Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1·09, combined p= 2·4×10-8) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10-8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10-4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix. © 2011 Elsevier Ltd.

Identification of a novel fusion transcript between human relaxin-1 (RLN1) and human relaxin-2 (RLN2) in prostate cancer

Simultaneous expression of highly homologous RLN1 and RLN2 genes in prostate impairs their accurate delineation. We used PacBio SMRT sequencing and RNA-Seq in LNCaP cells in order to dissect the expression of RLN1 and RLN2 variants. We identified a novel fusion transcript comprising the RLN1 and RLN2 genes and found evidence of its expression in the normal and prostate cancer tissues. The RLN1-RLN2 fusion putatively encodes RLN2 isoform with the deleted secretory signal peptide. The identification of the fusion transcript provided information to determine unique RLN1-RLN2 fusion and RLN1 regions. The RLN1-RLN2 fusion was co-expressed with RLN1 in LNCaP cells, but the two gene products were inversely regulated by androgens. We showed that RLN1 is underrepresented in common PCa cell lines in comparison to normal and PCa tissue. The current study brings a highly relevant update to the relaxin field, and will encourage further studies of RLN1 and RLN2 in PCa and broader.

A three-dimensional hybrid smoothed finite element method (H-SFEM) for nonlinear solid mechanics problems

This paper presents a novel three-dimensional hybrid smoothed finite element method (H-SFEM) for solid mechanics problems. In 3D H-SFEM, the strain field is assumed to be the weighted average between compatible strains from the finite element method (FEM) and smoothed strains from the node-based smoothed FEM with a parameter α equipped into H-SFEM. By adjusting α, the upper and lower bound solutions in the strain energy norm and eigenfrequencies can always be obtained. The optimized α value in 3D H-SFEM using a tetrahedron mesh possesses a close-to-exact stiffness of the continuous system, and produces ultra-accurate solutions in terms of displacement, strain energy and eigenfrequencies in the linear and nonlinear problems. The novel domain-based selective scheme is proposed leading to a combined selective H-SFEM model that is immune from volumetric locking and hence works well for nearly incompressible materials. The proposed 3D H-SFEM is an innovative and unique numerical method with its distinct features, which has great potential in the successful application for solid mechanics problems.

A new method for the in vivo identification of mechanical properties in arteries from cine MRI images: Theoretical framework and validation

Quantifying the stiffness properties of soft tissues is essential for the diagnosis of many cardiovascular diseases such as atherosclerosis. In these pathologies it is widely agreed that the arterial wall stiffness is an indicator of vulnerability. The present paper focuses on the carotid artery and proposes a new inversion methodology for deriving the stiffness properties of the wall from cine-MRI (magnetic resonance imaging) data. We address this problem by setting-up a cost function defined as the distance between the modeled pixel signals and the measured ones. Minimizing this cost function yields the unknown stiffness properties of both the arterial wall and the surrounding tissues. The sensitivity of the identified properties to various sources of uncertainty is studied. Validation of the method is performed on a rubber phantom. The elastic modulus identified using the developed methodology lies within a mean error of 9.6%. It is then applied to two young healthy subjects as a proof of practical feasibility, with identified values of 625 kPa and 587 kPa for one of the carotid of each subject.

Study on tracheal collapsibility, compliance, and stress by considering nonlinear mechanical property of cartilage

Tracheal cartilage has been widely regarded as a linear elastic material either in experimental studies or in analytic and numerical models. However, it has been recently demonstrated that, like other fiber-oriented biological tissues, tracheal cartilage is a nonlinear material, which displays higher strength in compression than in extension. Considering the nonlinearity requires a more complex theoretical frame work and costs more to simulate. This study aims to quantify the deviation due to the simplified treatment of the tracheal cartilage as a linear material. It also evaluates the improved accuracy gained by considering the nonlinearity. Pig tracheal rings were used to exam the mechanical properties of cartilage and muscular membrane. By taking into account the asymmetric shape of tracheal cartilage, the collapse behavior of complete rings was simulated, and the compliance of airway and stress in the muscular membrane were discussed. The results obtained were compared with those assuming linear mechanical properties. The following results were found: (1) Models based on both types of material properties give a small difference in representing collapse behavior; (2) regarding compliance, the relative difference is big, ranging from 10 to 40% under negative pressure conditions; and (3) the difference in determining stress in the muscular membrane is small too: <5%. In conclusion, treating tracheal cartilage as a linear material will not cause big deviations in representing the collapse behavior, and mechanical stress in the muscular part, but it will induce a big deviation in predicting the compliance, particularly when the transmural pressure is lower than -0.5 kPa. The results obtained in this study may be useful in both understanding the collapse behavior of trachea and in evaluating the error induced by the simplification of treating the tracheal cartilage as a linear elastic material.

Nonlinear mechanical property of tracheal cartilage: A theoretical and experimental study

Background: Despite being the stiffest airway of the bronchial tree, the trachea undergoes significant deformation due to intrathoracic pressure during breathing. The mechanical properties of the trachea affect the flow in the airway and may contribute to the biological function of the lung. Method: A Fung-type strain energy density function was used to investigate the nonlinear mechanical behavior of tracheal cartilage. A bending test on pig tracheal cartilage was performed and a mathematical model for analyzing the deformation of tracheal cartilage was developed. The constants included in the strain energy density function were determined by fitting the experimental data. Result: The experimental data show that tracheal cartilage is a nonlinear material displaying higher strength in compression than in tension. When the compression forces varied from -0.02 to -0.03 N and from -0.03 to -0.04 N, the deformation ratios were 11.03±2.18% and 7.27±1.59%, respectively. Both were much smaller than the deformation ratios (20.01±4.49%) under tension forces of 0.02 to 0.01 N. The Fung-type strain energy density function can capture this nonlinear behavior very well, whilst the linear stress-strain relation cannot. It underestimates the stability of trachea by exaggerating the displacement in compression. This study may improve our understanding of the nonlinear behavior of tracheal cartilage and it may be useful for the future study on tracheal collapse behavior under physiological and pathological conditions.

Working-correlation-structure identification in generalized estimating equations

Selecting an appropriate working correlation structure is pertinent to clustered data analysis using generalized estimating equations (GEE) because an inappropriate choice will lead to inefficient parameter estimation. We investigate the well-known criterion of QIC for selecting a working correlation Structure. and have found that performance of the QIC is deteriorated by a term that is theoretically independent of the correlation structures but has to be estimated with an error. This leads LIS to propose a correlation information criterion (CIC) that substantially improves the QIC performance. Extensive simulation studies indicate that the CIC has remarkable improvement in selecting the correct correlation structures. We also illustrate our findings using a data set from the Madras Longitudinal Schizophrenia Study.

Podiatry scope of practice: The role of gender in identification as a specialist

Background Ensuring efficient and effective delivery of health care to an aging population has been a major driver for a review of the health workforce in Australia. As part of this review a new National Registration and Accreditation Scheme (NRAS) has evolved with one goal being to improve workforce flexibility. With increased flexibility there have been discussions about the role specialist scopes of practice plays. This study explored the role of gender and other work related characteristics in relation to contemporary scope of podiatry practice and specialisation in Australia. Methods A cross sectional survey was administered through an on-line survey tool on behalf of the Australasian Podiatry Council. Descriptive data was collected over a three-week period. Queensland University of Technology Human Research Ethics approval was sought and confirmed exemption from review, exemption number 1400000791. Results Of the podiatrists participating in this survey (n=218), they were predominately female (66%), early career (34%, 0-9 years) and work in private practices (78%) in multi-podiatrists centres (41%). Relationship between clinical activities performed and “self-perception” of performing a “specialist role” was significant for practitioners who undertook treatment of specific patient groups. The largest area of interest was biomechanics (n=65), followed closely by diabetes (n=61), a third area identified was paediatrics (n=26). Self-perception of specialist status was compared with gender, years of experience, location, primary work environment and clinical practice. When practitioners are asked to categorise themselves to be either “generalist” or “specialist/ generalist with a special interest” podiatrist, male gender was identified as being the only factor which would predict perception of status; 64% males identified as specialist, as opposed to 49% of female survey respondents (Chi square, df = 1, P = 0.044). Self-perception of specialist status was not explained by years of experience, location, working in rural versus urban environment, state worked in, or part-time/full-time work status. Conclusions In conclusion; gender, work environment plus area of interest form a complex relationship, which appear to influence both perception and reality of service provision. Incorporation of specialisation activity (surgical podiatry along with endorsement for use of scheduled medicines) will have lasting impact on the scope of the podiatry profession in Australia. To meet community expectation and maintain high standards, the addition of new subspecialties may be indicated.

Nonlinear analysis for the pre- and post-yield behaviour of a composite structure with the refined plastic hinge approach

The computational technique of the full ranges of the second-order inelastic behaviour evaluation of steel-concrete composite structure is not always sought forgivingly, and therefore it hinders the development and application of the performance-based design approach for the composite structure. To this end, this paper addresses of the advanced computational technique of the higher-order element with the refined plastic hinges to capture the all-ranges behaviour of an entire steel-concrete composite structure. Moreover, this paper presents the efficient and economical cross-section analysis to evaluate the element section capacity of the non-uniform and arbitrary composite section subjected to the axial and bending interaction. Based on the same single algorithm, it can accurately and effectively evaluate nearly continuous interaction capacity curve from decompression to pure bending technically, which is the important capacity range but highly nonlinear. Hence, this cross-section analysis provides the simple but unique algorithm for the design approach. In summary, the present nonlinear computational technique can simulate both material and geometric nonlinearities of the composite structure in the accurate, efficient and reliable fashion, including partial shear connection and gradual yielding at pre-yield stage, plasticity and strain-hardening effect due to axial and bending interaction at post-yield stage, loading redistribution, second-order P-δ and P-Δ effect, and also the stiffness and strength deterioration. And because of its reliable and accurate behavioural evaluation, the present technique can be extended for the design of the high-strength composite structure and potentially for the fibre-reinforced concrete structure.

Correction factors for dynamic state estimation of aggregated generators

This paper presents an approach for dynamic state estimation of aggregated generators by introducing a new correction factor for equivalent inter-area power flows. The spread of generators from the center of inertia of each area is summarized by the correction term α on the equivalent power flow between the areas and is applied to the identification and estimation process. A nonlinear time varying Kalman filter is applied to estimate the equivalent angles and velocities of coherent areas by reducing the effect of local modes on the estimated states. The approach is simulated on two test systems and the results show the effect of the correction factor and the performance of the state estimation by estimating the inter-area dynamics of the system.

Androgenetic alopecia: Identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 x 10(-8)

Identification of seven loci affecting mean telomere length and their association with disease

Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 x 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25,000 single-nucleotide polymorphisms (SNPs) located within approximately 14,000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case-control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

The identification of teaching interactions used in one-to-one teaching of number in the early years of schooling

This research paper reports on phase one of an investigation of video recorded intensive one-to-one teaching interactions with 6–7-year-old students who were in their second year of schooling in Australia and identified by the their teacher as low attaining in early number. The two-phased study from which this paper emerges was originally conducted in 1998 as part of my Bachelor of Teaching Honours (Research) program at Southern Cross University Lismore, New South Wales. That study identified teaching interactions particularly suited to one-to-one teaching in the Maths Recovery Program, a program designed for these students who were at risk of failure in early number. Since that time a great deal has not changed with limited literature available that comprehensively reports on teaching interactions in intensive one-to-one settings. Revisiting the original study is considered timely given the increasing number of withdrawal and intensive programs now funded and adopted by schools and yet, rarely reported on in terms of the effectiveness of the teaching interactions that occur in such settings. This paper then presents a discussion of a preliminary series of teaching interactions that either positively and or negatively influence an intensive one-to-one teaching and learning setting

Enrichment and identification of glycoproteins in human saliva using lectin magnetic bead arrays

Aberrant glycosylation of proteins is a hallmark of tumorigenesis, and could provide diagnostic value in cancer detection. Human saliva is an ideal source of glycoproteins due to the relatively high proportion of glycosylated proteins in the salivary proteome. Moreover, saliva collection is non-invasive, technically straightforward and the sample collection and storage is relatively easy. Although, differential glycosylation of proteins can be indicative of disease states, identification of differential glycosylation from clinical samples is not trivial. To facilitate salivary glycoprotein biomarker discovery, we optimised a method for differential glycoprotein enrichment from human saliva based on lectin magnetic bead arrays (saLeMBA). Selected lectins from distinct reactivity groups were used in the saLeMBA platform to enrich salivary glycoproteins from healthy volunteer saliva. The technical reproducibility of saLeMBA was analysed with LC-MS/MS to identify the glycosylated proteins enriched by each lectin. Our saLeMBA platform enabled robust glycoprotein enrichment in a glycoprotein- and lectin-specific manner consistent with known protein-specific glycan profiles. We demonstrated that saLeMBA is a reliable method to enrich and detect glycoproteins present in human saliva.