The FAT10- and ubiquitin-dependent degradation machineries exhibit common and distinct requirements for MHC class I antigen presentation

Like ubiquitin (Ub), the ubiquitin-like protein FAT10 can serve as a signal for proteasome-dependent protein degradation. Here, we investigated the contribution of FAT10 substrate modification to MHC class I antigen presentation. We show that N-terminal modification of the human cytomegalovirus-derived pp65 antigen to FAT10 facilitates direct presentation and dendritic cell-mediated cross-presentation of the HLA-A2 restricted pp65(495-503) epitope. Interestingly, our data indicate that the pp65 presentation initiated by either FAT10 or Ub partially relied on the 19S proteasome subunit Rpn10 (S5a). However, FAT10 distinguished itself from Ub in that it promoted a pp65 response which was not influenced by immunoproteasomes or PA28. Further divergence occurred at the level of Ub-binding proteins with NUB1 supporting the pp65 presentation arising from FAT10, while it exerted no effect on that initiated by Ub. Collectively, our data establish FAT10 modification as a distinct and alternative signal for facilitated MHC class I antigen presentation.     

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.     

Heterogeneous bioenergetic behaviour of subsarcolemmal and intermyofibrillar mitochondria in fed and fasted rats

This study was designed to examine energetic behaviour of skeletal muscle subsarcolemmal and intermyofibrillar mitochondrial populations. The data show that subsarcolemmal mitochondria exhibited a lower degree of coupling and efficiency than intermyofibrillar ones, and can therefore be considered less efficient at producing ATP. In addition, subsarcolemmal mitochondria showed an increased sensitivity to palmitate-induced uncoupling, in line with high adenine nucleotide translocator content and decreased oxidative damage. We then determined the effect of 24 h fasting on energetic characteristics of skeletal muscle mitochondrial populations. We found that fasting enhanced proton leak and decreased the degree of coupling and efficiency, both in the absence and in the presence of palmitate only in subsarcolemmal mitochondria. Moreover, this mitochondrial population showed lower oxidative damage, probably due to a counter-regulatory mechanism mediated by uncoupling protein 3. Subsarcolemmal and intermyofibrillar mitochondria appear to exhibit different energetic characteristics and can be differently affected by physiological stimuli. Received 28 September 2005; received after revision 9 November 2005; accepted 28 November 2005     

Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid.

Endophilin I is a presynaptic protein of unknown function that binds to dynamin, a GTPase that is implicated in endocytosis and recycling of synaptic vesicles. Here we show that endophilin I is essential for the formation of synaptic-like microvesicles (SLMVs) from the plasma membrane. Endophilin I exhibits lysophosphatidic acid acyl transferase (LPAAT) activity, and endophilin-I-mediated SLMV formation requires the transfer of the unsaturated fatty acid arachidonate to lysophosphatidic acid, converting it to phosphatidic acid. A deletion mutant lacking the SH3 domain through which endophilin I interacts with dynamin still exhibits LPAAT activity but no longer mediates SLMV formation. These results indicate that endophilin I may induce negative membrane curvature by converting an inverted-cone-shaped lipid to a cone-shaped lipid in the cytoplasmic leaflet of the bilayer. We propose that, through this action, endophilin I works with dynamin to mediate synaptic vesicle invagination from the plasma membrane and fission.     

Home births in the UK, 1955 to 2006

This article presents data on trends in the percentage of maternities taking place at home in the UK. As well as the national trend, the article examines how home maternity levels vary according to mother's age, number of previous live births within marriage, country of birth, region, local authority and NHS Trust. Examination of trends and variations in home maternity levels provides a context for debates regarding factors that may influence where women give birth.     

Enabling Political Legitimacy and Conceptual Integration for Climate Change Adaptation Research within an Agricultural Bureaucracy: a Systemic Inquiry

The value of using systems approaches, for situations framed as ‘super wicked’, is examined from the perspective of research managers and stakeholders in a state-based climate change adaptation (CCA) program (CliChAP). Polycentric drivers influencing the development of CCA research pre-2010 in Victoria, Australia are reflected on, using Soft Systems Methodology (SSM) to generate a boundary critique of CCA research as a human activity system. We experienced the complexity of purpose with research practices pulling in different directions, reflected on the appropriateness of agricultural bureaucracies’ historical new public management (NPM) practices, and focused on realigning management theory with emerging demands for adaptation research skills and capability. Our analysis conceptualised CliChAP as a subsystem, generating novelty in a wider system, concerned with socio-ecological co-evolution. Constraining/enabling conditions at the time dealing with political legitimacy and conceptual integration were observed as potential catalysts for innovation in research management towards better handling of uncertainty as a social process using systemic thinking in practice (StiP).

     

Dissecting the genomic complexity underlying medulloblastoma

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.     

Re-orienting discussions of scientific explanation: A functional perspective

Philosophy of science offers a rich lineage of analysis concerning the nature of scientific explanation, but the vast majority of this work, aiming to provide an analysis of the relation that binds a given explanans to its corresponding explanandum, presumes the proper analytic focus rests at the level of individual explanations. There are, however, other questions we could ask about explanation in science, such as: What role(s) does explanatory practice play in science? Shifting focus away from explanations, as achievements, toward explaining, as a coordinated activity of communities, the functional perspective aims to reveal how the practice of explanatory discourse functions within scientific communities given their more comprehensive aims and practices. In this paper, I outline the functional perspective, argue that taking the functional perspective can reveal important methodological roles for explanation in science, and consequently, that beginning here provides resources for developing more adequate responses to traditional concerns. In particular, through an examination of the ideal gas law, I emphasize the normative status of explanations within scientific communities and discuss how such status underwrites a compelling rationale for explanatory power as a theoretical virtue.