Genome-wide association study identifies five new schizophrenia loci

We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).

A TMA De-Arraying Method for High Throughput Biomarker Discovery in Tissue Research

Background: Tissue MicroArrays (TMAs) represent a potential high-throughput platform for the analysis and discovery of tissue biomarkers. As TMA slides are produced manually and subject to processing and sectioning artefacts, the layout of TMA cores on the final slide and subsequent digital scan (TMA digital slide) is often disturbed making it difficult to associate cores with their original position in the planned TMA map. Additionally, the individual cores can be greatly altered and contain numerous irregularities such as missing cores, grid rotation and stretching. These factors demand the development of a robust method for de-arraying TMAs which identifies each TMA core, and assigns them to their appropriate coordinates on the constructed TMA slide.

Methodology: This study presents a robust TMA de-arraying method consisting of three functional phases: TMA core segmentation, gridding and mapping. The segmentation of TMA cores uses a set of morphological operations to identify each TMA core. Gridding then utilises a Delaunay Triangulation based method to find the row and column indices of each TMA core. Finally, mapping correlates each TMA core from a high resolution TMA whole slide image with its name within a TMAMap.

Conclusion: This study describes a genuine robust TMA de-arraying algorithm for the rapid identification of TMA cores from digital slides. The result of this de-arraying algorithm allows the easy partition of each TMA core for further processing. Based on a test group of 19 TMA slides (3129 cores), 99.84% of cores were segmented successfully, 99.81% of cores were gridded correctly and 99.96% of cores were mapped with their correct names via TMAMaps. The gridding of TMA cores were also extensively tested using a set of 113 pseudo slide (13,536 cores) with a variety of irregular grid layouts including missing cores, rotation and stretching. 100% of the cores were gridded correctly.

Education for global citizenship in a divided society? Young people's views and experiences

Global citizenship education has been suggested as a means of overcoming the limitations of national citizenship in an increasingly globalised world. In divided societies, global citizenship education is especially relevant and problematic as it offers the opportunity to explore identities and conflict in a wider context. This paper therefore explores young people's understandings of global citizenship in Northern Ireland, a divided society emerging from conflict. Results from focus groups with primary and post-primary pupils reflect some theoretical conceptualisations of global citizenship, including an awareness of global issues, understandings of environmental interdependence and global responsibility, though other elements appear to be less well understood. We argue that global citizenship education will fail to overcome engrained cultural divisions locally and may perpetuate cultural stereotypes globally, unless local and global controversial issues are acknowledged and issues of identity and interdependence critically examined at both levels.

Gingival fibroblast response to cyclosporin A and transforming growth factor beta(1)

This study investigates a potential role for TGF beta(1), in the pathogenesis of cyclosporin A-induced gingival overgrowth (CsA-OG). TGF beta(1) was localized immunohistochemically in the connective tissue of both normal gingiva and CsA-OG. Intense staining for TGF beta(1) was detected at the tips of the dermal papillae of the overgrown gingiva. In addition, fibroblasts derived from healthy gingiva and fibroblasts derived from CsA-OG were cultured both as monolayers or embedded in a 3D-collagen gel. Fibroblast activity was monitored in terms of protein and collagen production in the presence of (i) 1 ng/ml TGF beta(1), (ii) 500 ng/ml CsA, or (iii) 500 ng/ml CsA and 1 ng/ml TGF beta(1). In monolayer culture TGF beta(1) significantly increased protein and collagen production in all cell strains (p

Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis

Papillon-Lefevre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients(1,2). Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset(3-6). The PLS locus has been mapped to chromosome 11q14-q21 (refs 7-9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.

SurfaceSlide: A Multitouch Digital Pathology Platform

Background: Digital pathology provides a digital environment for the management and interpretation of pathological images and associated data. It is becoming increasing popular to use modern computer based tools and applications in pathological education, tissue based research and clinical diagnosis. Uptake of this new technology is stymied by its single user orientation and its prerequisite and cumbersome combination of mouse and keyboard for navigation and annotation.

Methodology: In this study we developed SurfaceSlide, a dedicated viewing platform which enables the navigation and annotation of gigapixel digitised pathological images using fingertip touch. SurfaceSlide was developed using the Microsoft Surface, a 30 inch multitouch tabletop computing platform. SurfaceSlide users can perform direct panning and zooming operations on digitised slide images. These images are downloaded onto the Microsoft Surface platform from a remote server on-demand. Users can also draw annotations and key in texts using an on-screen virtual keyboard. We also developed a smart caching protocol which caches the surrounding regions of a field of view in multi-resolutions thus providing a smooth and vivid user experience and reducing the delay for image downloading from the internet. We compared the usability of SurfaceSlide against Aperio ImageScope and PathXL online viewer.

Conclusion: SurfaceSlide is intuitive, fast and easy to use. SurfaceSlide represents the most direct, effective and intimate human–digital slide interaction experience. It is expected that SurfaceSlide will significantly enhance digital pathology tools and applications in education and clinical practice.

The spatial distribution of Holocene cryptotephras in north-west Europe since 7 ka: implications for understanding ash fall events from Icelandic eruptions

We present distribution maps for all cryptotephras (distal volcanic ash layers) younger than 7 ka that have been reported from three or more lakes or peatlands in north-west Europe. All but one of the tephras originates from Iceland; the exception has been attributed to Jan Mayen. We find strong spatial patterning in tephra occurrence at the landscape scale; most, but not all of the tephra occurrences are significantly spatially clustered, which likely reflects atmospheric and weather patterns at the time of the eruptions. Contrary to expectations based on atmospheric modelling studies, tephras appear to be at least as abundant in Ireland and northern Scotland as in Scandinavia. Rhyolitic and other felsic tephras occur in lakes and peatlands throughout the study region, but andesitic and basaltic tephras are largely restricted to lake sites in the Faroe Islands and Ireland. Explanations of some of these patterns will require further research on the effects of different methodologies for locating and characterizing cryptotephras. These new maps will help to guide future investigations in tephrochronology and volcanic hazard analysis.

NEUROPEPTIDE F-IMMUNOREACTIVITY IN THE MONOGENEAN PARASITE DICLIDOPHORA-MERLANGI

The localisation and distribution of neuropeptide F (NPF)-immunoreactivity (IR) in the monogenean fish-gill parasite, Diclidophora merlangi, have been investigated by whole-mount immunocytochemistry interfaced with confocal scanning laser microscopy and, at the ultrastructural level, by indirect immunogold labeling. Using antisera directed to intact synthetic NPF (Moniezia expansa, residues 1-39) or to the C-terminal decapeptide (residues 30-39) of synthetic NPF (M. expansa), immunostaining was found throughout the central (CNS) and peripheral nervous systems (PNS), including the innervation of the reproductive system. Immunoreactivity was found to be more intense using the antiserum to the C-terminal decapeptide fragment of NPF. At the subcellular level, gold labeling of NPF-IR was found exclusively over the contents of dense-cored vesicles that occupied nerve axons of both the CNS and the PNS. The distribution pattern of immunostaining for NPF mirrored exactly that previously documented for the vertebrate pancreatic polypeptide (PP) family of peptides and for FMRFamide. This finding and the results of preabsorption experiments strongly suggest that NPF is the predominant native neuropeptide in D. merlangi and that it accounts for most of the immunostaining previously obtained with PP and FMRFamide antisera.

Discovery of Main-Belt Comet P/2006 VW139 by Pan-STARRS 1

The main-belt asteroid (300163) 2006 VW139 (later designated P/2006 VW139) was discovered to exhibit comet-like activity by the Pan-STARRS1 (PS1) survey telescope using automated point-spread-function analyses performed by PS1's Moving Object Processing System. Deep follow-up observations show both a short (~10'') antisolar dust tail and a longer (~60'') dust trail aligned with the object's orbit plane, similar to the morphology observed for another main-belt comet (MBC), P/2010 R2 (La Sagra), and other well-established comets, implying the action of a long-lived, sublimation-driven emission event. Photometry showing the brightness of the near-nucleus coma remaining constant over ~30 days provides further evidence for this object's cometary nature, suggesting it is in fact an MBC, and not a disrupted asteroid. A spectroscopic search for CN emission was unsuccessful, though we find an upper limit CN production rate of Q CN 100 Myr, while a search for a potential asteroid family around the object reveals a cluster of 24 asteroids within a cutoff distance of 68 m s-1. At 70 m s-1, this cluster merges with the Themis family, suggesting that it could be similar to the Beagle family to which another MBC, 133P/Elst-Pizarro, belongs.

Ecohydrological feedbacks confound peat-based climate reconstructions

Water-table reconstructions from Holocene peatlands are increasingly being used as indicators of terrestrial palaeoclimate in many regions of the world. However, the links between peatland water tables, climate, and long-term peatland development are poorly understood. Here we use a combination of high-resolution proxy climate data and a model of long-term peatland development to examine the relationship between rapid hydrological fluctuations in peatlands and climatic forcing. We show that changes in water-table depth can occur independently of climate forcing. Ecohydrological feedbacks inherent in peatland development can lead to a degree of homeostasis that partially disconnects peatland water-table behaviour from external climatic influences. We conclude by suggesting that further work needs to be done before peat-based climate reconstructions can be used to test climate models.

Experiences of fathering a baby admitted to neonatal intensive care: A critical gender analysis

More fathers than ever before attend at the birth of their child and, internationally, there is a palpable pressure on maternity and neonatal services to include and engage with fathers. It is, thus, more important than ever to understand how fathers experience reproductive and neonatal health services and to understand how fathers can be successfully accommodated in these environments alongside their partners. In this paper we advance a theoretical framework for re-thinking fatherhood and health services approaches to fatherhood based on Critical Studies of Men and Masculinities (CSM). We illustrate the importance of this feminist-informed theoretical approach to understanding the gendered experiences of fathers in a Neonatal Intensive Care Unit (NICU) setting. Using a longitudinal follow-up research design, with two data collection points, a total of 39 in-depth semi-structured interviews was conducted with 21 fathers of infants admitted to NICU between August 2008 and December 2009. The findings demonstrate: (i) ways in which men are forging new gendered identities around the birth of their baby but, over time, acknowledge women as the primary caregivers; (ii) how social class is a key determinant of men’s ability to enact hegemonic forms of ‘involved fatherhood’ in the NICU, and; (iii) how men also encounter resistance from their partners and health professionals in challenging a gender order which associates women with the competent care of infants. An understanding of these gendered experiences operating at both individual and structural levels is critical to leading change for the inclusion of fathers as equal parents in healthcare settings. © 2012 Elsevier Ltd. All rights reserved.