Storage - the necessity for a Smart-Grid

Energy policy is driving renewable energy deployment with most of the developed countries having some form of renewable energy portfolio standard and emissions reduction target. To deliver upon these ambitious targets, those renewable energy technologies that are commercially available, such as wind and solar, are being deployed, but inherently have issues with intermittency of supply. To overcome these issues, storage options will need to be introduced into the distribution network with benefits for both demand management and power systems quality. How this can be utilised most effectively within the distribution network will allow for an even greater proportion of our energy demand to be met through renewable resources and meet the aspirational targets set. The distribution network will become a network of smart-grids, but to work efficiently and effectively, power quality issues surrounding intermittency must be overcome, with storage being a major factor in this solution.

Robust vision-based underwater homing using self-similar landmarks

Next-generation autonomous underwater vehicles (AUVs) will be required to robustly identify underwater targets for tasks such as inspection, localization, and docking. Given their often unstructured operating environments, vision offers enormous potential in underwater navigation over more traditional methods; however, reliable target segmentation often plagues these systems. This paper addresses robust vision-based target recognition by presenting a novel scale and rotationally invariant target design and recognition routine based on self-similar landmarks that enables robust target pose estimation with respect to a single camera. These algorithms are applied to an AUV with controllers developed for vision-based docking with the target. Experimental results show that the system performs exceptionally on limited processing power and demonstrates how the combined vision and controller system enables robust target identification and docking in a variety of operating conditions.

Gene expression profiling in human breast cancer – toward personalised therapeutics?

The most integrated approach toward understanding the multiple molecular events and mechanisms by which cancer may develop is the application of gene expression profiling using microarray technologies. As molecular alterations in breast cancer are complex and involve cross-talk between multiple cellular signalling pathways, microarray technology provides a means of capturing and comparing the expression patterns of the entire genome across multiple samples in a high throughput manner. Since the development of microarray technologies, together with the advances in RNA extraction methodologies, gene expression studies have revolutionised the means by which genes suitable as targets for drug development and individualised cancer treatment can be identified. As of the mid-1990s, expression microarrays have been extensively applied to the study of cancer and no cancer type has seen as much genomic attention as breast cancer. The most abundant area of breast cancer genomics has been the clarification and interpretation of gene expression patterns that unite both biological and clinical aspects of tumours. It is hoped that one day molecular profiling will transform diagnosis and therapeutic selection in human breast cancer toward more individualised regimes. Here, we review a number of prominent microarray profiling studies focussed on human breast cancer and examine their strengths, their limitations, clinical implications including prognostic relevance and gene signature significance along with potential improvements for the next generation of microarray studies.

The association of single nucleotide polymorphisms with endometrial cancer risk and prognosis

Endometrial cancer is one of the most common female diseases in developed nations and is the most commonly diagnosed gynaecological cancer in Australia. The disease is commonly classified by histology: endometrioid or non-endometrioid endometrial cancer. While non-endometrioid endometrial cancers are accepted to be high-grade, aggressive cancers, endometrioid cancers (comprising 80% of all endometrial cancers diagnosed) generally carry a favourable patient prognosis. However, endometrioid endometrial cancer patients endure significant morbidity due to surgery and radiotherapy used for disease treatment, and patients with recurrent disease have a 5-year survival rate of less than 50%. Genetic analysis of women with endometrial cancer could uncover novel markers associated with disease risk and/or prognosis, which could then be used to identify women at high risk and for the use of specialised treatments. Proteases are widely accepted to play an important role in the development and progression of cancer. This PhD project hypothesised that SNPs from two protease gene families, the matrix metalloproteases (MMPs, including their tissue inhibitors, TIMPs) and the tissue kallikrein-related peptidases (KLKs) would be associated with endometrial cancer susceptibility and/or prognosis. In the first part of this study, optimisation of the genotyping techniques was performed. Results from previously published endometrial cancer genetic association studies were attempted to be validated in a large, multicentre replication set (maximum cases n = 2,888, controls n = 4,483, 3 studies). The rs11224561 progesterone receptor SNP (PGR, A/G) was observed to be associated with increased endometrial cancer risk (per A allele OR 1.31, 95% CI 1.12-1.53; p-trend = 0.001), a result which was initially reported among a Chinese sample set. Previously reported associations for the remaining 8 SNPs investigated for this section of the PhD study were not confirmed, thereby reinforcing the importance of validation of genetic association studies. To examine the effect of SNPs from the MMP and KLK families on endometrial cancer risk, we selected the most significantly associated MMP and KLK SNPs from genome-wide association study analysis (GWAS) to be genotyped in the GWAS replication set (cases n = 4,725, controls n = 9,803, 13 studies). The significance of the MMP24 rs932562 SNP was unchanged after incorporation of the stage 2 samples (Stage 1 per allele OR 1.18, p = 0.002; Combined Stage 1 and 2 OR 1.09, p = 0.002). The rs10426 SNP, located 3' to KLK10 was predicted by bioinformatic analysis to effect miRNA binding. This SNP was observed in the GWAS stage 1 result to exhibit a recessive effect on endometrial cancer risk, a result which was not validated in the stage 2 sample set (Stage 1 OR 1.44, p = 0.007; Combined Stage 1 and 2 OR 1.14, p = 0.08). Investigation of the regions imputed surrounding the MMP, TIMP and KLK genes did not reveal any significant targets for further analysis. Analysis of the case data from the endometrial cancer GWAS to identify genetic variation associated with cancer grade did not reveal SNPs from the MMP, TIMP or KLK genes to be statistically significant. However, the representation of SNPs from the MMP, TIMP and KLK families by the GWAS genotyping platform used in this PhD project was examined and observed to be very low, with the genetic variation of four genes (MMP23A, MMP23B, MMP28 and TIMP1) not captured at all by this technique. This suggests that comprehensive candidate gene association studies will be required to assess the role of SNPs from these genes with endometrial cancer risk and prognosis. Meta-analysis of gene expression microarray datasets curated as part of this PhD study identified a number of MMP, TIMP and KLK genes to display differential expression by endometrial cancer status (MMP2, MMP10, MMP11, MMP13, MMP19, MMP25 and KLK1) and histology (MMP2, MMP11, MMP12, MMP26, MMP28, TIMP2, TIMP3, KLK6, KLK7, KLK11 and KLK12). In light of these findings these genes should be prioritised for future targeted genetic association studies. Two SNPs located 43.5 Mb apart on chromosome 15 were observed from the GWAS analysis to be associated with increased endometrial cancer grade, results that were validated in silico in two independent datasets. One of these SNPs, rs8035725 is located in the 5' untranslated region of a MYC promoter binding protein DENND4A (Stage 1 OR 1.15, p = 9.85 x 10P -5 P, combined Stage 1 and in silico validation OR 1.13, p = 5.24 x 10P -6 P). This SNP has previously been reported to alter the expression of PTPLAD1, a gene involved in the synthesis of very long fatty acid chains and in the Rac1 signaling pathway. Meta-analysis of gene expression microarray data found PTPLAD1 to display increased expression in the aggressive non-endometrioid histology compared with endometrioid endometrial cancer, suggesting that the causal SNP underlying the observed genetic association may influence expression of this gene. Neither rs8035725 nor significant SNPs identified by imputation were predicted bioinformatically to affect transcription factor binding sites, indicating that further studies are required to assess their potential effect on other regulatory elements. The other grade- associated SNP, rs6606792, is located upstream of an inferred pseudogene, ELMO2P1 (Stage 1 OR 1.12, p = 5 x 10P -5 P; combined Stage 1 and in silico validation OR 1.09, p = 3.56 x 10P -5 P). Imputation of the ±1 Mb region surrounding this SNP revealed a cluster of significantly associated variants which are predicted to abolish various transcription factor binding sites, and would be expected to decrease gene expression. ELMO2P1 was not included on the microarray platforms collected for this PhD, and so its expression could not be investigated. However, the high sequence homology of ELMO2P1 with ELMO2, a gene important to cell motility, indicates that ELMO2 could be the parent gene for ELMO2P1 and as such, ELMO2P1 could function to regulate the expression of ELMO2. Increased expression of ELMO2 was seen to be associated with increasing endometrial cancer grade, as well as with aggressive endometrial cancer histological subtypes by microarray meta-analysis. Thus, it is hypothesised that SNPs in linkage disequilibrium with rs6606792 decrease the transcription of ELMO2P1, reducing the regulatory effect of ELMO2P1 on ELMO2 expression. Consequently, ELMO2 expression is increased, cell motility is enhanced leading to an aggressive endometrial cancer phenotype. In summary, these findings have identified several areas of research for further study. The results presented in this thesis provide evidence that a SNP in PGR is associated with risk of developing endometrial cancer. This PhD study also reports two independent loci on chromosome 15 to be associated with increased endometrial cancer grade, and furthermore, genes associated with these SNPs to be differentially expressed according in aggressive subtypes and/or by grade. The studies reported in this thesis support the need for comprehensive SNP association studies on prioritised MMP, TIMP and KLK genes in large sample sets. Until these studies are performed, the role of MMP, TIMP and KLK genetic variation remains unclear. Overall, this PhD study has contributed to the understanding of genetic variation involvement in endometrial cancer susceptibility and prognosis. Importantly, the genetic regions highlighted in this study could lead to the identification of novel gene targets to better understand the biology of endometrial cancer and also aid in the development of therapeutics directed at treating this disease.

The role of EBV-encoded microRNAs in B cell differentiation

Epstein Barr virus (EBV) is a common γ-herpes virus, infecting approximately 90% of the world‟s population. It is also one of the first known viruses known to be oncogenic, and is associated with a number of tumour types, primarily lymphomas. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and many human miRNAs have been associated with the development of malignancies including cancer. EBV was the first human virus identified to express miRNAs and encodes more than 40 miRNAs within its genome. Yet, an understanding of the targets of EBV-miRNAs, and thereby the function of them in pathogenesis remains sadly limited. This study identifies a potential novel target of EBV-miRNAs, MECP2 and characterises the miRNA:mRNA interactions between two previously identified novel targets; Bim and EBF1. In particular, this study focuses upon the interaction between EBF1 and the EBV-miRNA BART11-5p, demonstrating a 151bp region of the EBF1 3‟UTR that is capable of mediating the silencing of luciferase expression by BART11-5p but is not capable of silencing a full length EBF1-3‟UTR luciferase construct. This study provides evidence that EBF1 may be a target of one or more EBV-miRNAs.

An examination of learning design in elite springboard diving

The overarching aim of this programme of work was to evaluate the effectiveness of the existing learning environment within the Australian Institute of Sport (AIS) elite springboard diving programme. Unique to the current research programme, is the application of ideas from an established theory of motor learning, specifically ecological dynamics, to an applied high performance training environment. In this research programme springboard diving is examined as a complex system, where individual, task, and environmental constraints are continually interacting to shape performance. As a consequence, this thesis presents some necessary and unique insights into representative learning design and movement adaptations in a sample of elite athletes. The questions examined in this programme of work relate to how best to structure practice, which is central to developing an effective learning environment in a high performance setting. Specifically, the series of studies reported in the chapters of this doctoral thesis: (i) provide evidence for the importance of designing representative practice tasks in training; (ii) establish that completed and baulked (prematurely terminated) take-offs are not different enough to justify the abortion of a planned dive; and (iii), confirm that elite athletes performing complex skills are able to adapt their movement patterns to achieve consistent performance outcomes from variable dive take-off conditions. Chapters One and Two of the thesis provide an overview of the theoretical ideas framing the programme of work, and include a review of literature pertinent to the research aims and subsequent empirical chapters. Chapter Three examined the representativeness of take-off tasks completed in the two AIS diving training facilities routinely used in springboard diving. Results highlighted differences in the preparatory phase of reverse dive take-offs completed by elite divers during normal training tasks in the dry-land and aquatic training environments. The most noticeable differences in dive take-off between environments began during the hurdle (step, jump, height and flight) where the diver generates the necessary momentum to complete the dive. Consequently, greater step lengths, jump heights and flight times, resulted in greater board depression prior to take-off in the aquatic environment where the dives required greater amounts of rotation. The differences observed between the preparatory phases of reverse dive take-offs completed in the dry-land and aquatic training environments are arguably a consequence of the constraints of the training environment. Specifically, differences in the environmental information available to the athletes, and the need to alter the landing (feet first vs. wrist first landing) from the take-off, resulted in a decoupling of important perception and action information and a decomposition of the dive take-off task. In attempting to only practise high quality dives, many athletes have followed a traditional motor learning approach (Schmidt, 1975) and tried to eliminate take-off variations during training. Chapter Four examined whether observable differences existed between the movement kinematics of elite divers in the preparation phases of baulked (prematurely terminated) and completed take-offs that might justify this approach to training. Qualitative and quantitative analyses of variability within conditions revealed greater consistency and less variability when dives were completed, and greater variability amongst baulked take-offs for all participants. Based on these findings, it is probable that athletes choose to abort a planned take-off when they detect small variations from the movement patterns (e.g., step lengths, jump height, springboard depression) of highly practiced comfortable dives. However, with no major differences in coordination patterns (topology of the angle-angle plots), and the potential for negative performance outcomes in competition, there appears to be no training advantage in baulking on unsatisfactory take-offs during training, except when a threat of injury is perceived by the athlete. Instead, it was considered that enhancing the athletes' movement adaptability would be a more functional motor learning strategy. In Chapter Five, a twelve-week training programme was conducted to determine whether a sample of elite divers were able to adapt their movement patterns and complete dives successfully, regardless of the perceived quality of their preparatory movements on the springboard. The data indeed suggested that elite divers were able to adapt their movements during the preparatory phase of the take-off and complete good quality dives under more varied take-off conditions; displaying greater consistency and stability in the key performance outcome (dive entry). These findings are in line with previous research findings from other sports (e.g., shooting, triple jump and basketball) and demonstrate how functional or compensatory movement variability can afford greater flexibility in task execution. By previously only practising dives with good quality take-offs, it can be argued that divers only developed strong couplings between information and movement under very specific performance circumstances. As a result, this sample was sometimes characterised by poor performance in competition when the athletes experienced a suboptimal take-off. Throughout this training programme, where divers were encouraged to minimise baulking and attempt to complete every dive, they demonstrated that it was possible to strengthen the information and movement coupling in a variety of performance circumstances, widening of the basin of performance solutions and providing alternative couplings to solve a performance problem even when the take-off was not ideal. The results of this programme of research provide theoretical and experimental implications for understanding representative learning design and movement pattern variability in applied sports science research. Theoretically, this PhD programme contributes empirical evidence to demonstrate the importance of representative design in the training environments of high performance sports programmes. Specifically, this thesis advocates for the design of learning environments that effectively capture and enhance functional and flexible movement responses representative of performance contexts. Further, data from this thesis showed that elite athletes performing complex tasks were able to adapt their movements in the preparatory phase and complete good quality dives under more varied take-off conditions. This finding signals some significant practical implications for athletes, coaches and sports scientists. As such, it is recommended that care should be taken by coaches when designing practice tasks since the clear implication is that athletes need to practice adapting movement patterns during ongoing regulation of multi-articular coordination tasks. For example, volleyball servers can adapt to small variations in the ball toss phase, long jumpers can visually regulate gait as they prepare for the take-off, and springboard divers need to continue to practice adapting their take-off from the hurdle step. In summary, the studies of this programme of work have confirmed that the task constraints of training environments in elite sport performance programmes need to provide a faithful simulation of a competitive performance environment in order that performance outcomes may be stabilised with practice. Further, it is apparent that training environments can be enhanced by ensuring the representative design of task constraints, which have high action fidelity with the performance context. Ultimately, this study recommends that the traditional coaching adage 'perfect practice makes perfect", be reconsidered; instead advocating that practice should be, as Bernstein (1967) suggested, "repetition without repetition".

A high-throughput panel for identifying clinically relevant mutation profiles in melanoma

Success with molecular-based targeted drugs in the treatment of cancer has ignited extensive research efforts within the field of personalized therapeutics. However, successful application of such therapies is dependent on the presence or absence of mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Building on these findings, we developed a high-throughput mutation panel for the identification of frequently occurring and clinically relevant mutations in melanoma. An extensive literature search and interrogation of the Catalogue of Somatic Mutations in Cancer database identified more than 1,000 melanoma mutations. Applying a filtering strategy to focus on mutations amenable to the development of targeted drugs, we initially screened 120 known mutations in 271 samples using the Sequenom MassARRAY system. A total of 252 mutations were detected in 17 genes, the highest frequency occurred in BRAF (n = 154, 57%), NRAS (n = 55, 20%), CDK4 (n = 8, 3%), PTK2B (n = 7, 2.5%), and ERBB4 (n = 5, 2%). Based on this initial discovery screen, a total of 46 assays interrogating 39 mutations in 20 genes were designed to develop a melanoma-specific panel. These assays were distributed in multiplexes over 8 wells using strict assay design parameters optimized for sensitive mutation detection. The final melanoma-specific mutation panel is a cost effective, sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular-based therapeutics for the treatment of melanoma. When used in a clinical research setting, the panel may rapidly and accurately identify potentially effective treatment strategies using novel or existing molecularly targeted drugs

Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

Whole genome and exome sequencing of melanoma

Melanoma has historically been refractive to traditional therapeutic approaches. As such, the development of novel drug strategies has been needed to improve rates of overall survival in patients with melanoma, particularly those with late stage or disseminated disease. Recent success with molecularly based targeted drugs, such as Vemurafenib in BRAF-mutant melanomas, has now made “personalized medicine” a reality within some oncology clinics. In this sense, tailored drugs can be administered to patients according to their tumor “mutation profiles.” The success of these drug strategies, in part, can be attributed to the identification of the genetic mechanisms responsible for the development and progression of metastatic melanoma. Recently, the advances in sequencing technology have allowed for comprehensive mutation analysis of tumors and have led to the identification of a number of genes involved in the etiology of metastatic melanoma. As the methodology and costs associated with next-generation sequencing continue to improve, this technology will be rapidly adopted into routine clinical oncology practices and will significantly impact on personalized therapy. This review summarizes current and emerging molecular targets in metastatic melanoma, discusses the potential application of next-generation sequencing within the paradigm of personalized medicine, and describes the current limitations for the adoption of this technology within the clinic.

Timed Probabilistic Automaton : a bridge between Raven and Song Scope for automatic species recognition

Raven and Song Scope are two automated sound anal-ysis tools based on machine learning technique for en-vironmental monitoring. Many research works have been conducted upon them, however, no or rare explo-ration mentions about the performance and comparison between them. This paper investigates the comparisons from six aspects: theory, software interface, ease of use, detection targets, detection accuracy, and potential application. Through deep exploration one critical gap is identified that there is a lack of approach to detect both syllables and call structures, since Raven only aims to detect syllables while Song Scope targets call structures. Therefore, a Timed Probabilistic Automata (TPA) system is proposed which separates syllables first and clusters them into complex structures after.

A cross-discipline and collaborative approach to identifying the predictors of environmentally friendly and health protective behaviour

Background. As a society, our interaction with the environment is having a negative impact on human health. For example, an increase in car use for short trips, over walking or cycling, has contributed to an increase in obesity, diabetes and poor heart health and also contributes to pollution, which is associated with asthma and other respiratory diseases. In order to change the nature of that interaction, to be more positive and healthy, it is recommended that individuals adopt a range of environmentally friendly behaviours (such as walking for transport and reducing the use of plastics). Effective interventions aimed at increasing such behaviours will need to be evidence based and there is a need for the rapid communication of information from the point of research, into policy and practice. Further, a number of health disciplines, including psychology and public health, share a common mission to promote health and well-being. Therefore, the objective of this project is to take a cross-discipline and collaborative approach to reveal psychological mechanisms driving environmentally friendly behaviour. This objective is further divided into three broad aims, the first of which is to take a cross-discipline and collaborative approach to research. The second aim is to explore and identify the salient beliefs which most strongly predict environmentally friendly behaviour. The third aim is to build an augmented model to explain environmentally friendly behaviour. The thesis builds on the understanding that an interdisciplinary collaborative approach will facilitate the rapid transfer of knowledge to inform behaviour change interventions. Methods. The application of this approach involved two surveys which explored the psycho-social predictors of environmentally friendly behaviour. Following a qualitative pilot study, and in collaboration with an expert panel comprising academics, industry professionals and government representatives, a self-administered, Theory of Planned Behaviour (TPB) based, mail survey was distributed to a random sample of 3000 residents of Brisbane and Moreton Bay Region (Queensland, Australia). This survey explored specific beliefs including attitudes, norms, perceived control, intention and behaviour, as well as environmental altruism and green identity, in relation to walking for transport and switching off lights when not in use. Following analysis of the mail survey data and based on feedback from participants and key stakeholders, an internet survey was employed (N=451) to explore two additional behaviours, switching off appliances at the wall when not in use, and shopping with reusable bags. This work is presented as a series of interrelated publications which address each of the research aims. Presentation of Findings. Chapter five of this thesis consists of a published paper which addresses the first aim of the research and outlines the collaborative and multidisciplinary approach employed in the mail survey. The paper argued that forging alliances with those who are in a position to immediately utilise the findings of research has the potential to improve the quality and timely communication of research. Illustrating this timely communication, Chapter six comprises a report presented to Moreton Bay Regional Council (MBRC). This report addresses aim's one and two. The report contains a summary of participation in a range of environmentally friendly behaviours and identifies the beliefs which most strongly predicted walking for transport and switching off lights (from the mail survey). These salient beliefs were then recommended as targets for interventions and included: participants believing that they might save money; that their neighbours also switch off lights; that it would be inconvenient to walk for transport and that their closest friend also walks for transport. Chapter seven also addresses the second aim and presents a published conference paper in which the salient beliefs predicting the four specified behaviours (from both surveys) are identified and potential applications for intervention are discussed. Again, a range of TPB based beliefs, including descriptive normative beliefs, were predictive of environmentally friendly behaviour. This paper was also provided to MBRC, along with recommendations for applying the findings. For example, as descriptive normative beliefs were consistently correlated with environmentally friendly behaviour, local councils could engage in marketing and interventions (workshops, letter box drops, internet promotions) which encourage parents and friends to model, rather than simply encourage, environmentally friendly behaviour. The final two papers, presented in Chapters eight and nine, addresses the third aim of the project. These papers each present two behaviours together to inform a TPB based theoretical model with which to predict environmentally friendly behaviour. A generalised model is presented, which is found to predict the four specific behaviours under investigation. The role of demographics was explored across each of the behaviour specific models. It was found that some behaviour's differ by age, gender, income or education. In particular, adjusted models predicted more of the variance in walking for transport amongst younger participants and females. Adjusted models predicted more variance in switching off lights amongst those with a bachelor degree or higher and predicted more variance in switching off appliances amongst those on a higher income. Adjusted models predicted more variance in shopping with reusable bags for males, people 40 years or older, those on a higher income and those with a bachelor degree or higher. However, model structure and general predictability was relatively consistent overall. The models provide a general theoretical framework from which to better understand the motives and predictors of environmentally friendly behaviour. Conclusion. This research has provided an example of the benefits of a collaborative interdisciplinary approach. It has identified a number of salient beliefs which can be targeted for social marketing campaigns and educational initiatives; and these findings, along with recommendations, have been passed on to a local council to be used as part of their ongoing community engagement programs. Finally, the research has informed a practical model, as well as behaviour specific models, for predicting sustainable living behaviours. Such models can highlight important core constructs from which targeted interventions can be designed. Therefore, this research represents an important step in undertaking collaborative approaches to improving population health through human-environment interactions.