The MS risk allele of CD40 is associated with reduced cell-membrane bound expression in antigen presenting cells: Implications for gene function

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS. © 2015 Field et al.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P 1 × 10 5 were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10 17), 16q22 (CDH1 and CDH3; P = 2.8 × 10 8) and 7q31 (LAMB1; P = 3.0 × 10 8). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis. © 2009 Nature America, Inc. All rights reserved.

Science, ICT and Mathematics Education in Rural and Regional Australia: The SiMERR National Survey

The SiMERR National Survey was one of the first priorities of the National Centre of Science, Information and Communication Technology and Mathematics Education for Rural and Regional Australia (SiMERR Australia), established at the University of New England in July 2004 through a federal government grant. With university based ‘hubs’ in each state and territory, SiMERR Australia aims to support rural and regional teachers, students and communities in improving educational outcomes in these subject areas. The purpose of the survey was to identify the key issues affecting these outcomes. The National Survey makes six substantial contributions to our understanding of issues in rural education. First, it focuses specifically on school science, ICT and mathematics education, rather than on education more generally. Second, it compares the different circumstances and needs of teachers across a nationally agreed geographical framework, and quantifies these differences. Third, it compares the circumstances and needs of teachers in schools with different proportions of Indigenous students. Fourth, it provides greater detail than previous studies on the specific needs of schools and teachers in these subject areas. Fifth, the analyses of teacher ‘needs’ have been controlled for the socio-economic background of school locations, resulting in findings that are more tightly associated with geographic location than with economic circumstances. Finally, most previous reports on rural education in Australia were based upon focus interviews, public submissions or secondary analyses of available data. In contrast, the National Survey has generated a sizable body of original quantitative and qualitative data.

Rethinking connectedness: improving access to professional learning for regional and remote teachers

Transformation of Australian education is occurring at a rapid rate through the implementation of a number of initiatives. These initiatives include the Digital Education Revolution, the move to a National Curriculum and the implementation of a National Framework for Professional Standards for Teachers and Principals. As these initiatives are rolled out to schools across Australia, the equitable access to professional learning to support all teachers, regardless of their geographical location, is in question. A number of studies have been conducted in Australia that highlight the importance of professional learning and the difficulty faced by regional and remote teachers with regard to access (Gerard Daniels, 2007; Lysons, Cooksey, Panizzon, Parnell & Pegg 2006; Ministerial Review of Schooling, 1994, Rural and Remote Education Advisory Council, 2000; Vinson, 2002). Along with access to professional learning, has been the discussion of effective modes of delivery. Face to face professional learning, in regional and metropolitan areas, is offered in isolation, or in some cases, is complimented with virtual learning environments. The need for a more sustainable approach to professional learning is highly necessary. A mixed method research approach was utilised in order to answer the primary research question "In what ways might technology be used to support professional learning of regional and remote teachers in Western Australia?" This research paper outlines the findings from the study including the significance of travel time; impact of limited relief teachers; implications for promotion and teacher registration; professional learning communities being valued but often limited by small staff numbers; professional learning conducted in the local context being preferred; professional learning established at the teacher and school level being desirable; teachers being confident in using technology and accessing PD online if required; and social cohesiveness being valued and often limited by isolation. Further, this research has culminated in the development of a "model of rethinking connectedness" that would facilitate improving the amount and variety of professional learning available to regional and remote teachers.

Quarantine and surveillance strategies for plant pathogen detection and control

Incursions of plant pests and diseases pose serious threats to food security, agricultural productivity and the natural environment. One of the challenges in confidently delimiting and eradicating incursions is how to choose from an arsenal of surveillance and quarantine approaches in order to best control multiple dispersal pathways. Anthropogenic spread (propagules carried on humans or transported on produce or equipment) can be controlled with quarantine measures, which in turn can vary in intensity. In contrast, environmental spread processes are more difficult to control, but often have a temporal signal (e.g. seasonality) which can introduce both challenges and opportunities for surveillance and control. This leads to complex decisions regarding when, where and how to search. Recent modelling investigations of surveillance performance have optimised the output of simulation models, and found that a risk-weighted randomised search can perform close to optimally. However, exactly how quarantine and surveillance strategies should change to reflect different dispersal modes remains largely unaddressed. Here we develop a spatial simulation model of a plant fungal-pathogen incursion into an agricultural region, and its subsequent surveillance and control. We include structural differences in dispersal via the interplay of biological, environmental and anthropogenic connectivity between host sites (farms). Our objective was to gain broad insights into the relative roles played by different spread modes in propagating an invasion, and how incorporating knowledge of these spread risks may improve approaches to quarantine restrictions and surveillance. We find that broad heuristic rules for quarantine restrictions fail to contain the pathogen due to residual connectivity between sites, but surveillance measures enable early detection and successfully lead to suppression of the pathogen in all farms. Alternative surveillance strategies attain similar levels of performance by incorporating environmental or anthropogenic dispersal risk in the prioritisation of sites. Our model provides the basis to develop essential insights into the effectiveness of different surveillance and quarantine decisions for fungal pathogen control. Parameterised for authentic settings it will aid our understanding of how the extent and resolution of interventions should suitably reflect the spatial structure of dispersal processes.