Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis

Objective. We have previously identified a single-nucleotide polymorphism (SNP) haplotype involving the lymphotoxin α (LTA) and tumor necrosis factor (TNF) loci (termed haplotype LTA-TNF2) on chromosome 6 that shows differential association with rheumatoid arthritis (RA) on HLA-DRB1*0404 and *0401 haplotypes, suggesting the presence of additional non-HLA-DRB1 RA susceptibility genes on these haplotypes. To refine this association, we performed a case-control association study using both SNPs and microsatellite markers in haplotypes matched either for HLA-DRB1*0404 or for HLA-DRB1*0401. Methods. Fourteen SNPs lying between HLA-DRB1 and LTA were genotyped in 87 DRB1*04-positive families. High-density microsatellite typing was performed using 24 markers spanning 2,500 kb centered around the TNF gene in 305 DRB1*0401 or *0404 cases and 400 DRB1*0401 or *0404 controls. Single-marker, 2-marker, and 3-marker minihaplotypes were constructed and their frequencies compared between the DRB1*0401 and DRB1*0404 matched case and control haplotypes. Results. Marked preservation of major histocompatibility complex haplotypes was seen, with chromosomes carrying LTA-TNF2 and either DRB1*0401 or DRB1*0404 both carrying an identical SNP haplotype across the 1-Mb region between TNF and HLA-DRB1. Using microsatellite markers, we observed two 3-marker minihaplotypes that were significantly overrepresented in the DRB1*0404 case haplotypes (P = 0.00024 and P = 0.00097). Conclusion. The presence of a single extended SNP haplotype between LTA-TNF2 and both DRB1*0401 and DRB1*0404 is evidence against this region harboring the genetic effects in linkage disequillbrium with LTA-TNF2. Two RA-associated haplotypes on the background of DRB1*0404 were identified in a 126-kb region surrounding and centromeric to the TNF locus.

Common variants in the HLA-DRB1-HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

To identify susceptibility loci for visceral leishmaniasis, we undertook genome-wide association studies in two populations: 989 cases and 1,089 controls from India and 357 cases in 308 Brazilian families (1,970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, and combined analysis across the three cohorts for rs9271858 at this locus showed P combined = 2.76 × 10 -17 and odds ratio (OR) = 1.41, 95% confidence interval (CI) = 1.30-1.52. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion, the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species. © 2013 Nature America, Inc. All rights reserved.

Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis

Objective. The heritability of RA has been estimated to be ∼55%, of which the MHC contributes about one-third. HLA-DRB1 alleles are strongly associated with RA, but it is likely that significant non-DRB1 MHC genetic susceptibility factors are involved. Previously, we identified two three-marker haplotypes in a 106-kb region in the MHC class III region immediately centromeric to TNF, which are strongly associated with RA on HLA-DRB1*0404 haplotypes. In the present study, we aimed to refine these associations further using a combination of genotyping and gene expression studies. Methods. Thirty-nine nucleotide polymorphisms (SNPs) were genotyped in 95 DRB1*0404 carrying unrelated RA cases, 125 DRB1*0404 - carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB1*04. Quantitative RT-PCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2β and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and β2-microglobulin (B2M) in 31 RA cases and 21 ethnically, age- and sex-matched healthy controls. Synovial membrane specimens from RA, PsA and OA cases were stained by an indirect immunoperoxidase technique using a mouse-anti-human AIF1 monoclonal antibody. Results. Association was observed between RA and single markers or two marker haplotypes involving AIF1, BAT3 and CSNK. AIF1 was also significantly overexpressed in RA mononuclear cells (1.5- to 1.9-fold difference, P = 0.02 vs HPRT, P = 0.002 vs B2M). AIF1 protein was clearly expressed by synovial macrophages in all the inflammatory synovial samples in contrast to the non-inflammatory OA samples. Conclusions. The results of the genotyping and expression studies presented here suggest a role for AIF1 in both the aetiology and pathogenesis of RA.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

Embedding sustainability in a real-world context: Developing a world class early learning centre

This symposium describes what is possible when early childhood professionals work with designers to develop a vision for an exemplary early childhood centre with a focus on Education for Sustainability (EfS). The symposium provides insights into cross-disciplinary initiatives between QUT Early childhood and Design staff and students, who have worked together with the iconic Lone Pine Koala Sanctuary in Brisbane, to explore imperatives around EfS, including leadership and professionalism. This practical, real world project has seen all stakeholders engage in a focus on sustainability which has opened new ways of thinking about early childhood centre design. Cross-disciplinarity has created space to re-think the potential of the disciplines to interweave, and in so doing opened different ways for thinking about early childhood centres – their operation and their function. For the first time in Queensland, this project creates strategic alliances between EfS, childcare, business and sustainable design. EfS is essential for addressing local and global environmental issues and early childhood EfS research has been gaining international momentum, with governments nominating this area as having significant capacity to empower communities and promote change. While models for collaboration exist in the early childhood programs in Reggio Emilia, we offer sustainability as a unique and contemporary focus with immense potential to generate international and national interest. To date Early Childhood degree students enrolled in a leadership and management unit/subject have worked collaboratively with Design students to explore the sustainable design of the proposed Lone Pine early childhood centre. Providing students with a ‘real world’ project sees them re-positioned from ‘novice’ to ‘professional’, where their knowledge, expertise and perspectives are simultaneously validated and challenged. These learning experiences are enabling students to practice a new model of early childhood leadership, one that is vital for leading in an increasingly complex world. The symposium will be comprised of three discrete, though interconnected presentations, that work together to tell the story of this project. Three key facets of the project will be explored during the 90 minute session, as the perspectives of key stakeholders are shared. The first presentation (A/Prof Julie Davis, Dr Lyndal O’Gorman& Dr Megan Gibson) will outline the role of QUT School of Early Childhood staff and students, with attention to the ways in which the project was embedded in students’ work in the final year of their degree program of study. The second presentation (Ms Lindy Osborne) will provide insights into the Design students’ collaborative work in the project. Finally, the key role of the Lone Pine Koala Sanctuary and their commitment for EfS (Ms Peta Wilson & Dr Sue Elliott) will map out the philosophy that underpins the project. Together, the authors will conclude key project outcomes that have been achieved through this real-world, cross-disciplinary work.

The politics of race, class and special education: The selected works of Sally Tomlinson

Upon reading this esteemed collection of Sally Tomlinson’s works, published in Routledge’s prestigious World Library of Educationalists series, I was struck by three things. First, Sally is one of only three women among the 26 scholars whose collections have been published in this series to date, and the only scholar researching questions relating to disability and special education. Second, her early work on the sociology of special education Tomlinson, 1982) is just as pertinent today as her most recent research on the political scapegoating of low-attainers in a global knowledge economy (Tomlinson, 2012). Third, I was reminded of the extent to which her research has both inspired and guided me as I now grapple with the same research problems, albeit in a different country and at a different time, but always from a similar sociological standpoint (Graham & Jahnukainen, 2011; Graham & Sweller, 2011; Graham, 2012; Graham, 2014; Graham, Van Bergen & Sweller, 2014). Not surprisingly, the phrase that kept echoing through my head as I read through the 11 chapters chronicling a rich and immensely productive academic career was: ‘history repeats’. And, throughout the book are numerous examples and observations as to why it does. To paraphrase, the answer is power, status and politics.

Susceptibility locus on chromosome 1q23-25 for a schizophrenia subtype resembling deficit schizophrenia identified by latent class analysis

Context: Identifying susceptibility genes for schizophrenia may be complicated by phenotypic heterogeneity, with some evidence suggesting that phenotypic heterogeneity reflects genetic heterogeneity. Objective: To evaluate the heritability and conduct genetic linkage analyses of empirically derived, clinically homogeneous schizophrenia subtypes. Design: Latent class and linkage analysis. Setting: Taiwanese field research centers. Participants: The latent class analysis included 1236 Han Chinese individuals with DSM-IV schizophrenia. These individuals were members of a large affected-sibling-pair sample of schizophrenia (606 ascertained families), original linkage analyses of which detected a maximum logarithm of odds (LOD) of 1.8 (z = 2.88) on chromosome 10q22.3. Main Outcome Measures: Multipoint exponential LOD scores by latent class assignment and parametric heterogeneity LOD scores. Results: Latent class analyses identified 4 classes, with 2 demonstrating familial aggregation. The first (LC2) described a group with severe negative symptoms, disorganization, and pronounced functional impairment, resembling “deficit schizophrenia.” The second (LC3) described a group with minimal functional impairment, mild or absent negative symptoms, and low disorganization. Using the negative/deficit subtype, we detected genome-wide significant linkage to 1q23-25 (LOD = 3.78, empiric genome-wide P = .01). This region was not detected using the DSM-IV schizophrenia diagnosis, but has been strongly implicated in schizophrenia pathogenesis by previous linkage and association studies.Variants in the 1q region may specifically increase risk for a negative/deficit schizophrenia subtype. Alternatively, these results may reflect increased familiality/heritability of the negative class, the presence of multiple 1q schizophrenia risk genes, or a pleiotropic 1q risk locus or loci, with stronger genotype-phenotype correlation with negative/deficit symptoms. Using the second familial latent class, we identified nominally significant linkage to the original 10q peak region. Conclusion: Genetic analyses of heritable, homogeneous phenotypes may improve the power of linkage and association studies of schizophrenia and thus have relevance to the design and analysis of genome-wide association studies.

Latent class and genetic analysis does not support migraine with aura and migraine without aura as separate entities

Latent class and genetic analyses were used to identify subgroups of migraine sufferers in a community sample of 6,265 Australian twins (55% female) aged 25-36 who had completed an interview based on International Headache Society (IHS) criteria. Consistent with prevalence rates from other population-based studies, 703 (20%) female and 250 (9%) male twins satisfied the IHS criteria for migraine without aura (MO), and of these, 432 (13%) female and 166 (6%) male twins satisfied the criteria for migraine with aura (MA) as indicated by visual symptoms. Latent class analysis (LCA) of IHS symptoms identified three major symptomatic classes, representing 1) a mild form of recurrent nonmigrainous headache, 2) a moderately severe form of migraine, typically without visual aura symptoms (although 40% of individuals in this class were positive for aura), and 3) a severe form of migraine typically with visual aura symptoms (although 24% of individuals were negative for aura). Using the LCA classification, many more individuals were considered affected to some degree than when using IHS criteria (35% vs. 13%). Furthermore, genetic model fitting indicated a greater genetic contribution to migraine using the LCA classification (heritability, h(2)=0.40; 95% CI, 0.29-0.46) compared with the IHS classification (h(2)=0.36; 95% CI, 0.22-0.42). Exploratory latent class modeling, fitting up to 10 classes, did not identify classes corresponding to either the IHS MO or MA classification. Our data indicate the existence of a continuum of severity, with MA more severe but not etiologically distinct from MO. In searching for predisposing genes, we should therefore expect to find some genes that may underlie all major recurrent headache subtypes, with modifying genetic or environmental factors that may lead to differential expression of the liability for migraine.

Zygosity diagnosis in the absence of genotypic data: An approach using latent class analysis

For zygosity diagnosis in the absence of genotypic data, or in the recruitment phase of a twin study where only single twins from same-sex pairs are being screened, or to provide a test for sample duplication leading to the false identification of a dizygotic pair as monozygotic, the appropriate analysis of respondents' answers to questions about zygosity is critical. Using data from a young adult Australian twin cohort (N = 2094 complete pairs and 519 singleton twins from same-sex pairs with complete responses to all zygosity items), we show that application of latent class analysis (LCA), fitting a 2-class model, yields results that show good concordance with traditional methods of zygosity diagnosis, but with certain important advantages. These include the ability, in many cases, to assign zygosity with specified probability on the basis of responses of a single informant (advantageous when one zygosity type is being oversampled); and the ability to quantify the probability of misassignment of zygosity, allowing prioritization of cases for genotyping as well as identification of cases of probable laboratory error. Out of 242 twins (from 121 like-sex pairs) where genotypic data were available for zygosity confirmation, only a single case was identified of incorrect zygosity assignment by the latent class algorithm. Zygosity assignment for that single case was identified by the LCA as uncertain (probability of being a monozygotic twin only 76%), and the co-twin's responses clearly identified the pair as dizygotic (probability of being dizygotic 100%). In the absence of genotypic data, or as a safeguard against sample duplication, application of LCA for zygosity assignment or confirmation is strongly recommended.

Emotional climate of a pre-service science teacher education class in Bhutan

This study explored pre-service secondary science teachers’ perceptions of classroom emotional climate in the context of the Bhutanese macro-social policy of Gross National Happiness. Drawing upon sociological perspectives of human emotions and using Interaction Ritual Theory this study investigated how pre-service science teachers may be supported in their professional development. It was a multi-method study involving video and audio recordings of teaching episodes supported by interviews and the researcher’s diary. Students also registered their perceptions of the emotional climate of their classroom at 3-minute intervals using audience response technology. In this way, emotional events were identified for video analysis. The findings of this study highlighted that the activities pre-service teachers engaged in matter to them. Positive emotional climate was identified in activities involving students’ presentations using video clips and models, coteaching, and interactive whole class discussions. Decreases in emotional climate were identified during formal lectures and when unprepared presenters led presentations. Emotions such as frustration and disappointment characterized classes with negative emotional climate. The enabling conditions to sustain a positive emotional climate are identified. Implications for sustaining macro-social policy about Gross National Happiness are considered in light of the climate that develops in science teacher education classes.

Classifying patients by their characteristics and clinical presentations; the use of latent class analysis

In this article, we introduce the general statistical analysis approach known as latent class analysis and discuss some of the issues associated with this type of analysis in practice. Two recent examples from the respiratory health literature are used to highlight the types of research questions that have been addressed using this approach.

A Bayesian latent class safety performance function for identifying motor vehicle crash blackspots

The current state of the practice in Blackspot Identification (BSI) utilizes safety performance functions based on total crash counts to identify transport system sites with potentially high crash risk. This paper postulates that total crash count variation over a transport network is a result of multiple distinct crash generating processes including geometric characteristics of the road, spatial features of the surrounding environment, and driver behaviour factors. However, these multiple sources are ignored in current modelling methodologies in both trying to explain or predict crash frequencies across sites. Instead, current practice employs models that imply that a single underlying crash generating process exists. The model mis-specification may lead to correlating crashes with the incorrect sources of contributing factors (e.g. concluding a crash is predominately caused by a geometric feature when it is a behavioural issue), which may ultimately lead to inefficient use of public funds and misidentification of true blackspots. This study aims to propose a latent class model consistent with a multiple crash process theory, and to investigate the influence this model has on correctly identifying crash blackspots. We first present the theoretical and corresponding methodological approach in which a Bayesian Latent Class (BLC) model is estimated assuming that crashes arise from two distinct risk generating processes including engineering and unobserved spatial factors. The Bayesian model is used to incorporate prior information about the contribution of each underlying process to the total crash count. The methodology is applied to the state-controlled roads in Queensland, Australia and the results are compared to an Empirical Bayesian Negative Binomial (EB-NB) model. A comparison of goodness of fit measures illustrates significantly improved performance of the proposed model compared to the NB model. The detection of blackspots was also improved when compared to the EB-NB model. In addition, modelling crashes as the result of two fundamentally separate underlying processes reveals more detailed information about unobserved crash causes.

Class-specific sparse codes for representing activities

In this paper we investigate the effectiveness of class specific sparse codes in the context of discriminative action classification. The bag-of-words representation is widely used in activity recognition to encode features, and although it yields state-of-the art performance with several feature descriptors it still suffers from large quantization errors and reduces the overall performance. Recently proposed sparse representation methods have been shown to effectively represent features as a linear combination of an over complete dictionary by minimizing the reconstruction error. In contrast to most of the sparse representation methods which focus on Sparse-Reconstruction based Classification (SRC), this paper focuses on a discriminative classification using a SVM by constructing class-specific sparse codes for motion and appearance separately. Experimental results demonstrates that separate motion and appearance specific sparse coefficients provide the most effective and discriminative representation for each class compared to a single class-specific sparse coefficients.

See you in class: Promoting a quality program for pre-service educators in regional locations through a virtual classroom

The quality of an online university degree is paramount to the student, the reputation of the university and most importantly, the profession that will be entered. At the School of Education within Curtin University, we aim to ensure that students within rural and remote areas are provided with high quality degrees equal to their city counterparts who access face-to-face classes on campus.In 2010, the School of Education moved to flexible delivery of a fully online Bachelor of Education degree for their rural students. In previous years, the degree had been delivered in physical locations around the state. Although this served the purpose for the time, it restricted the degree to only those rural students who were able to access the physical campus. The new model in 2010 allows access for students in any rural area who have a computer and an internet connection, regardless of their geographical location. As a result enrolments have seen a positive increase in new students. Academic staff had previously used an asynchronous environment to deliver learning modules housed within a learning management system (LMS). To enhance the learning environment and to provide high quality learning experiences to students learning at a distance, the adoption of synchronous software was introduced. This software is a real-time virtual classroom environment that allows for communication through Voice over Internet Protocol (VoIP) and videoconferencing, along with a large number of collaboration tools to engage learners. This research paper reports on the professional development of academic staff to integrate a live e-learning solution into their current LMS environment. It involved professional development, including technical orientation for teaching staff and course participants simultaneously. Further, pedagogical innovations were offered to engage the students in a collaborative learning environment. Data were collected from academic staff through semi-structured interviews and participant observation. The findings discuss the perceived value of the technology, problems encountered and solutions sought.

3D QSAR studies of N-4-arylacryloylpiperazin-1-yl-phenyl-oxazolidinones: A novel class of antibacterial agents

Three-dimensional QSAR studies for N-4-arylacryloylpiperazin-1-yl-phenyl-oxazolidinones were conducted using TSAR 3.3. The in vitro activities (MICs) of the compounds against Staphylococcus aureus ATCC 25923 exhibited a strong correlation with the prediction made by the model developed in the present study.