Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases

The Kallikrein (KLK) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated as a high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms (SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation, can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations.

Guerrilla research tactics: alternative research methods

This case-study explores alternative and experimental methods of research data acquisition, through an emerging research methodology, ‘Guerrilla Research Tactics’ [GRT]. The premise is that the researcher develops covert tactics for attracting and engaging with research participants. These methods range between simple analogue interventions to physical bespoke artefacts which contain an embedded digital link to a live, interactive data collecting resource, such as an online poll, survey or similar. These artefacts are purposefully placed in environments where the researcher anticipates an encounter and response from the potential research participant. The choice of design and placement of artefacts is specific and intentional. DESCRIPTION: Additional information may include: the outcomes; key factors or principles that contribute to its effectiveness; anticipated impact/evidence of impact. This case-study assesses the application of ‘Guerrilla Research Tactics’ [GRT] Methodology as an alternative, engaging and interactive method of data acquisition for higher degree research. Extending Gauntlett’s definition of ‘new creative methods… an alternative to language driven qualitative research methods' (2007), this case-study contributes to the existing body of literature addressing creative and interactive approaches to HDR data collection. The case-study was undertaken with Masters of Architecture and Urban Design research students at QUT, in 2012. Typically students within these creative disciplines view research as a taxing and boring process, distracting them from their studio design focus. An obstacle that many students face, is acquiring data from their intended participant groups. In response to these challenges the authors worked with students to develop creative, fun, and engaging research methods for both the students and their research participants. GRT are influenced by and developed from a combination of participatory action research (Kindon, 2008) and unobtrusive research methods (Kellehear, 1993), to enhance social research. GRT takes un-obtrusive research in a new direction, beyond the typical social research methods. The Masters research students developed alternative methods for acquiring data, which relied on a combination of analogue design interventions and online platforms commonly distributed through social networks. They identified critical issues that required action by the community, and the processes they developed focused on engaging with communities, to propose solutions. Key characteristics shared between both GRT and Guerrilla Activism, are notions of political issues, the unexpected, the unconventional, and being interactive, unique and thought provoking. The trend of Guerrilla Activism has been adapted to: marketing, communication, gardening, craftivism, theatre, poetry, and art. Focusing on the action element and examining elements of current trends within Guerrilla marketing, we believe that GRT can be applied to a range of research areas within various academic disciplines.

Psychology students’ beliefs about integrating Complementary and Alternative Therapy (CAT) into their future psychology practice

We investigated whether belief-based differences exist between students who have strong and weak intentions to integrate complementary and alternative therapy (CAT) into future psychology practice by recommending CAT or specific CAT practitioners to clients. A cross-sectional methodology was used. Psychology undergraduate students (N = 106) participated in a paper-based questionnaire design to explore their underlying beliefs related to CAT integration. The study was undertaken at a major university in Queensland, Australia. The theory of planned behaviour belief-based framework guided the study. Multivariate analyses of variance examined the influence of behavioural, normative, and control beliefs on the strong and weak intention groups. A multiple regression analysis investigated the relative importance of these belief sets for predicting intentions. We found that clear differences emerged between strong and weak intenders on behavioural and normative beliefs, but not control beliefs. Strong intenders perceived the positive outcomes of integrating CAT, such as being able to offer clients a more holistic practice and having confidence in the practitioners/practices, as more likely to occur than weak intenders, and perceived the negative outcome of compromising my professional practice as less likely. Strong in-tenders were more likely than weak intenders to perceive that a range of important referents (e.g., clients) would think they should integrate CAT. Results of the regression analysis revealed the same pattern of results in that behavioural and normative beliefs, but not control beliefs, significantly predicted intentions. The findings from this study can be used to inform policy and educational initiatives that aim to encourage CAT use in psychology practice.

Genetic association of the KLK4 locus with risk of prostate cancer

The Kallikrein-related peptidase, KLK4, has been shown to be significantly overexpressed in prostate tumours in numerous studies and is suggested to be a potential biomarker for prostate cancer. KLK4 may also play a role in prostate cancer progression through its involvement in epithelial-mesenchymal transition, a more aggressive phenotype, and metastases to bone. It is well known that genetic variation has the potential to affect gene expression and/or various protein characteristics and hence we sought to investigate the possible role of single nucleotide polymorphisms (SNPs) in the KLK4 gene in prostate cancer. Assessment of 61 SNPs in the KLK4 locus (±10 kb) in approximately 1300 prostate cancer cases and 1300 male controls for associations with prostate cancer risk and/or prostate tumour aggressiveness (Gleason score <7 versus ≥7) revealed 7 SNPs to be associated with a decreased risk of prostate cancer at the Ptrend<0.05 significance level. Three of these SNPs, rs268923, rs56112930 and the HapMap tagSNP rs7248321, are located several kb upstream of KLK4; rs1654551 encodes a non-synonymous serine to alanine substitution at position 22 of the long isoform of the KLK4 protein, and the remaining 3 risk-associated SNPs, rs1701927, rs1090649 and rs806019, are located downstream of KLK4 and are in high linkage disequilibrium with each other (r2≥0.98). Our findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition.

Saturated core high-temperature superconducting fault current limiters as an alternative to conventional series reactors in a distribution grid

Series reactors are used in distribution grids to reduce the short-circuit fault level. Some of the disadvantages of the application of these devices are the voltage drop produced across the reactor and the steep front rise of the transient recovery voltage (TRV), which generally exceeds the rating of the associated circuit breaker. Simulations were performed to compare the characteristics of a saturated core High-Temperature Superconducting Fault Current Limiter (HTS FCL) and a series reactor. The design of the HTS FCL was optimized using the evolutionary algorithm. The resulting Pareto frontier curve of optimum solution is presented in this paper. The results show that the steady-state impedance of an HTS FCL is significantly lower than that of a series reactor for the same level of fault current limiting. Tests performed on a prototype 11 kV HTS FCL confirm the theoretical results. The respective transient recovery voltages (TRV) of the HTS FCL and an air core reactor of comparable fault current limiting capability are also determined. The results show that the saturated core HTS FCL has a significantly lower effect on the rate of rise of the circuit breaker TRV as compared to the air core reactor. The simulations results are validated with shortcircuit test results.

Genome-wide search for markers associated with bovine spongiform encephalopathy

A genome-wide search for markers associated with BSE incidence was performed by using Transmission-Disequilibrium Tests (TDTs). Significant segregation distortion, i.e., unequal transmission probabilities of alleles within a locus, was found for three marker loci on Chromosomes (Chrs) 5, 10, and 20. Although TDTs are robust to false associations owing to hidden population substructures, it cannot distinguish segregation distortion caused by a true association between a marker and bovine spongiform encephalopathy (BSE) from a population-wide distortion. An interaction test and a segregation distortion analysis in half-sib controls were used to disentangle these two alternative hypotheses. None of the markers showed any significant interaction between allele transmission rates and disease status, and only the marker on Chr 10 showed a significant segregation distortion in control individuals. Nevertheless, the control group may have been a mixture of resistant and susceptible but unchallenged individuals. When new genotypes were generated in the vicinity of these three markers, evidence for an association with BSE was confirmed for the locus on Chr 5.

Utility of an alternative bicycle commute route of lower proximity to motorised traffic in decreasing exposure to ultra-fine particles, respiratory symptoms and airway inflammation - a structured exposure experiment

Background: Bicycle commuting in an urban environment of high air pollution is known as a potential health risk, especially for susceptible individuals. While risk management strategies aimed to reduce motorised traffic emissions exposure have been suggested, limited studies have assessed the utility of such strategies in real-world circumstances. Objectives: The potential of reducing exposure to ultrafine particles (UFP; < 0.1 µm) during bicycle commuting by lowering interaction with motorised traffic was investigated with real-time air pollution and acute inflammatory measurements in healthy individuals using their typical, and an alternative to their typical, bicycle commute route. Methods: Thirty-five healthy adults (mean ± SD: age = 39 ± 11 yr; 29% female) each completed two return trips of their typical route (HIGH) and a pre-determined altered route of lower interaction with motorised traffic (LOW; determined by the proportion of on-road cycle paths). Particle number concentration (PNC) and diameter (PD) were monitored in real-time in-commute. Acute inflammatory indices of respiratory symptom incidence, lung function and spontaneous sputum (for inflammatory cell analyses) were collected immediately pre-commute, and one and three hours post-commute. Results: LOW resulted in a significant reduction in mean PNC (1.91 x e4 ± 0.93 x e4 ppcc vs. 2.95 x e4 ± 1.50 x e4 ppcc; p ≤ 0.001). Besides incidence of in-commute offensive odour detection (42 vs. 56 %; p = 0.019), incidence of dust and soot observation (33 vs. 47 %; p = 0.038) and nasopharyngeal irritation (31 vs. 41 %; p = 0.007), acute inflammatory indices were not significantly associated to in-commute PNC, nor were these indices reduced with LOW compared to HIGH. Conclusions: Exposure to PNC, and the incidence of offensive odour and nasopharyngeal irritation, can be significantly reduced when utilising a strategy of lowering interaction with motorised traffic whilst bicycle commuting, which may bring important benefits for both healthy and susceptible individuals.

Sample selection in a model of female labour supply : an alternative approach

Suggests an alternative and computationally simpler approach of non-random sampling of labour economics and represents an observed outcome of an individual female′s choice of whether or not to participate in the labour market. Concludes that there is an alternative to the Heckman two-step estimator.

Genetic variability and antimicrobial resistance of Ureaplasma parvum in response to maternal erythromycin treatment : a study in pregnant sheep

Background: Ureaplasmas are the most frequently isolated microorganisms from the amniotic fluid (AF) of pregnant women and can cause chronic infections that are difficult to eradicate with standard macrolide treatment. We tested the effects of erythromycin treatment on phenotypic and genotypic markers of ureaplasmal antimicrobial resistance in sheep. Method: At 50 days of gestation (d, term=145d) 12 pregnant ewes received intra-amniotic injections of U. parvum serovar 3 (erythromycin-sensitive, 2x104 colony-forming-units). At 100d ewes received: erythromycin treatment (500 mg, q3h for 4 days, IM, n=6) or no treatment (n=6). Fetuses were delivered surgically (125d) and AF and chorioamnion were collected for: culture, minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC) testing; 23S rRNA sequencing; and detection of macrolide-lincosamide-streptogramin resistance (MLSr) genes. Results: MICs of erythromycin, azithromycin and roxithromycin against AF isolates were low (range = 0.06 mg/L to 1.0 mg/L); however, chorioamnion isolates demonstrated increased resistance to roxithromycin (0.13 – 5.33 mg/L). 62.5% of chorioamnion ureaplasmas formed biofilms in vitro and mutations (125 nucleotides, 29.6%) were found in the 23S rRNA gene (domain V) of chorioamnion (but not AF) ureaplasmas. MLSr genes (ermB, msrC and msrD) were detected in 100% of chorioamnion isolates and only msrD was detected in AF isolates (40%). Conclusions: 23S rRNA mutations and MLSr genes occurred independently of erythromycin treatment, suggesting that the anatomical site of infection and microenvironment may exert selective pressures on ureaplasmas that cause genetic changes and alter antimicrobial sensitivity profiles. These results have serious implications for treatment of in utero infections.

Offsetting methane emissions : an alternative to emission equivalence metrics

It is widely recognised that defining trade-offs between greenhouse gas emissions using ‘emission equivalence’ based on global warming potentials (GWPs) referenced to carbon dioxide produces anomalous results when applied to methane. The short atmospheric lifetime of methane, compared to the timescales of CO2 uptake, leads to the greenhouse warming depending strongly on the temporal pattern of emission substitution. We argue that a more appropriate way to consider the relationship between the warming effects of methane and carbon dioxide is to define a ‘mixed metric’ that compares ongoing methane emissions (or reductions) to one-off emissions (or reductions) of carbon dioxide. Quantifying this approach, we propose that a one-off sequestration of 1 t of carbon would offset an ongoing methane emission in the range 0.90–1.05 kg CH4 per year. We present an example of how our approach would apply to rangeland cattle production, and consider the broader context of mitigation of climate change, noting the reverse trade-off would raise significant challenges in managing the risk of non-compliance. Our analysis is consistent with other approaches to addressing the criticisms of GWP-based emission equivalence, but provides a simpler and more robust approach while still achieving close equivalence of climate mitigation outcomes ranging over decadal to multi-century timescales.

Alternative modes of entrepreneurial opportunity exploitation : the case on inter-organizational project

While entrepreneurship research has taken firm formation to be the predominant mode of opportunity exploitation, entrepreneurship can take place through many other types of organizational arrangements. In the present article, we consider one such alternative arrangement, namely the formation of inter-organizational projects (IOPs). We propose a multi-level contingency model that suggests that uncertainty both at the level of the firm and at the level of the environment makes the exploitation of opportunities through IOPs more likely. The model is tested by telephone survey data collected amongst a panel of 1725 SMEs and longitudinal industry data. Our findings provide strong support for the industry-level part of the model, but interestingly, only partial support for the firm level part of the model. This indicates that the effects of uncertainty need to be dissected into different levels of analysis to understand the conditions under which alternative modes of opportunity exploitation can be a prominent entrepreneurial alternative to new firm formation.

Binocular rivalry and visuospatial ability in individuals with schizophrenia

Visual abnormalities, both at the sensory input and the higher interpretive levels, have been associated with many of the symptoms of schizophrenia. Individuals with schizophrenia typically experience distortions of sensory perception, resulting in perceptual hallucinations and delusions that are related to the observed visual deficits. Disorganised speech, thinking and behaviour are commonly experienced by sufferers of the disorder, and have also been attributed to perceptual disturbances associated with anomalies in visual processing. Compounding these issues are marked deficits in cognitive functioning that are observed in approximately 80% of those with schizophrenia. Cognitive impairments associated with schizophrenia include: difficulty with concentration and memory (i.e. working, visual and verbal), an impaired ability to process complex information, response inhibition and deficits in speed of processing, visual and verbal learning. Deficits in sustained attention or vigilance, poor executive functioning such as poor reasoning, problem solving, and social cognition, are all influenced by impaired visual processing. These symptoms impact on the internal perceptual world of those with schizophrenia, and hamper their ability to navigate their external environment. Visual processing abnormalities in schizophrenia are likely to worsen personal, social and occupational functioning. Binocular rivalry provides a unique opportunity to investigate the processes involved in visual awareness and visual perception. Binocular rivalry is the alternation of perceptual images that occurs when conflicting visual stimuli are presented to each eye in the same retinal location. The observer perceives the opposing images in an alternating fashion, despite the sensory input to each eye remaining constant. Binocular rivalry tasks have been developed to investigate specific parts of the visual system. The research presented in this Thesis provides an explorative investigation into binocular rivalry in schizophrenia, using the method of Pettigrew and Miller (1998) and comparing individuals with schizophrenia to healthy controls. This method allows manipulations to the spatial and temporal frequency, luminance contrast and chromaticity of the visual stimuli. Manipulations to the rival stimuli affect the rate of binocular rivalry alternations and the time spent perceiving each image (dominance duration). Binocular rivalry rate and dominance durations provide useful measures to investigate aspects of visual neural processing that lead to the perceptual disturbances and cognitive dysfunction attributed to schizophrenia. However, despite this promise the binocular rivalry phenomenon has not been extensively explored in schizophrenia to date. Following a review of the literature, the research in this Thesis examined individual variation in binocular rivalry. The initial study (Chapter 2) explored the effect of systematically altering the properties of the stimuli (i.e. spatial and temporal frequency, luminance contrast and chromaticity) on binocular rivalry rate and dominance durations in healthy individuals (n=20). The findings showed that altering the stimuli with respect to temporal frequency and luminance contrast significantly affected rate. This is significant as processing of temporal frequency and luminance contrast have consistently been demonstrated to be abnormal in schizophrenia. The current research then explored binocular rivalry in schizophrenia. The primary research question was, "Are binocular rivalry rates and dominance durations recorded in participants with schizophrenia different to those of the controls?" In this second study binocular rivalry data that were collected using low- and highstrength binocular rivalry were compared to alternations recorded during a monocular rivalry task, the Necker Cube task to replicate and advance the work of Miller et al., (2003). Participants with schizophrenia (n=20) recorded fewer alternations (i.e. slower alternation rates) than control participants (n=20) on both binocular rivalry tasks, however no difference was observed between the groups on the Necker cube task. Magnocellular and parvocellular visual pathways, thought to be abnormal in schizophrenia, were also investigated in binocular rivalry. The binocular rivalry stimuli used in this third study (Chapter 4) were altered to bias the task for one of these two pathways. Participants with schizophrenia recorded slower binocular rivalry rates than controls in both binocular rivalry tasks. Using a ‘within subject design’, binocular rivalry data were compared to data collected from a backwardmasking task widely accepted to bias both these pathways. Based on these data, a model of binocular rivalry, based on the magnocellular and parvocellular pathways that contribute to the dorsal and ventral visual streams, was developed. Binocular rivalry rates were compared with performance on the Benton’s Judgment of Line Orientation task, in individuals with schizophrenia compared to healthy controls (Chapter 5). The Benton’s Judgment of Line Orientation task is widely accepted to be processed within the right cerebral hemisphere, making it an appropriate task to investigate the role of the cerebral hemispheres in binocular rivalry, and to investigate the inter-hemispheric switching hypothesis of binocular rivalry proposed by Pettigrew and Miller (1998, 2003). The data were suggestive of intra-hemispheric rather than an inter-hemispheric visual processing in binocular rivalry. Neurotransmitter involvement in binocular rivalry, backward masking and Judgment of Line Orientation in schizophrenia were investigated using a genetic indicator of dopamine receptor distribution and functioning; the presence of the Taq1 allele of the dopamine D2 receptor (DRD2) receptor gene. This final study (Chapter 6) explored whether the presence of the Taq1 allele of the DRD2 receptor gene, and thus, by inference the distribution of dopamine receptors and dopamine function, accounted for the large individual variation in binocular rivalry. The presence of the Taq1 allele was associated with slower binocular rivalry rates or poorer performance in the backward masking and Judgment of Line Orientation tasks seen in the group with schizophrenia. This Thesis has contributed to what is known about binocular rivalry in schizophrenia. Consistently slower binocular rivalry rates were observed in participants with schizophrenia, indicating abnormally-slow visual processing in this group. These data support previous studies reporting visual processing abnormalities in schizophrenia and suggest that a slow binocular rivalry rate is not a feature specific to bipolar disorder, but may be a feature of disorders with psychotic features generally. The contributions of the magnocellular or dorsal pathways and parvocellular or ventral pathways to binocular rivalry, and therefore to perceptual awareness, were investigated. The data presented supported the view that the magnocellular system initiates perceptual awareness of an image and the parvocellular system maintains the perception of the image, making it available to higher level processing occurring within the cortical hemispheres. Abnormal magnocellular and parvocellular processing may both contribute to perceptual disturbances that ultimately contribute to the cognitive dysfunction associated with schizophrenia. An alternative model of binocular rivalry based on these observations was proposed.

Damage diagnosis for complex steel truss bridges using multi-layer genetic algorithm

Considerate amount of research has proposed optimization-based approaches employing various vibration parameters for structural damage diagnosis. The damage detection by these methods is in fact a result of updating the analytical structural model in line with the current physical model. The feasibility of these approaches has been proven. But most of the verification has been done on simple structures, such as beams or plates. In the application on a complex structure, like steel truss bridges, a traditional optimization process will cost massive computational resources and lengthy convergence. This study presents a multi-layer genetic algorithm (ML-GA) to overcome the problem. Unlike the tedious convergence process in a conventional damage optimization process, in each layer, the proposed algorithm divides the GA’s population into groups with a less number of damage candidates; then, the converged population in each group evolves as an initial population of the next layer, where the groups merge to larger groups. In a damage detection process featuring ML-GA, as parallel computation can be implemented, the optimization performance and computational efficiency can be enhanced. In order to assess the proposed algorithm, the modal strain energy correlation (MSEC) has been considered as the objective function. Several damage scenarios of a complex steel truss bridge’s finite element model have been employed to evaluate the effectiveness and performance of ML-GA, against a conventional GA. In both single- and multiple damage scenarios, the analytical and experimental study shows that the MSEC index has achieved excellent damage indication and efficiency using the proposed ML-GA, whereas the conventional GA only converges at a local solution.