Association between prostinogen (KLK15) genetic variants and prostate cancer risk and aggressiveness in Australia and a meta-analysis of GWAS data

Background: Kallikrein 15 (KLK15)/Prostinogen is a plausible candidate for prostate cancer susceptibility. Elevated KLK15 expression has been reported in prostate cancer and it has been described as an unfavorable prognostic marker for the disease. Objectives: We performed a comprehensive analysis of association of variants in the KLK15 gene with prostate cancer risk and aggressiveness by genotyping tagSNPs, as well as putative functional SNPs identified by extensive bioinformatics analysis. Methods and Data Sources: Twelve out of 22 SNPs, selected on the basis of linkage disequilibrium pattern, were analyzed in an Australian sample of 1,011 histologically verified prostate cancer cases and 1,405 ethnically matched controls. Replication was sought from two existing genome wide association studies (GWAS): the Cancer Genetic Markers of Susceptibility (CGEMS) project and a UK GWAS study. Results: Two KLK15 SNPs, rs2659053 and rs3745522, showed evidence of association (p, 0.05) but were not present on the GWAS platforms. KLK15 SNP rs2659056 was found to be associated with prostate cancer aggressiveness and showed evidence of association in a replication cohort of 5,051 patients from the UK, Australia, and the CGEMS dataset of US samples. A highly significant association with Gleason score was observed when the data was combined from these three studies with an Odds Ratio (OR) of 0.85 (95% CI = 0.77-0.93; p = 2.7610 24). The rs2659056 SNP is predicted to alter binding of the RORalpha transcription factor, which has a role in the control of cell growth and differentiation and has been suggested to control the metastatic behavior of prostate cancer cells. Conclusions: Our findings suggest a role for KLK15 genetic variation in the etiology of prostate cancer among men of European ancestry, although further studies in very large sample sets are necessary to confirm effect sizes.

Novel molecular markers of Chlamydia pecorum genetic diversity in the koala (Phascolarctos cinereus)

Background Chlamydia pecorum is an obligate intracellular bacterium and the causative agent of reproductive and ocular disease in several animal hosts including koalas, sheep, cattle and goats. C. pecorum strains detected in koalas are genetically diverse, raising interesting questions about the origin and transmission of this species within koala hosts. While the ompA gene remains the most widely-used target in C. pecorum typing studies, it is generally recognised that surface protein encoding genes are not suited for phylogenetic analysis and it is becoming increasingly apparent that the ompA gene locus is not congruent with the phylogeny of the C. pecorum genome. Using the recently sequenced C. pecorum genome sequence (E58), we analysed 10 genes, including ompA, to evaluate the use of ompA as a molecular marker in the study of koala C. pecorum genetic diversity. Results Three genes (incA, ORF663, tarP) were found to contain sufficient nucleotide diversity and discriminatory power for detailed analysis and were used, with ompA, to genotype 24 C. pecorum PCR-positive koala samples from four populations. The most robust representation of the phylogeny of these samples was achieved through concatenation of all four gene sequences, enabling the recreation of a "true" phylogenetic signal. OmpA and incA were of limited value as fine-detailed genetic markers as they were unable to confer accurate phylogenetic distinctions between samples. On the other hand, the tarP and ORF663 genes were identified as useful "neutral" and "contingency" markers respectively, to represent the broad evolutionary history and intra-species genetic diversity of koala C. pecorum. Furthermore, the concatenation of ompA, incA and ORF663 sequences highlighted the monophyletic nature of koala C. pecorum infections by demonstrating a single evolutionary trajectory for koala hosts that is distinct from that seen in non-koala hosts. Conclusions While the continued use of ompA as a fine-detailed molecular marker for epidemiological analysis appears justified, the tarP and ORF663 genes also appear to be valuable markers of phylogenetic or biogeographic divisions at the C. pecorum intra-species level. This research has significant implications for future typing studies to understand the phylogeny, genetic diversity, and epidemiology of C. pecorum infections in the koala and other animal species.

Persistence of multiple genetic lineages within intra-host populations of Ross River virus

We examined the structure and extent of genetic diversity in intrahost populations of Ross River virus (RRV) in samples from six human patients, focusing on the nonstructural (nsP3) and structural (E2) protein genes. Strikingly, although the samples were collected from contrasting ecological settings 3,000 kilometers apart in Australia, we observed multiple viral lineages in four of the six individuals, which is indicative of widespread mixed infections. In addition, a comparison with previously published RRV sequences revealed that these distinct lineages have been in circulation for at least 5 years, and we were able to document their long-term persistence over extensive geographical distances

Contractual relationships for better stewardship of privatised critical infrastructures

Governments increasingly rely on forms of privatisation to provide critical public infrastructure yet when those infrastructures fail to meet community expectations government bears the political and economic risks, being held accountable by the public as steward for those infrastructures. Reconfiguration of the contractual relationships may achieve better stewardship. Many of the forms of privatization rely on Agency theory prescriptions, conceptualizing organisations and individuals as motivated solely by self-interest. Stewardship theory (Van Slyke 2007) has developed as a complement to Agency theory offering the possibility of contractual relationships which maximize stewardship outcome. Stewardship theory asserts that pro-stewardship factors cause the agent/steward to act in the interests of the principal. This research has interrogated the literature finding that of the pro-stewardship factors, sense of responsibility is pre-eminent and has a significant link to the agent acting as a steward. The research has explored how important it is that the steward feel sense of responsibility and the actions that sense of responsibility. Case studies of privatized core elements of urban water systems infrastructure were explored. Data has been gathered primarily from archival sources and individual interviews of government and private sector executives key to those systems. This paper reports the findings as to the extent of stewardship, how important it is that the steward acts in the interests of the principal, even to the steward’s detriment and the importance of the steward feeling a sense of responsibility. The actions which increase that sense of responsibility will be assembled to position the research to better proceed with the analysis of the data as to these actions.

Correlation-based damage detection for complicated truss bridges using multi-layer genetic algorithms

The study presents a multi-layer genetic algorithm (GA) approach using correlation-based methods to facilitate damage determination for through-truss bridge structures. To begin, the structure’s damage-suspicious elements are divided into several groups. In the first GA layer, the damage is initially optimised for all groups using correlation objective function. In the second layer, the groups are combined to larger groups and the optimisation starts over at the normalised point of the first layer result. Then the identification process repeats until reaching the final layer where one group includes all structural elements and only minor optimisations are required to fine tune the final result. Several damage scenarios on a complicated through-truss bridge example are nominated to address the proposed approach’s effectiveness. Structural modal strain energy has been employed as the variable vector in the correlation function for damage determination. Simulations and comparison with the traditional single-layer optimisation shows that the proposed approach is efficient and feasible for complicated truss bridge structures when the measurement noise is taken into account.