p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation

p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the 'high-p53'Mdm4+/- mouse to the well-established TP-ras0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP-ras0/+ mice on the Mdm4+/- background developed fewer tumors with a delay in the age of onset of melanomas compared to TP-ras0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP-ras0/+: Mdm4+/- mice. Thus, p53 effectively prevented the conversion of small benign tumors to malignant and metastatic melanoma. p53 activation in cultured primary melanocyte and melanoma cell lines using Nutlin-3, a specific Mdm2 antagonist, supported these findings. Moreover, global gene expression and network analysis of Nutlin-3-treated primary human melanocytes indicated that cell cycle regulation through the p21WAF1/CIP1 signaling network may be the key anti-melanomagenic activity of p53.

Targeting mutant fibroblast growth factor receptors in cancer

Fibroblast growth factor receptors (FGFRs) play diverse roles in the control of cell proliferation, cell differentiation, angiogenesis and development. Activating the mutations of FGFRs in the germline has long been known to cause a variety of skeletal developmental disorders, but it is only recently that a similar spectrum of somatic FGFR mutations has been associated with human cancers. Many of these somatic mutations are gain-of-function and oncogenic and create dependencies in tumor cell lines harboring such mutations. A combination of knockdown studies and pharmaceutical inhibition in preclinical models has further substantiated genomically altered FGFR as a therapeutic target in cancer, and the oncology community is responding with clinical trials evaluating multikinase inhibitors with anti-FGFR activity and a new generation of specific pan-FGFR inhibitors.

Stochastic models and simulation of ion channel dynamics

The behaviour of ion channels within cardiac and neuronal cells is intrinsically stochastic in nature. When the number of channels is small this stochastic noise is large and can have an impact on the dynamics of the system which is potentially an issue when modelling small neurons and drug block in cardiac cells. While exact methods correctly capture the stochastic dynamics of a system they are computationally expensive, restricting their inclusion into tissue level models and so approximations to exact methods are often used instead. The other issue in modelling ion channel dynamics is that the transition rates are voltage dependent, adding a level of complexity as the channel dynamics are coupled to the membrane potential. By assuming that such transition rates are constant over each time step, it is possible to derive a stochastic differential equation (SDE), in the same manner as for biochemical reaction networks, that describes the stochastic dynamics of ion channels. While such a model is more computationally efficient than exact methods we show that there are analytical problems with the resulting SDE as well as issues in using current numerical schemes to solve such an equation. We therefore make two contributions: develop a different model to describe the stochastic ion channel dynamics that analytically behaves in the correct manner and also discuss numerical methods that preserve the analytical properties of the model.

Robust designs for Poisson regression models

We consider the problem of how to construct robust designs for Poisson regression models. An analytical expression is derived for robust designs for first-order Poisson regression models where uncertainty exists in the prior parameter estimates. Given certain constraints in the methodology, it may be necessary to extend the robust designs for implementation in practical experiments. With these extensions, our methodology constructs designs which perform similarly, in terms of estimation, to current techniques, and offers the solution in a more timely manner. We further apply this analytic result to cases where uncertainty exists in the linear predictor. The application of this methodology to practical design problems such as screening experiments is explored. Given the minimal prior knowledge that is usually available when conducting such experiments, it is recommended to derive designs robust across a variety of systems. However, incorporating such uncertainty into the design process can be a computationally intense exercise. Hence, our analytic approach is explored as an alternative.

Some novel techniques of parameter estimation for the dynamical models in biological systems

Inverse problems based on using experimental data to estimate unknown parameters of a system often arise in biological and chaotic systems. In this paper, we consider parameter estimation in systems biology involving linear and non-linear complex dynamical models, including the Michaelis–Menten enzyme kinetic system, a dynamical model of competence induction in Bacillus subtilis bacteria and a model of feedback bypass in B. subtilis bacteria. We propose some novel techniques for inverse problems. Firstly, we establish an approximation of a non-linear differential algebraic equation that corresponds to the given biological systems. Secondly, we use the Picard contraction mapping, collage methods and numerical integration techniques to convert the parameter estimation into a minimization problem of the parameters. We propose two optimization techniques: a grid approximation method and a modified hybrid Nelder–Mead simplex search and particle swarm optimization (MH-NMSS-PSO) for non-linear parameter estimation. The two techniques are used for parameter estimation in a model of competence induction in B. subtilis bacteria with noisy data. The MH-NMSS-PSO scheme is applied to a dynamical model of competence induction in B. subtilis bacteria based on experimental data and the model for feedback bypass. Numerical results demonstrate the effectiveness of our approach.

Linear models for endocytic transformations from live cell imaging

Endocytosis is the process by which cells internalise molecules including nutrient proteins from the extracellular media. In one form, macropinocytosis, the membrane at the cell surface ruffles and folds over to give rise to an internalised vesicle. Negatively charged phospholipids within the membrane called phosphoinositides then undergo a series of transformations that are critical for the correct trafficking of the vesicle within the cell, and which are often pirated by pathogens such as Salmonella. Advanced fluorescent video microscopy imaging now allows the detailed observation and quantification of these events in live cells over time. Here we use these observations as a basis for building differential equation models of the transformations. An initial investigation of these interactions was modelled with reaction rates proportional to the sum of the concentrations of the individual constituents. A first order linear system for the concentrations results. The structure of the system enables analytical expressions to be obtained and the problem becomes one of determining the reaction rates which generate the observed data plots. We present results with reaction rates which capture the general behaviour of the reactions so that we now have a complete mathematical model of phosphoinositide transformations that fits the experimental observations. Some excellent fits are obtained with modulated exponential functions; however, these are not solutions of the linear system. The question arises as to how the model may be modified to obtain a system whose solution provides a more accurate fit.

Hypothetical model of hydrophilic lubrication in synovial joints

This paper presents a new insight into the mechanism of biolubrication of articulating mammalian joints that includes the function of surface-active phospholipids (SAPLs). SAPLs can be adsorbed on surface of cartilage membranes as a hydrophobic monolayer (H-phobic-M Madel or Hills' Model) or as a newly proposed hydrophilic bilayer (H-philic-B Model). With respect to the synovial joint's frictionless work, three processes are identified namely: monolayer/bilayer phospholipids binding to cartilage with lubricin interaction; influence of induced-pressure on interaction of hyaluronan with phospholipids; and biolubrication arising from two gliding articular hydrophilic surfaces acting as reverse micelle. Lubricin is considered to play critical role as a supplier of phospholipids, which overlay the articular surface of articular cartilage. Hyaluronic acid is considered to play a critical mediating role in the interaction between the hydrophilic part of phospholipids, the articular surface and water (hydration) in facilitating the lubrication process. Tivo models of frictionless lubrication processes, namely hydrophobic (H-phobic-M Model) and our conceptual hydrophilic (H-philic-B Model), are compared. © Institution of Engineers Australia, 2008.

Large scale participatory acoustic sensor data analysis : tools and reputation models to enhance effectiveness

Acoustic sensors play an important role in augmenting the traditional biodiversity monitoring activities carried out by ecologists and conservation biologists. With this ability however comes the burden of analysing large volumes of complex acoustic data. Given the complexity of acoustic sensor data, fully automated analysis for a wide range of species is still a significant challenge. This research investigates the use of citizen scientists to analyse large volumes of environmental acoustic data in order to identify bird species. Specifically, it investigates ways in which the efficiency of a user can be improved through the use of species identification tools and the use of reputation models to predict the accuracy of users with unidentified skill levels. Initial experimental results are reported.

Computer-intensive simulations for cellular models

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Continuous innovation in SMEs : how design innovation shapes business performance through doing more with less

Firms face the challenge to survive and thrive in an increasingly competitive global market, developing strategies to continuously innovate, often having to do more with less. Increasing awareness of the benefits of stimulating continuous innovation in small and medium enterprises has led to the development and implementation of design innovation programs, with many western countries investing in design innovation programs for better firm performance. This paper investigates how firms respond to a design innovation program and engage in continuous innovation, doing more business with a focused less diverse strategy. Early findings from a study of companies engaged in a design innovation program indicate that applying design principles to all aspects of their business has delivered better business performance and better positioning in global markets.

Urban Informatics Research and Insights for Libraries, Cultural Industries and Innovation Systems

Over less than a decade, we have witnessed a seismic shift in the way knowledge is produced and exchanged. This is opening up new opportunities for civic and community engagement, entrepreneurial behaviour, sustainability initiatives and creative practices. It also has the potential to create fresh challenges in areas of privacy, cyber-security and misuse of data and personal information. The field of urban informatics focuses on the use and impacts of digital media technology in urban environments. Urban informatics is a dynamic and cross-disciplinary area of inquiry that encapsulates social media, ubiquitous computing, mobile applications and location-based services. Its insights suggest the emergence of a new economic force with the potential for driving innovation, wealth and prosperity through technological advances, digital media and online networks that affect patterns of both social and economic development. Urban informatics explores the intersections between people, place and technology, and their implications for creativity, innovation and engagement. This paper examines how the key learnings from this field can be used to position creative and cultural institutions such as galleries, libraries, archives and museums (GLAM) to take advantage of the opportunities presented by these changing social and technological developments. This paper introduces the underlying principles, concepts and research areas of urban informatics, against the backdrop of modern knowledge economies. Both theoretical ideas and empirical examples are covered in this paper. The first part discusses three challenges: a. People, and the challenge of creativity: The paper explores the opportunities and challenges of urban informatics that can lead to the design and development of new tools, methods and applications fostering participation, the democratisation of knowledge, and new creative practices. b. Technology, and the challenge of innovation: The paper examines how urban informatics can be applied to support user-led innovation with a view to promoting entrepreneurial ideas and creative industries. c. Place, and the challenge of engagement: The paper discusses the potential to establish place-based applications of urban informatics, using the example of library spaces designed to deliver community and civic engagement strategies. The discussion of these challenges is illustrated by a review of projects as examples drawn from diverse fields such as urban computing, locative media, community activism, and sustainability initiatives. The second part of the paper introduces an empirically grounded case study that responds to these three challenges: The Edge, the Queensland Government’s Digital Culture Centre which is an initiative of the State Library of Queensland to explore the nexus of technology and culture in an urban environment. The paper not only explores the new role of libraries in the knowledge economy, but also how the application of urban informatics in prototype engagement spaces such as The Edge can provide transferable insights that can inform the design and development of responsive and inclusive new library spaces elsewhere. To set the scene and background, the paper begins by drawing the bigger picture and outlining some key characteristics of the knowledge economy and the role that the creative and cultural industries play in it, grasping new opportunities that can contribute to the prosperity of Australia.

Library and information science education 2.0 : guiding principles and models of best practice ALTC Fellowship Report

This ALTC Teaching Fellowship aimed to establish Guiding Principles for Library and Information Science Education 2.0. The aim was achieved by (i) identifying the current and anticipated skills and knowledge required by successful library and information science (LIS) professionals in the age of web 2.0 (and beyond), (ii) establishing the current state of LIS education in Australia in supporting the development of librarian 2.0, and in doing so, identify models of best practice. The fellowship has contributed to curriculum renewal in the LIS profession. It has helped to ensure that LIS education in Australia continues to meet the changing skills and knowledge requirements of the profession it supports. It has also provided a vehicle through which LIS professionals and LIS educators may find opportunities for greater collaboration and more open communication. This will help bridge the gap between LIS theory and practice and will foster more authentic engagement between LIS education and other parts of the LIS industry in the education of the next generation of professionals. Through this fellowship the LIS discipline has become a role model for other disciplines who will be facing similar issues in the coming years. Eighty-one members of the Australian LIS profession participated in a series of focus groups exploring the current and anticipated skills and knowledge needed by the LIS professional in the web 2.0 world and beyond. Whilst each focus group tended to draw on specific themes of interest to that particular group of people, there was a great deal of common ground. Eight key themes emerged: technology, learning and education, research or evidence-based practice, communication, collaboration and team work, user focus, business savvy and personal traits. It was acknowledged that the need for successful LIS professionals to possess transferable skills and interpersonal attributes was not new. It was noted however that the speed with which things are changing in the web 2.0 world was having a significant impact and that this faster pace is placing a new and unexpected emphasis on the transferable skills and knowledge. It was also acknowledged that all librarians need to possess these skills, knowledge and attributes and not just the one or two role models who lead the way. The most interesting finding however was that web 2.0, library 2.0 and librarian 2.0 represented a ‘watershed’ for the LIS profession. Almost all the focus groups spoke about how they are seeing and experiencing a culture change in the profession. Librarian 2.0 requires a ‘different mindset or attitude’. The Levels of Perspective model by Daniel Kim provides one lens by which to view this finding. The focus group findings suggest that we are witnessing a re-awaking of the Australian LIS profession as it begins to move towards the higher levels of Kim’s model (ie mental models, vision). Thirty-six LIS educators participated in telephone interviews aimed at exploring the current state of LIS education in supporting the development of librarian 2.0. Skills and knowledge of LIS professionals in a web 2.0 world that were identified and discussed by the LIS educators mirrored those highlighted in the focus group discussions with LIS professionals. Similarly it was noted that librarian 2.0 needed a focus less on skills and knowledge and more on attitude. However, whilst LIS professionals felt that there was a paradigm shift within the profession. LIS educators did not speak with one voice on this matter with quite a number of the educators suggesting that this might be ‘overstating it a bit’. This study provides evidence for “disparate viewpoints” (Hallam, 2007) between LIS educators and LIS professionals that can have a significant implications for the future of not just LIS professional education specifically but for the profession generally. Library and information science education 2.0: guiding principles and models of best practice 1 Inviting the LIS academics to discuss how their teaching and learning activities support the development of librarian 2.0 was a core part of the interviews conducted. The strategies used and the challenges faced by LIS educators in developing their teaching and learning approaches to support the formation of librarian 2.0 are identified and discussed. A core part of the fellowship was the identification of best practice examples on how LIS educators were developing librarian 2.0. Twelve best practice examples were identified. Each educator was recorded discussing his or her approach to teaching and learning. Videos of these interviews are available via the Fellowship blog at .The LIS educators involved in making the videos felt uncomfortable with the term ‘best practice’. Many acknowledged that there simply seeking to do the best by their students and that there was always room for improvement. For this reason these videos are offered as examples of “great practice”. The videos are a tool for other educators to use, regardless of discipline, in developing their teaching and learning approaches to supporting web 2.0 professionals. It has been argued that the main purpose of professional education is transformation (Dall’ Alba, 2009; Dall’Alba & Barnacle, 2007). As such professional education should focus not just on skills and knowledge acquisition but also on helping students to develop ways of being the professionals in question (ie LIS professionals, teachers, lawyers, engineers).The aim of this fellowship was to establish Guidelines for Library and Information Science Education 2.0 it has however become apparent that at this point in time it is not yet possible to fulfil this aim. The fellowship has clearly identified skills and knowledge needed by the LIS professional in web 2.0 world (and beyond). It has also identified examples of ‘great practice’ by LIS educators as they endeavour to develop LIS professionals who will be successful in a web 20 world. The fellowship however has also shown that the LIS profession is currently undergoing significant attitudinal and conceptual change. Consequently, before a philosophy of LIS education 2.0 can be expressed, the Australian LIS profession must first explore and articulate what it means to be an LIS professional in the 21st century (ie a world of web 2.0 and beyond). In short, the LIS profession in Australia must take stock not of “what we know and can do” but on “who we are becoming” (Dall’Alba, 2009, p 34).

Cross likelihood ratio based speaker clustering using eigenvoice models

This paper proposes the use of eigenvoice modeling techniques with the Cross Likelihood Ratio (CLR) as a criterion for speaker clustering within a speaker diarization system. The CLR has previously been shown to be a robust decision criterion for speaker clustering using Gaussian Mixture Models. Recently, eigenvoice modeling techniques have become increasingly popular, due to its ability to adequately represent a speaker based on sparse training data, as well as an improved capture of differences in speaker characteristics. This paper hence proposes that it would be beneficial to capitalize on the advantages of eigenvoice modeling in a CLR framework. Results obtained on the 2002 Rich Transcription (RT-02) Evaluation dataset show an improved clustering performance, resulting in a 35.1% relative improvement in the overall Diarization Error Rate (DER) compared to the baseline system.

Determinants of skin self-examination (SSE) in men aged 50 years or older

Background: Queensland men aged 50 years and older are at high risk for melanoma. Early detection via skin self examination (SSE) (particularly whole-body SSE) followed by presentation to a doctor with suspicious lesions, may decrease morbidity and mortality from melanoma. Prevalence of whole-body SSE (wbSSE) is lower in Queensland older men compared to other population subgroups. With the exception of the present study no previous research has investigated the determinants of wbSSE in older men, or interventions to increase the behaviour in this population. Furthermore, although past SSE intervention studies for other populations have cited health behaviour models in the development of interventions, no study has tested these models in full. The Skin Awareness Study: A recent randomised trial, called the Skin Awareness Study, tested the impact of a video-delivered intervention compared to written materials alone on wbSSE in men aged 50 years or older (n=930). Men were recruited from the general population and interviewed over the telephone at baseline and 13 months. The proportion of men who reported wbSSE rose from 10% to 31% in the control group, and from 11% to 36% in the intervention group. Current research: The current research was a secondary analysis of data collected for the Skin Awareness Study. The objectives were as follows: • To describe how men who did not take up any SSE during the study period differed from those who did take up examining their skin. • To determine whether the intervention program was successful in affecting the constructs of the Health Belief Model it was aimed at (self-efficacy, perceived threat, and outcome expectations); and whether this in turn influenced wbSSE. • To determine whether the Health Action Process Approach (HAPA) was a better predictor of wbSSE behaviour compared to the Health Belief Model (HBM). Methods: For objective 1, men who did not report any past SSE at baseline (n=308) were categorised as having ‘taken up SSE’ (reported SSE at study end) or ‘resisted SSE’ (reported no SSE at study end). Bivariate logistic regression, followed by multivariable regression, investigated the association between participant characteristics measured at baseline and resisting SSE. For objective 2 proxy measures of self-efficacy, perceived threat, and outcome expectations were selected. To determine whether these mediated the effect of the intervention on the outcome, a mediator analysis was performed with all participants who completed interviews at both time points (n=830) following the Baron and Kenny approach, modified for use with structural equation modelling (SEM). For objective 3, control group participants only were included (n=410). Proxy measures of all HBM and HAPA constructs were selected and SEM was used to build up models and test the significance of each hypothesised pathway. A likelihood ratio test compared the HAPA to the HBM. Results: Amongst men who did not report any SSE at baseline, 27% did not take up any SSE by the end of the study. In multivariable analyses, resisting SSE was associated with having more freckly skin (p=0.027); being unsure about the statement ‘if I saw something suspicious on my skin, I’d go to the doctor straight away’ (p=0.028); not intending to perform SSE (p=0.015), having lower SSE self-efficacy (p<0.001), and having no recommendation for SSE from a doctor (p=0.002). In the mediator analysis none of the tested variables mediated the relationship between the intervention and wbSSE. In regards to health behaviour models, the HBM did not predict wbSSE well overall. Only the construct of self-efficacy was a significant predictor of future wbSSE (p=0.001), while neither perceived threat (p=0.584) nor outcome expectations (p=0.220) were. By contrast, when the HAPA constructs were added, all three HBM variables predicted intention to perform SSE, which in turn predicted future behaviour (p=0.015). The HAPA construct of volitional self-efficacy was also associated with wbSSE (p=0.046). The HAPA was a significantly better model compared to the HBM (p<0.001). Limitations: Items selected to measure HBM and HAPA model constructs for objectives 2 and 3 may not have accurately reflected each construct. Conclusions: This research added to the evidence base on how best to target interventions to older men; and on the appropriateness of particular health behaviour models to guide interventions. Findings indicate that to overcome resistance those men with more negative pre-existing attitudes to SSE (not intending to do it, lower initial self-efficacy) may need to be targeted with more intensive interventions in the future. Involving general practitioners in recommending SSE to their patients in this population, alongside disseminating an intervention, may increase its success. Comparison of the HBM and HAPA showed that while two of the three HBM variables examined did not directly predict future wbSSE, all three were associated with intention to self-examine skin. This suggests that in this population, intervening on these variables may increase intention to examine skin, but not necessarily the behaviour itself. Future interventions could potentially focus on increasing both the motivational variables of perceived threat and outcome expectations as well as a combination of both action and volitional self-efficacy; with the aim of increasing intention as well as its translation to taking up and maintaining regular wbSSE.