Melanoma cell invasiveness is regulated by miR-211 suppression of the BRN2 transcription factor

To identify microRNAs potentially involved in melanomagenesis, we compared microRNA expression profiles between melanoma cell lines and cultured melanocytes. The most differentially expressed microRNA between the normal and tumor cell lines was miR-211. We focused on this pigment-cell-enriched miRNA as it is derived from the microphthalmia-associated transcription factor (MITF)-regulated gene, TRPM1 (melastatin). We find that miR-211 expression is greatly decreased in melanoma cells and melanoblasts compared to melanocytes. Bioinformatic analysis identified a large number of potential targets of miR-211, including POU3F2 (BRN2). Inhibition of miR-211 in normal melanocytes resulted in increased BRN2 protein, indicating that endogenous miR-211 represses BRN2 in differentiated cells. Over-expression of miR-211 in melanoma cell lines changed the invasive potential of the cells in vitro through directly targeting BRN2 translation. We propose a model for the apparent non-overlapping expression levels of BRN2 and MITF in melanoma, mediated by miR-211 expression.

Safety, feasibility and effects of an individualised walking intervention for women undergoing chemotherapy for ovarian cancer : a pilot study

Background: Exercise interventions during adjuvant cancer therapy have been shown to increase functional capacity, relieve fatigue and distress and may assist rates of chemotherapy completion. These studies have been limited to breast, gastric and mixed cancer groups and it is not yet known if a similar intervention is even feasible among women with ovarian cancer. We aimed to assess safety, feasibility and potential effect of a walking intervention in women undergoing chemotherapy for ovarian cancer. Methods: Women newly diagnosed with ovarian cancer were recruited to participate in an individualised walking intervention throughout chemotherapy and were assessed pre-and post-intervention. Feasibility measures included session adherence, compliance with exercise physiologist prescribed walking targets and self-reported program acceptability. Changes in objective physical functioning (6 minute walk test), self-reported distress (Hospital Anxiety and Depression Scale), symptoms (Memorial Symptom Assessment Scale - Physical) and quality of life (Functional Assessment of Cancer Therapy - Ovarian) were calculated, and chemotherapy completion and adverse intervention effects recorded. Results: Seventeen women were enrolled (63% recruitment rate). Mean age was 60 years (SD = 8 years), 88% were diagnosed with FIGO stage III or IV disease, 14 women underwent adjuvant and three neo-adjuvant chemotherapy. On average, women adhered to > 80% of their intervention sessions and complied with 76% of their walking targets, with the majority walking four days a week at moderate intensity for 30 minutes per session. Meaningful improvements were found in physical functioning, physical symptoms, physical well-being and ovarian cancerspecific quality of life. Most women (76%) completed ≥85% of their planned chemotherapy dose. There were no withdrawals or serious adverse events and all women reported the program as being helpful. Conclusions: These positive preliminary results suggest that this walking intervention for women receiving chemotherapy for ovarian cancer is safe, feasible and acceptable and could be used in development of future work. Trial registration: ACTRN12609000252213

Acoustic component detection for automatic species recognition in environmental monitoring

Automatic species recognition plays an important role in assisting ecologists to monitor the environment. One critical issue in this research area is that software developers need prior knowledge of specific targets people are interested in to build templates for these targets. This paper proposes a novel approach for automatic species recognition based on generic knowledge about acoustic events to detect species. Acoustic component detection is the most critical and fundamental part of this proposed approach. This paper gives clear definitions of acoustic components and presents three clustering algorithms for detecting four acoustic components in sound recordings; whistles, clicks, slurs, and blocks. The experiment result demonstrates that these acoustic component recognisers have achieved high precision and recall rate.

Self-Government and the fashioning of resilient personae : legal education, criminal justice, and the government of mental health

This paper explores attempts to shape resilient personae through relations of self-government, and highlights the way that this features as part of advanced liberal forms of rule. As an example of this process, it focuses on the way that undergraduate law students are encouraged to fashion resilient personae throughout their legal studies, so as to avoid, or effectively respond to, experiences that may have a detrimental effect on their mental health. This paper argues that the production of such resilience relies on students being encouraged to take up psychologically- and biomedically-infused subject positions, becoming well-disciplined subjects, entrepreneurs of the self, and even virtuous persons. It highlights that the fashioning of resilient personae in this way involves extensions to the targets and practices of self-government and reinforces advanced liberal government. The paper then suggests how insights into fashioning resilience in this context can inform further research on resilience, particularly resilience produced within criminal justice professionals.

National Environmental Law Review Issue 2011: 3, Editorial: Federal Developments

Clean Energy Agreement of the MPCCC On 10 July 2011, details of the Multi-Party Climate Change Committee’s Clean Energy Agreement for implementing a carbon price were released. This included an agreed package of measures that the Committee considered would enable Australia to meet its emissions reduction targets in an environmentally and economically efficient way. A copy of the agreement can be found on the website of the Department of Climate Change and Energy Efficiency...

Autonomous aerial navigation and tracking of marine animals

In this paper, we describe the development of an independent and on-board visual servoing system which allows a computationally impoverished aerial vehicle to autonomously identify and track a moving surface target. Our image segmentation and target identification algorithms were developed with the specific task of monitoring whales at sea but could be adapted for other targets. Observing whales is important for many marine biology tasks and is currently performed manually from the shore or from boats. We also present hardware experiments which demonstrate the capabilities of our algorithms for object identification and tracking that enable a flying vehicle to track a moving target.

A randomized trial of a telephone-delivered exercise intervention for non-urban dwelling women newly diagnosed with breast cancer : exercise for health

Physical activity is important following breast cancer. Trials of non-face-to-face interventions are needed to assist in reaching women living outside major metropolitan areas. This study seeks to evaluate the feasibility and effectiveness of a telephone-delivered, mixed aerobic and resistance exercise intervention for non-urban Australian women with breast cancer. A randomized controlled trial comparing an 8-month intervention delivered by exercise physiologists (n = 73) to usual care (n = 70). Sixty-one percent recruitment rate and 96% retention at 12 months; 79% of women in the intervention group received at least 75% of calls; odds (OR, 95% CI) of meeting intervention targets favored the intervention group for resistance training (OR 3.2; 1.2, 8.9) and aerobic (OR 2.1; 0.8, 5.5) activity. Given the limited availability of physical activity programs for non-urban women with breast cancer, results provide strong support for feasibility and modest support for the efficacy of telephone-delivered interventions.

Application of operations research techniques to improve efficiency in the emergency department

The main aim of this thesis is to analyse and optimise a public hospital Emergency Department. The Emergency Department (ED) is a complex system with limited resources and a high demand for these resources. Adding to the complexity is the stochastic nature of almost every element and characteristic in the ED. The interaction with other functional areas also complicates the system as these areas have a huge impact on the ED and the ED is powerless to change them. Therefore it is imperative that OR be applied to the ED to improve the performance within the constraints of the system. The main characteristics of the system to optimise included tardiness, adherence to waiting time targets, access block and length of stay. A validated and verified simulation model was built to model the real life system. This enabled detailed analysis of resources and flow without disruption to the actual ED. A wide range of different policies for the ED and a variety of resources were able to be investigated. Of particular interest was the number and type of beds in the ED and also the shift times of physicians. One point worth noting was that neither of these resources work in isolation and for optimisation of the system both resources need to be investigated in tandem. The ED was likened to a flow shop scheduling problem with the patients and beds being synonymous with the jobs and machines typically found in manufacturing problems. This enabled an analytic scheduling approach. Constructive heuristics were developed to reactively schedule the system in real time and these were able to improve the performance of the system. Metaheuristics that optimised the system were also developed and analysed. An innovative hybrid Simulated Annealing and Tabu Search algorithm was developed that out-performed both simulated annealing and tabu search algorithms by combining some of their features. The new algorithm achieves a more optimal solution and does so in a shorter time.

Rational design of serine protease inhibitors

Proteases regulate a spectrum of diverse physiological processes, and dysregulation of proteolytic activity drives a plethora of pathological conditions. Understanding protease function is essential to appreciating many aspects of normal physiology and progression of disease. Consequently, development of potent and specific inhibitors of proteolytic enzymes is vital to provide tools for the dissection of protease function in biological systems and for the treatment of diseases linked to aberrant proteolytic activity. The studies in this thesis describe the rational design of potent inhibitors of three proteases that are implicated in disease development. Additionally, key features of the interaction of proteases and their cognate inhibitors or substrates are analysed and a series of rational inhibitor design principles are expounded and tested. Rational design of protease inhibitors relies on a comprehensive understanding of protease structure and biochemistry. Analysis of known protease cleavage sites in proteins and peptides is a commonly used source of such information. However, model peptide substrate and protein sequences have widely differing levels of backbone constraint and hence can adopt highly divergent structures when binding to a protease’s active site. This may result in identical sequences in peptides and proteins having different conformations and diverse spatial distribution of amino acid functionalities. Regardless of this, protein and peptide cleavage sites are often regarded as being equivalent. One of the key findings in the following studies is a definitive demonstration of the lack of equivalence between these two classes of substrate and invalidation of the common practice of using the sequences of model peptide substrates to predict cleavage of proteins in vivo. Another important feature for protease substrate recognition is subsite cooperativity. This type of cooperativity is commonly referred to as protease or substrate binding subsite cooperativity and is distinct from allosteric cooperativity, where binding of a molecule distant from the protease active site affects the binding affinity of a substrate. Subsite cooperativity may be intramolecular where neighbouring residues in substrates are interacting, affecting the scissile bond’s susceptibility to protease cleavage. Subsite cooperativity can also be intermolecular where a particular residue’s contribution to binding affinity changes depending on the identity of neighbouring amino acids. Although numerous studies have identified subsite cooperativity effects, these findings are frequently ignored in investigations probing subsite selectivity by screening against diverse combinatorial libraries of peptides (positional scanning synthetic combinatorial library; PS-SCL). This strategy for determining cleavage specificity relies on the averaged rates of hydrolysis for an uncharacterised ensemble of peptide sequences, as opposed to the defined rate of hydrolysis of a known specific substrate. Further, since PS-SCL screens probe the preference of the various protease subsites independently, this method is inherently unable to detect subsite cooperativity. However, mean hydrolysis rates from PS-SCL screens are often interpreted as being comparable to those produced by single peptide cleavages. Before this study no large systematic evaluation had been made to determine the level of correlation between protease selectivity as predicted by screening against a library of combinatorial peptides and cleavage of individual peptides. This subject is specifically explored in the studies described here. In order to establish whether PS-SCL screens could accurately determine the substrate preferences of proteases, a systematic comparison of data from PS-SCLs with libraries containing individually synthesised peptides (sparse matrix library; SML) was carried out. These SML libraries were designed to include all possible sequence combinations of the residues that were suggested to be preferred by a protease using the PS-SCL method. SML screening against the three serine proteases kallikrein 4 (KLK4), kallikrein 14 (KLK14) and plasmin revealed highly preferred peptide substrates that could not have been deduced by PS-SCL screening alone. Comparing protease subsite preference profiles from screens of the two types of peptide libraries showed that the most preferred substrates were not detected by PS SCL screening as a consequence of intermolecular cooperativity being negated by the very nature of PS SCL screening. Sequences that are highly favoured as result of intermolecular cooperativity achieve optimal protease subsite occupancy, and thereby interact with very specific determinants of the protease. Identifying these substrate sequences is important since they may be used to produce potent and selective inhibitors of protolytic enzymes. This study found that highly favoured substrate sequences that relied on intermolecular cooperativity allowed for the production of potent inhibitors of KLK4, KLK14 and plasmin. Peptide aldehydes based on preferred plasmin sequences produced high affinity transition state analogue inhibitors for this protease. The most potent of these maintained specificity over plasma kallikrein (known to have a very similar substrate preference to plasmin). Furthermore, the efficiency of this inhibitor in blocking fibrinolysis in vitro was comparable to aprotinin, which previously saw clinical use to reduce perioperative bleeding. One substrate sequence particularly favoured by KLK4 was substituted into the 14 amino acid, circular sunflower trypsin inhibitor (SFTI). This resulted in a highly potent and selective inhibitor (SFTI-FCQR) which attenuated protease activated receptor signalling by KLK4 in vitro. Moreover, SFTI-FCQR and paclitaxel synergistically reduced growth of ovarian cancer cells in vitro, making this inhibitor a lead compound for further therapeutic development. Similar incorporation of a preferred KLK14 amino acid sequence into the SFTI scaffold produced a potent inhibitor for this protease. However, the conformationally constrained SFTI backbone enforced a different intramolecular cooperativity, which masked a KLK14 specific determinant. As a consequence, the level of selectivity achievable was lower than that found for the KLK4 inhibitor. Standard mechanism inhibitors such as SFTI rely on a stable acyl-enzyme intermediate for high affinity binding. This is achieved by a conformationally constrained canonical binding loop that allows for reformation of the scissile peptide bond after cleavage. Amino acid substitutions within the inhibitor to target a particular protease may compromise structural determinants that support the rigidity of the binding loop and thereby prevent the engineered inhibitor reaching its full potential. An in silico analysis was carried out to examine the potential for further improvements to the potency and selectivity of the SFTI-based KLK4 and KLK14 inhibitors. Molecular dynamics simulations suggested that the substitutions within SFTI required to target KLK4 and KLK14 had compromised the intramolecular hydrogen bond network of the inhibitor and caused a concomitant loss of binding loop stability. Furthermore in silico amino acid substitution revealed a consistent correlation between a higher frequency of formation and the number of internal hydrogen bonds of SFTI-variants and lower inhibition constants. These predictions allowed for the production of second generation inhibitors with enhanced binding affinity toward both targets and highlight the importance of considering intramolecular cooperativity effects when engineering proteins or circular peptides to target proteases. The findings from this study show that although PS-SCLs are a useful tool for high throughput screening of approximate protease preference, later refinement by SML screening is needed to reveal optimal subsite occupancy due to cooperativity in substrate recognition. This investigation has also demonstrated the importance of maintaining structural determinants of backbone constraint and conformation when engineering standard mechanism inhibitors for new targets. Combined these results show that backbone conformation and amino acid cooperativity have more prominent roles than previously appreciated in determining substrate/inhibitor specificity and binding affinity. The three key inhibitors designed during this investigation are now being developed as lead compounds for cancer chemotherapy, control of fibrinolysis and cosmeceutical applications. These compounds form the basis of a portfolio of intellectual property which will be further developed in the coming years.

Bridge to field experience

The DVD targets identified concerns of culturally and linguistically diverse pre-service teachers in relation to their field experience placements in Australian sites. It provides specific information to support them in learning about the culture of school plus expected roles and responsibilities of pre-service teachers in the classroom. The five episodes of the DVD include the authentic voices of pre-service teachers and supervising teachers, addressing the various aspects of field experience that concern them most. This resource could be used by both undergraduate and post-graduate pre-service teachers, staff involved in teaching field experience units, university liaison academics who work with culturally and linguistically diverse pre-service teachers, supervising teachers in sites and staff in the Field Experience Office who place pre-service teachers in sites.

The role of anxiety and perspective-taking strategy on affective empathic responses

Empathy is an important pro-social behaviour critical to a positive clientetherapist relationship. Therapist anxiety has been linked to reduced ability to empathise and lower client satisfaction with therapy. However, the nature of the relationship between anxiety and empathy is currently unclear. The current study investigated the effect of experimentally-induced anxiety on empathic responses elicited during three different perspective-taking tasks. Perspective-taking was manipulated within-subjects with all participants (N¼ 52) completing imagine-self, imagine-other and objective conditions. A threat of shock manipulation was used to vary anxiety between-subjects. Participants in the threat of shock condition reported higher levels of anxiety during the experiment and lower levels of empathyrelated distress for the targets than participants in the control condition. Perspective-taking was associated with higher levels of empathy-related distress and concern compared to the objective condition. The present results suggest that perspective-taking can to a large extent mitigate the influence of heightened anxiety on an individual’s ability to empathise.

A process evaluation of a comprehensive school based injury prevention program

A process evaluation enables understanding of critical issues that can inform the improved, ongoing implementation of an intervention program. This study describes the process evaluation of a comprehensive, multi-level injury prevention program for adolescents. The program targets change in injury associated with violence, transport and alcohol risks and incorporates two primary elements: an 8-week, teacher delivered attitude and behaviour change curriculum for Grade 8 students; and a professional development program for teachers on school level methods of protection, focusing on strategies to increase students’ connectedness to school.

The influence of culture on safety : culture, organisational culture and safety culture

Transport and Storage Sector - Identified as one of 4 primary targets in the National Occupational Health and Safety Strategy 2002-2012 (NOHSS) The Heavy Vehicle Industry -80% of the freight task -29% of the employees in Transport and Storage 5 years on: -Transport and Storage - 22% reduction -Heavy Vehicle Industry - only an 11% reduction Intervention strategies that aren’t targeted to a specific audience may have differing levels of success due to cultural beliefs and values (McLeroy et al., 1994) Research Goal: - To explore the influence of culture on safety in the heavy vehicle industry

Visual acuity with astigmatic blur

Abstract Purpose: To determine how high and low contrast visual acuities are affected by blur caused by crossed-cylinder lenses. Method: Crossed-cylinder lenses of power zero (no added lens), +0.12 DS/-0.25 DC, +0.25 DS/-0.50 DC and +0.37/-0.75 DC were placed over the correcting lenses of the right eyes of eight subjects. Negative cylinder axes used were 15-180 degrees in 15 degree step for the two higher crossed-cylinders and 30-180 degrees in 30 degree steps for the lowest crossed cylinder. Targets were single lines of letters based on the Bailey-Lovie chart. Successively smaller lines were read until the subject could not read any of the letters correctly. Two contrasts were used: high (100%) and low (10%). The screen luminance of 100 cd/m2, together with the room lighting, gave pupil sizes of 4.5 to 6 mm. Results: High contrast visual acuities were better than low contrast visual acuities by 0.1 to 0.2 log unit (1 to 2 chart lines) for the no added lens condition. Based on comparing the average of visual acuities for the 0.75 D crossed-cylinder with the best visual acuity for a given contrast and subject, the rates of change of visual acuity per unit blur strength were similar for high contrast (0.34± 0.05 logMAR/D) and low contrast (0.37± 0.09 logMAR/D). There were considerable asymmetry effects, with the average loss in visual acuity across the two contrasts and the 0.50D/0.75 D crossed-cylinders doubling between the 165± and 60± negative cylinder axes. The loss of visual acuity with 0.75 D crossed-cylinders was approximately twice times that occurring for defocus of the same blur strength. Conclusion: Small levels of crossed-cylinder blur (≤0.75D) produce losses in visual acuity that are dependent on the cylinder axis. 0.75 D crossed-cylinders produce losses in visual acuity that are twice those produced by defocus of the same blur strength.

Influence of field size on pupil diameter under photopic and mesopic light levels

Purpose: We investigated the interaction between adapting field size and luminance on pupil diameter when cones alone (photopic) or rods and cones (mesopic) were active. Method: Circular achromatic targets (1o to 24o diameter) were presented to eight young participants on a rectangular projector screen. The accommodative influence on pupil diameter was minimized using cycloplegia in the fixing right eye and the consensual pupil reflex was measured in the left eye. Target luminance was adjusted for each stimulus such that corneal flux density (product of field area and luminance) was constant at 3600 cd.deg2m-2 (photopic condition) and 1.49 cd.deg2m-2 (mesopic condition). Results: There were no statistically significant effects of adaptive field size on pupil diameter for either condition. Conclusion: If corneal flux density is kept constant, there will be no change in pupil diameter as the size of the stimulus field increases at either mesopic or photopic lighting levels up to at least 24°.