'Education, education, education' : legal, moral and clinical

This article brings together Professor Donald Nicolson's intellectual interest in professional legal ethics and his long-standing involvement with law clinics both as an advisor at the University of Cape Town and Director of the University of Bristol Law Clinic and the University of Strathclyde Law Clinic. In this article he looks at how legal education may help start this process of character development, arguing that the best means is through student involvement in voluntary law clinics. And here he builds upon his recent article which argues for voluntary, community service oriented law clinics over those which emphasise the education of students

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Biochemistry and molecular genetics of Leishmania glucose transporters

Glucose is utilized as a significant source of metabolic energy by Leishmania parasites. This sugar is accumulated by the parasite via a specific carrier-mediated transport system located in the parasite membrane. Parasites may also contain another transporter that shuttles glucose between the cytoplasm and the glycosome, a membrane-bound organelle where the early steps of glycolysis occur. The transport systems of both the insect stage promastigotes and the intracellular amastigotes have been characterized and shown to have kinetic properties that are consistent with the different physio-logical environments of the insect gut and the macrophage phagolysosome. Several genes have been cloned from Leishmania species which encode proteins with substantial sequence similarity to glucose transporters from mammals and lower eukaryotes. Two of these genes are expressed preferentially in the promastigote stage of the life cycle, where glucose is more readily available and more rapidly transported and metabolized than in the intracellular amastigotes. One of these two developmentally-regulated genes has been functionally expressed in Xenopus oocytes and shown to encode a glucose transporter. A third gene encodes a protein that is also a member of the glucose transporter family on the basis of sequence similarity and proposed secondary structure. However, the significant differences between this protein and the other two suggest that it is likely to transport a different substrate. Functional expression will be required to define the specific biochemical role of each gene within the parasite