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.

The ascidian natural product eusynstyelamide B is a novel topoisomerase II poison that induces DNA damage and growth arrest in prostate and breast cancer cells

As part of an anti-cancer natural product drug discovery program, we recently identified eusynstyelamide B (EB), which displayed cytotoxicity against MDA-MB-231 breast cancer cells (IC50 = 5 μM) and induced apoptosis. Here, we investigated the mechanism of action of EB in cancer cell lines of the prostate (LNCaP) and breast (MDA-MB-231). EB inhibited cell growth (IC50 = 5 μM) and induced a G2 cell cycle arrest, as shown by a significant increase in the G2/M cell population in the absence of elevated levels of the mitotic marker phospho-histone H3. In contrast to MDA-MB-231 cells, EB did not induce cell death in LNCaP cells when treated for up to 10 days. Transcript profiling and Ingenuity Pathway Analysis suggested that EB activated DNA damage pathways in LNCaP cells. Consistent with this, CHK2 phosphorylation was increased, p21CIP1/WAF1 was up-regulated and CDC2 expression strongly reduced by EB. Importantly, EB caused DNA double-strand breaks, yet did not directly interact with DNA. Analysis of topoisomerase II-mediated decatenation discovered that EB is a novel topoisomerase II poison.

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.

On the zeros of the Abelian integrals for a class of Liénard systems

A planar polynomial differential system has a finite number of limit cycles. However, finding the upper bound of the number of limit cycles is an open problem for the general nonlinear dynamical systems. In this paper, we investigated a class of Liénard systems of the form x'=y, y'=f(x)+y g(x) with deg f=5 and deg g=4. We proved that the related elliptic integrals of the Liénard systems have at most three zeros including multiple zeros, which implies that the number of limit cycles bifurcated from the periodic orbits of the unperturbed system is less than or equal to 3.

Exploring the influence of a science content course incorporating explicit nature of science and argumentation instruction on preservice primary teachers' views of nature of science

There exists a general consensus in the science education literature around the goal of enhancing students. and teachers. views of nature of science (NOS). An emerging area of research in science education explores NOS and argumentation, and the aim of this study was to explore the effectiveness of a science content course incorporating explicit NOS and argumentation instruction on preservice primary teachers. views of NOS. A constructivist perspective guided the study, and the research strategy employed was case study research. Five preservice primary teachers were selected for intensive investigation in the study, which incorporated explicit NOS and argumentation instruction, and utilised scientific and socioscientific contexts for argumentation to provide opportunities for participants to apply their NOS understandings to their arguments. Four primary sources of data were used to provide evidence for the interpretations, recommendations, and implications that emerged from the study. These data sources included questionnaires and surveys, interviews, audio- and video-taped class sessions, and written artefacts. Data analysis involved the formation of various assertions that informed the major findings of the study, and a variety of validity and ethical protocols were considered during the analysis to ensure the findings and interpretations emerging from the data were valid. Results indicated that the science content course was effective in enabling four of the five participants. views of NOS to be changed. All of the participants expressed predominantly limited views of the majority of the examined NOS aspects at the commencement of the study. Many positive changes were evident at the end of the study with four of the five participants expressing partially informed and/or informed views of the majority of the examined NOS aspects. A critical analysis of the effectiveness of the various course components designed to facilitate the development of participants‟ views of NOS in the study, led to the identification of three factors that mediated the development of participants‟ NOS views: (a) contextual factors (including context of argumentation, and mode of argumentation), (b) task-specific factors (including argumentation scaffolds, epistemological probes, and consideration of alternative data and explanations), and (c) personal factors (including perceived previous knowledge about NOS, appreciation of the importance and utility value of NOS, and durability and persistence of pre-existing beliefs). A consideration of the above factors informs recommendations for future studies that seek to incorporate explicit NOS and argumentation instruction as a context for learning about NOS.

The S.T.A.B. Trial - Standardised Testing of Artificial Blood. A comparative study of various products that may be used as artificial blood for high fidelity simulation training in the critical care setting

Aim: In the current climate of medical education, there is an ever-increasing demand for and emphasis on simulation as both a teaching and training tool. The objective of our study was to compare the realism and practicality of a number of artificial blood products that could be used for high-fidelity simulation. Method: A literature and internet search was performed and 15 artificial blood products were identified from a variety of sources. One product was excluded due to its potential toxicity risks. Five observers, blinded to the products, performed two assessments on each product using an evaluation tool with 14 predefined criteria including color, consistency, clotting, and staining potential to manikin skin and clothing. Each criterion was rated using a five-point Likert scale. The products were left for 24 hours, both refrigerated and at room temperature, and then reassessed. Statistical analysis was performed to identify the most suitable products, and both inter- and intra-rater variability were examined. Results: Three products scored consistently well with all five assessors, with one product in particular scoring well in almost every criterion. This highest-rated product had a mean rating of 3.6 of 5.0 (95% posterior Interval 3.4-3.7). Inter-rater variability was minor with average ratings varying from 3.0 to 3.4 between the highest and lowest scorer. Intrarater variability was negligible with good agreement between first and second rating as per weighted kappa scores (K = 0.67). Conclusion: The most realistic and practical form of artificial blood identified was a commercial product called KD151 Flowing Blood Syrup. It was found to be not only realistic in appearance but practical in terms of storage and stain removal.

Evaluation of separation management algorithms in Class G airspace

Use of Unmanned Aerial Vehicles (UAVs) in support of government applications has already seen significant growth and the potential for use of UAVs in commercial applications is expected to rapidly expand in the near future. However, the issue remains on how such automated or operator-controlled aircraft can be safely integrated into current airspace. If the goal of integration is to be realized, issues regarding safe separation in densely populated airspace must be investigated. This paper investigates automated separation management concepts in uncontrolled airspace that may help prepare for an expected growth of UAVs in Class G airspace. Not only are such investigations helpful for the UAV integration issue, the automated separation management concepts investigated by the authors can also be useful for the development of new or improved Air Traffic Control services in remote regions without any existing infrastructure. The paper will also provide an overview of the Smart Skies program and discuss the corresponding Smart Skies research and development effort to evaluate aircraft separation management algorithms using simulations involving realworld data communication channels, and verified against actual flight trials. This paper presents results from a unique flight test concept that uses real-time flight test data from Australia over existing commercial communication channels to a control center in Seattle for real-time separation management of actual and simulated aircraft. The paper also assesses the performance of an automated aircraft separation manager.

Students’ perceptions of teaching and learning: the influence of students’ approaches to learning and teachers’ approaches to teaching

Nearly 500 secondary students in 24 classes were surveyed and four students in each class interviewed concerning their approaches to learning and perceptions of their classroom environment. While interviewed students with deep approaches to learning generally demonstrated a more sophisticated understanding of the learning opportunities offered to them than did students with surface approaches, teaching strategies also influenced students' perceptions. When teachers focused strongly on actively engaging students and creating a supportive environment, students with both deep and surface approaches focused on student-centred aspects of the class. In contrast, when traditional expository teaching methods were used exclusively, students with deep and surface approaches both focused on transmission and reproduction.

Documenting reproduction and inequality : revisiting Jean Anyon’s “Social class and school knowledge”

Jean Anyon’s (1981) “Social class and school knowledge” was a landmark work in North American educational research. It provided a richly detailed qualitative description of differential, social-class-based constructions of knowledge and epistemological stance. This essay situates Anyon’s work in two parallel traditions of critical educational research: the sociology of the curriculum and classroom interaction and discourse analysis. It argues for the renewed importance of both quantitative and qualitative research on social reproduction and equity in the current policy context.