Comparative and molecular characterisation of a schizophrenia susceptibility locus

A substantial genetic contribution to the aetiology of schizophrenia and other major mental illnesses has been convincingly and repeatedly established by family, twin and adoption studies. However, phenotypic and genetic heterogeneity have severely hampered linkage and association studies, and consequently the molecular basis of the genetic contribution remains undefined. The use of cytogenetic abnormalities to identify disease loci is a well established technique that overcomes many of the problems of linkage and association studies. A balanced t(l;l I)(q42;q14) translocation segregates in a large Scottish family (LOD = 7.1) with schizophrenia and related psychiatric disorders. At least three independent studies have also identified the 1q42 region of the genome as a susceptibility locus for major mental illness. The chromosome 1 breakpoint region now represents one of the best-supported loci for susceptibility to major mental illness. Two novel genes are directly disrupted by the chromosome 1 breakpoint, Disrupted-In-Schizophrenia 1 and 2 (DISCI and DISC2). The central hypothesis of this work is that genes directly disrupted by, or near to the chromosome 1 breakpoint contribute a significant susceptibility to major mental illness. This thesis set out to characterise DISCI, DISC2 and neighboring genes through comparative sequence analysis. Specifically, the research aimed to better define the locus, the genes, their functions and regulatory sequences, to evaluate the functional consequences of the translocation and how these may relate to the t(1;11) phenotype.Human genomic sequence over the breakpoint region was assembled. The DISCI region of the Fugu rubripes genome was cloned and 45 kb of contiguous genomic sequence generated. The orthologous region of the mouse and chicken genomes was identified and characterised. A pipeline for preliminary genomic annotation and subsequent comparative genomic analysis was developed using the cystic fibrosis locus as a model, and subsequently applied to the DISCI locus. The method of "annotation anchored global sequence alignment" substantially increased the sensitivity in detection of biologically relevant conserved sequence motifs. Comparative genomic analysis, RT-PCR and cDNA clone identification were used to construct a transcriptional map of the Fugu genomic region and refine the human transcription map. Conservation of synteny between 0.7 Mb of the human genome and 45 kb of the Fugu genome was demonstrated, with one boundary of synteny being clearly defined. The region of conserved synteny contained the genes Egg Laying Nine-1 (EGLN1), Translin Associated factor X (TRAX) and DISCI in both species.EGLN1 was found to be a member of a previously undescribed gene family. The mouse and human members were identified and characterised. In addition, evolutionary evidence for a novel mechanism of host - pathogen interactions was discovered. TRAX and its homologue Translin were tentatively identified as members of a nucleic acid helicase family of proteins, providing a mechanistic basis for their known biological roles, and suggesting previously undescribed functional aspects of these proteins. DISCI was found to be rapidly evolving in both genomic structure and protein sequence, although three N-terminal motifs and blocks of coiled coil forming potential in the C-terminal half of the protein are conserved features, suggesting a general structure and function for the protein. Neither the antisense transcript DISC2 nor the intergenic splicing of TRAX to DISCI are conserved in Fugu.The work presented in this thesis has substantially enhanced understanding of the chromosome 1 breakpoint locus both at the genomic and encoded protein level. Two novel gene families have been defined and characterised, allowing a more complete evaluation of their functional candidacy in the aetiology of major mental illness. The sequence and clone resources resulting from this work also form the basis for protein functional studies and future characterisation of the locus in animal models

Blood-feeding in the young adult filarial worms litomosoides sigmodontis

In this study with the filarial model Litomosoides sigmodontis, we demonstrate that the worms ingest host red blood cells at a precise moment of their life-cycle, immediately after the fourth moult. The red blood cells (RBC) were identified microscopically in live worms immobilized in PBS at 4 degrees C, and their density assessed. Two hosts were used: Mongolian gerbils, where microfilaraemia is high, and susceptible BALB/c mice with lower microfilaraemia. Gerbils were studied at 12 time-points, between day 9 post-inoculation (the worms were young 4th stage larvae) and day 330 p.i. (worms were old adults). Only the very young adult filarial worms had red blood cells in their gut. Haematophagy was observed between days 25 and 56 p.i. and peaked between day 28 and day 30 p.i. in female worms. In males, haematophagy was less frequent and intense. Similar kinetics of haematophagy were found in BALB/c mice, but frequency and intensity tended to be lower. Haematophagy seems useful to optimize adult maturation. These observations suggest that haematophagy is an important step in the life-cycle of L. sigmodontis. This hitherto undescribed phenomenon might be characteristic of other filarial species including human parasites

Setting UBVRI Photometric Zero-Points Using Sloan Digital Sky Survey ugriz Magnitudes

We discuss the use of Sloan Digital Sky Survey (SDSS) ugriz point-spread function (PSF) photometry for setting the zero points of UBVRI CCD images. From a comparison with the Landolt (1992) standards and our own photometry we find that there is a fairly abrupt change in B, V, R, & I zero points around g, r, i ~ 14.5, and in the U zero point at u ~ 16. These changes correspond to where there is significant interpolation due to saturation in the SDSS PSF fluxes. There also seems to be another, much smaller systematic effect for stars with g, r > 19.5. The latter effect is consistent with a small Malmquist bias. Because of the difficulties with PSF fluxes of brighter stars, we recommend that comparisons of ugriz and UBVRI photometry should only be made for unsaturated stars with g, r and i in the range 14.5 - 19.5, and u in the range 16 - 19.5. We give a prescription for setting the UBVRI zero points for CCD images, and general equations for transforming from ugriz to UBVRI.Comment: 13 pages. 6 figures. Accepted for publication in the Astronomical Journa

Comment on "Drip Paintings and Fractal Analysis", arXiv:0710.4917v2, by K. Jones-Smith, H. Mathur and L.M. Krauss

In a recent manuscript (arXiv:0710.4917v2), Jones-Smith et al. attempt to use the well-established box-counting technique for fractal analysis to "demonstrate conclusively that fractal criteria are not useful for authentication". Here, in response to what we view to be an extremely simplistic misrepresentation of our earlier work by Jones-Smith et al., we reiterate our position regarding the potential of fractal analysis for artwork authentication. We also point out some of the flaws in the analysis presented in by Jones-Smith et al.Comment: Comment on arXiv:0710.4917v2 [cond-mat.stat-mech

Fidelity in complex behaviour change interventions : a standardised approach to evaluate intervention integrity

Objectives: The aim of this study was to (1) demonstrate the development and testing of tools and procedures designed to monitor and assess the integrity of a complex intervention for chronic pain (COping with persistent Pain, Effectiveness Research into Self-management (COPERS) course); and (2) make recommendations based on our experiences. Design: Fidelity assessment of a two-arm randomised controlled trial intervention, assessing the adherence and competence of the facilitators delivering the intervention. Setting: The intervention was delivered in the community in two centres in the UK: one inner city and one a mix of rural and urban locations. Participants: 403 people with chronic musculoskeletal pain were enrolled in the intervention arm and 300 attended the self-management course. Thirty lay and healthcare professionals were trained and 24 delivered the courses (2 per course). We ran 31 courses for up to 16 people per course and all were audio recorded. Interventions: The course was run over three and a half days; facilitators delivered a semistructured manualised course. Outcomes: We designed three measures to evaluate fidelity assessing adherence to the manual, competence and overall impression. Results: We evaluated a random sample of four components from each course (n=122). The evaluation forms were reliable and had good face validity. There were high levels of adherence in the delivery: overall adherence was two (maximum 2, IQR 1.67–2.00), facilitator competence exhibited more variability, and overall competence was 1.5 (maximum 2, IQR 1.25–2.00). Overall impression was three (maximum 4, IQR 2.00–3.00). Conclusions: Monitoring and assessing adherence and competence at the point of intervention delivery can be realised most efficiently by embedding the principles of fidelity measurement within the design stage of complex interventions and the training and assessment of those delivering the intervention. More work is necessary to ensure that more robust systems of fidelity evaluation accompany the growth of complex interventions

Sushi gets serious:the draft genome sequence of the pufferfish Fugu rubripes

The publication of the Fugu rubripes draft genome sequence will take this fish from culinary delicacy to potent tool in deciphering the mysteries of human genome function

Polarization Observations with the Cosmic Background Imager

We describe polarization observations of the CMBR with the Cosmic Background Imager, a 13 element interferometer which operates in the 26-36 GHz band from Llano de Chajnantour in northern Chile. The array consists of 90-cm Cassegrain antennas mounted on a steerable platform which can be rotated about the optical axis to facilitate polarization observations. The CBI employs single mode circularly polarized receivers which sample multipoles from ℓ~400 to ℓ~4250. The instrumental polarization of the CBI was calibrated with 3C279, a bright polarized point source which was monitored with the VLA

Preparing the foundations for video-based, practice-placement support: establishing the role from a students’ perspective

Currently, many placement-based health programme students within the UK are supported through face-to-face visits from university staff. Whilst cited in literature as being of value, the face-to-face nature of this contact is not supported. Alternatives including video-based communications methods offer the potential for cost effective, environmentally responsible support. However, in order to establish the fitness for purpose of alternative approaches, the content and purpose of current support needs to be understood. This project aimed to investigate student perceptions of the ideal content and purpose of clinical support visits, and alternatives to the current face-to-face approach. Fifty-six Physiotherapy undergraduate students responded to questionnaires with a further nine participating in a follow-up focus group. Participants emphasised the value of the visit in guiding learning, ensuring progression and resolving arising issues, and highlighted concerns over alternative approaches. Focus group participants discussed the importance of personal and professional confidence in directing requirements for support, and went on to propose a menu of options for methods of communication.Whilst limited in some applications, video technologies may be one of the options. Overall, however, this project supports the need for consideration of individualised learning journeys within curriculum planning

The meso-genomic era

A report from HGM2001, the sixth annual International Human Genome Meeting organized by The Human Genome Organisation (HUGO), Edinburgh, UK, 19-22 April 2001