Differential Regulation of Clusterin Isoforms by the Androgen Receptor

Clusterin (CLU) was initially reported as an androgen-repressed gene which is now shown to be an androgen-regulated ATP-independent cytoprotective molecular chaperone. CLU binds to a wide variety of client proteins to potently inhibit stress-induced protein aggregation and chaperone or stabilise conformations of proteins at times of cell stress. CLU is an enigmatic protein, being ascribed both pro- and anti-apoptotic roles. Recent evidence has shown that both secreted (sCLU) and nuclear (nCLU) isoforms can be produced, and that protein function is dependent on the sub-cellular localisation. We and others have shown that sCLU is cytoprotective, while nCLU is pro-apoptotic. It now seems likely that the apparently dichotomous functions of CLU result from the expression of different but related CLU isoforms and splice variants, and that cell survival depends in part on the relative expression of pro- versus anti-apoptotic CLU proteins. In cancer cells, increased sCLU expression is associated with increased resistance to apoptotic triggers and treatment resistance. CLU is a stress-induced protein upregulated after apoptotic triggers like androgen ablation and chemotherapy. Treatment strategies targeting stress-associated increases in sCLU expression enhance treatment-induced apoptosis and delay the emergence of androgen independence. Differential regulation of CLU isoforms and splice variants by androgens may be a pathway whereby cancer cells develop treatment resistance and evade apoptosis.

Phosphodiesterase PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

Background and purpose Phosphodiesterases PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1μM) or PDE4 inhibitor rolipram (1-10μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1Hz. The effects of (-)-noradrenaline, mediated through β1-adrenoceptors (β2-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2-adrenoceptors (β1-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s. Key results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P=0.037) of the positive inotropic effects of (-)-adrenaline (0.78±0.12 log units) than (-)-noradrenaline (0.47±0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1- and β2-adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2-adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.

Terms of engagement : consensus or control in remote Australian resource management?

Public engagement is a defining feature of collaborative approaches to environmental management (Petts 2006, Whelan and Oliver 2005). Public engagement in this context is focused on incorporating residents and communities of interest in activities like ecological restoration, catchment management, and environmental conservation in a wide range of situations (Nelson and Pettit 2004, Petts 2007). Some authors consider public engagement to be a sign of healthy democratic functioning in society (Skocpol and Fiorina 1999). Others draw attention to overcoming widely noted practical limitations of top-down mechanisms, emphasising that public engagement results in programs being implemented more effectively (Broderick 2005, Leach et al. 1999).

One tune, three dances : using a traumatic stress framework to understand trauma survivors as networked news sources

Newman and Nelson (2012) describe three ‘dances’ to explain the vacillating psychological states of trauma survivors: the dance of approach and avoidance; the dance of fragmentation and integration; and the dance of resilience and vulnerability. The first pair of seemingly opposite responses describes how survivors at times cope by ‘approaching’ the trauma, for example by gathering information about what happened; whilst at other times, the same person will cope by ‘avoiding’ the trauma by engaging in activities which distract them from the memory of the trauma or having to deal with the consequences of it. The ‘dance’ of fragmentation and integration describes the opposing individual or group experiences encountered after traumas or disasters. Individuals may experience fragmentation, or emotional disconnection, from the trauma as an adaptive means of survival. The ‘dance’ of resilience and vulnerability refers to an individual’s ability to ‘process’ trauma and return to a resilient state in which they re-learn to trust people and the world around them and ‘bounce back’ to a state of being resilient again. This paper will illustrate how an understanding of the three dances can be used to enable survivors of child sexual assault to engage with the media to tell their stories. I will give current examples from six months of journalism research, collaboration and writing of a series of news stories and features which broke an exclusive story simultaneously in The Australian and The Times in London during 2013.

Establishing a framework for transforming student engagement, success and retention in higher education institutions [Final Report]

The perennial issues of student engagement, success and retention (SESR) in higher education continue to attract attention as key indicators of learning and teaching quality. This project aimed to establish and provide a holistic framework that would allow higher education institutions (HEIs) manage and improve their student engagement and retention strategies and programs. The framework and main project deliverable is a Maturity Model (MM) for Student Engagement, Success and Retention (SESR-MM). The project involved three Australian universities with experience and reputations in SESR activities: Queensland University of Technology (lead institution), the University of Queensland and Griffith University, working cooperatively to develop and trial the project deliverables. Project findings suggest that the SESR-MM has the potential to positively transform the holistic—academic, social and personal—engagement experiences of students in Australian universities, and that the SESR-MM is a useful mechanism for sharing good practice and improving programs designed to enhance the student experience.

Stimulating organizational ingenuity with design methods

Organizations invest in ways to stimulate new ideas for new products and services for the benefit of the organization, engaging in tournaments and competitions to generate new ideas or to combine existing ideas in new ways for new products and services (Terweisch and Uhlrich, 2009). Specifically, some large companies have developed platforms for posting intractable problems to tap into the ideas and problem solving abilities of a broader range of people (Huston and Sakkab, 2006; Morgan and Wang, 2010), and to develop new and elegant solutions often in an open innovation approach (Chesbrough, 2003). The notion of ingenuity is often applied to individuals who create innovative solutions in situations of constraint, where ingenuity in the form of elegant solutions can be understood as one form of resourcefulness (Young, 2011). However, the notion of organizational ingenuity locates ingenuity more centrally to an organization's strategic decision making and implementation, embedding ingenuity into the company's culture. Studies of organizations displaying ingenuity indicate a range of possibilities from extreme ingenuity (Baker and Nelson, 2005) to less dramatic but substantial changes (Thomke, 2003), sometimes in an experimental phase or as part of a move towards a new and distinct identity for ongoing innovation.

Paracrine interactions between LNCaP prostate cancer cells and bioengineered bone in 3D in vitro culture reflect molecular changes during bone metastasis

As microenvironmental factors such as three-dimensionality and cell–matrix interactions are increasingly being acknowledged by cancer biologists, more complex 3D in vitro models are being developed to study tumorigenesis and cancer progression. To better understand the pathophysiology of bone metastasis, we have established and validated a 3D indirect co-culture model to investigate the paracrine interactions between prostate cancer (PCa) cells and human osteoblasts. Co-culture of the human PCa, LNCaP cells embedded within polyethylene glycol hydrogels with human osteoblasts in the form of a tissue engineered bone construct (TEB), resulted in reduced proliferation of LNCaP cells. LNCaP cells in both monoculture and co-culture were responsive to the androgen analog, R1881, as indicated by an increase in the expression (mRNA and/or protein induction) of androgen-regulated genes including prostate specific antigen and fatty acid synthase. Microarray gene expression analysis further revealed an up-regulation of bone markers and other genes associated with skeletal and vasculature development and a significant activation of transforming growth factor β1 downstream genes in LNCaP cells after co-culture with TEB. LNCaP cells co-cultured with TEB also unexpectedly showed similar changes in classical androgen-responsive genes under androgen-deprived conditions not seen in LNCaP monocultures. The molecular changes of LNCaP cells after co-culturing with TEBs suggest that osteoblasts exert a paracrine effect that may promote osteomimicry and modulate the expression of androgen-responsive genes in LNCaP cells. Taken together, we have presented a novel 3D in vitro model that allows the study of cellular and molecular changes occurring in PCa cells and osteoblasts that are relevant to metastatic colonization of bone. This unique in vitro model could also facilitate cancer biologists to dissect specific biological hypotheses via extensive genomic or proteomic assessments to further our understanding of the PCa-bone crosstalk.

The first year experience : looking back to inform the future

The importance of the first year experience (FYE) to success at university has been a focus of attention in the Australian higher education sector since the 1990s. For students a successful transition into university during their first year is now regarded as crucial for student engagement, success and retention. In this review we summarise a decade of research into FYE in the Australasian context. We draw on the findings arising from this comprehensive review of FYE programs and practices to describe FYE trends through the dual lenses of the first year curriculum principles and the generational approach to FYE initiatives. We contend that the generational approach to conceptualising the FYE and first year student engagement has made a useful but limited contribution to our understanding of the first year experience. Acknowledging the criticality of student engagement in a successful FYE, we propose an alternative— the Student Engagement Success and Retention Maturity Model (SESR-MM)— as a sophisticated vehicle for achieving whole-of-institution approaches to the FYE. The SESR-MM embodies the aspirations and characteristics of the transition pedagogy, highlights the need for institutional level evaluation of the FYE, focuses attention on the capacity of institutions to mobilise for first year student engagement, and importantly builds on the generational approach to allow an assessment of institutional capacity to initiate, plan, manage, evaluate and review institutional FYE practices.

STI-GMaS : an open-source environment for simulation of sexually-transmitted infections

Background Sexually-transmitted pathogens often have severe reproductive health implications if treatment is delayed or absent, especially in females. The complex processes of disease progression, namely replication and ascension of the infection through the genital tract, span both extracellular and intracellular physiological scales, and in females can vary over the distinct phases of the menstrual cycle. The complexity of these processes, coupled with the common impossibility of obtaining comprehensive and sequential clinical data from individual human patients, makes mathematical and computational modelling valuable tools in developing our understanding of the infection, with a view to identifying new interventions. While many within-host models of sexually-transmitted infections (STIs) are available in existing literature, these models are difficult to deploy in clinical/experimental settings since simulations often require complex computational approaches. Results We present STI-GMaS (Sexually-Transmitted Infections – Graphical Modelling and Simulation), an environment for simulation of STI models, with a view to stimulating the uptake of these models within the laboratory or clinic. The software currently focuses upon the representative case-study of Chlamydia trachomatis, the most common sexually-transmitted bacterial pathogen of humans. Here, we demonstrate the use of a hybrid PDE–cellular automata model for simulation of a hypothetical Chlamydia vaccination, demonstrating the effect of a vaccine-induced antibody in preventing the infection from ascending to above the cervix. This example illustrates the ease with which existing models can be adapted to describe new studies, and its careful parameterisation within STI-GMaS facilitates future tuning to experimental data as they arise. Conclusions STI-GMaS represents the first software designed explicitly for in-silico simulation of STI models by non-theoreticians, thus presenting a novel route to bridging the gap between computational and clinical/experimental disciplines. With the propensity for model reuse and extension, there is much scope within STI-GMaS to allow clinical and experimental studies to inform model inputs and drive future model development. Many of the modelling paradigms and software design principles deployed to date transfer readily to other STIs, both bacterial and viral; forthcoming releases of STI-GMaS will extend the software to incorporate a more diverse range of infections.

In-vehicle railway level crossing warning systems : can intelligent transport systems deliver?

Intelligent Transport System (ITS) technology is seen as a cost-effective way to increase the conspicuity of approaching trains and the effectiveness of train warnings at level crossings by providing an in-vehicle warning of an approaching train. The technology is often seen as a potential low-cost alternative to upgrading passive level crossings with traditional active warning systems (flashing lights and boom barriers). ITS platforms provide sensor, localization and dedicated short-range communication (DSRC) technologies to support cooperative applications such as collision avoidance for road vehicles. In recent years, in-vehicle warning systems based on ITS technology have been trialed at numerous locations around Australia, at level crossing sites with active and passive controls. While significant research has been conducted on the benefits of the technology in nominal operating modes, little research has focused on the effects of the failure modes, the human factors implications of unreliable warnings and the technology adoption process from the railway industry’s perspective. Many ITS technology suppliers originate from the road industry and often have limited awareness of the safety assurance requirements, operational requirements and legal obligations of railway operators. This paper aims to raise awareness of these issues and start a discussion on how such technology could be adopted. This paper will describe several ITS implementation cenarios and discuss failure modes, human factors considerations and the impact these scenarios are likely to have in terms of safety, railway safety assurance requirements and the practicability of meeting these requirements. The paper will identify the key obstacles impeding the adoption of ITS systems for the different implementation scenarios and a possible path forward towards the adoption of ITS technology.