, experimentally derived observations are reported that help in explaining why a proline→leucine mutation at position 50 of human GCAP1 results in cone-rod dystrophy in a family carrying this mutation. The primary amino acid sequence of wild-type GCAP1 was mutated using site-directed mutagenesis to give a leucine at position 50. In addition, serine replaced a glutamic acid residue at position 6 to promote N-terminal myristoylation, yielding the construct GCAP1 E6S/P50L. The enzyme was over-expressed in Escherichia coli cells, isolated and purified before being used in assays with RetGC1, characterized by circular dichroism (CD) spectroscopy, and investigated for protease resistance and thermal stability. Assays of cyclic guanosine monophosphate (cGMP) synthesis from guanosine triphosphate by RetGC1 in the presence of E6S/P50L showed that E6S/P50L could activate RetGC1 and displayed similar calcium sensitivity to wild-type GCAP1. In addition, E6S/P50L and wild-type GCAP1 possess similar CD spectra. However, there was a marked increase in the susceptibility to protease degradation and also a reduction in the thermal stability of E6S/P50L as observed by both the cGMP assay and CD spectroscopy. It is therefore suggested that although GCAP1 E6S/P50L has a similar activity and calcium dependency profile to the wild-type GCAP1, its lower stability could reduce its cellular concentration, which would in turn alter [Ca<SUP>2+</SUP>] and result in death of cells

Paradox of the institution: findings from a hospital labour ward ethnography

BackgroundInterest in the influence of culture on birth practices is on the rise, and with it comes a sense of urgency to implement practices that aid the normalisation and humanisation of birth. This groundswell is occurring despite a broader cultural milieu of escalating technology-use and medicalisation of birth across the globe. Against this background, rates of epidural analgesia use by women in labour are increasing, despite the risk of side effects. Socio-cultural norms and beliefs are likely to influence pain relief choices but there is currently scant research on this topic.MethodsThis study was undertaken to gain insight into the personal, social, cultural and institutional influences on women in deciding whether or not to use epidural analgesia in labour. The study had an ethnographic approach within a theoretical framework of Critical Medical Anthropology (CMA), Foucauldian and feminist theory. Given the nature of ethnographic research, it was assumed that using the subject of epidural analgesia to gain insight into Western birth practices could illuminate broader cultural ideals and that the epidural itself may not remain the focus of the research.ResultsFindings from the study showed how institutional surveillance, symbolised by the Journey Board led to an institutional momentum that in its attempt to keep women safe actually introduced new areas of risk, a situation which we named the Paradox of the institution.ConclusionsThese findings, showing a risk/safety paradox at the centre of institutionalised birth, add a qualitative dimension to the growing number of quantitative studies asserting that acute medical settings can be detrimental to normal birth practices and outcomes

The diabetic foot in end stage renal disease

Diabetic foot lesions remain a major cause of morbidity in patients with renal failure, especially those on dialysis. Foot complications are encountered at a more than twofold frequency in diabetic patients with end-stage renal disease, and the rate of amputations is 6.5-10 times higher in comparison to the general diabetic population. The causal pathways of the diabetic foot in renal failure are multiple and inter-related. Three major pathologies-neuropathy, ischemia, and infection-are the main contributory factors. Increased awareness of this condition and careful clinical examination are indispensable to avoid serious complications. Appropriate management needs to address all contributory factors. Treatment options include revascularization, off-loading to relieve high-pressure areas, and aggressive control of infection. Equally important is the collaboration between health care providers in a multidisciplinary foot care setting. Moreover, patient education on the measures required to achieve both primary and secondary prevention is of great value. Certainly, technical innovations have made considerable progress possible, but there is a need for further improvement to reduce the number of amputations