Kallikrein-related peptidase 4 activation of protease-activated receptor family members and association with prostate cancer

Two areas of particular importance in prostate cancer progression are primary tumour development and metastasis. These processes involve a number of physiological events, the mediators of which are still being discovered and characterised. Serine proteases have been shown to play a major role in cancer invasion and metastasis. The recently discovered phenomenon of their activation of a receptor family known as the protease activated receptors (PARs) has extended their physiological role to that of signaling molecule. Several serine proteases are expressed by malignant prostate cancer cells, including members of the kallikreinrelated peptidase (KLK) serine protease family, and increasingly these are being shown to be associated with prostate cancer progression. KLK4 is highly expressed in the prostate and expression levels increase during prostate cancer progression. Critically, recent studies have implicated KLK4 in processes associated with cancer. For example, the ectopic over-expression of KLK4 in prostate cancer cell lines results in an increased ability of these cells to form colonies, proliferate and migrate. In addition, it has been demonstrated that KLK4 is a potential mediator of cellular interactions between prostate cancer cells and osteoblasts (bone forming cells). The ability of KLK4 to influence cellular behaviour is believed to be through the selective cleavage of specific substrates. Identification of relevant in vivo substrates of KLK4 is critical to understanding the pathophysiological roles of this enzyme. Significantly, recent reports have demonstrated that several members of the KLK family are able to activate PARs. The PARs are relatively new members of the seven transmembrane domain containing G protein coupled receptor (GPCR) family. PARs are activated through proteolytic cleavage of their N-terminus by serine proteases, the resulting nascent N-terminal binds intramolecularly to initiate receptor activation. PARs are involved in a number of patho-physiological processes, including vascular repair and inflammation, and a growing body of evidence suggests roles in cancer. While expression of PAR family members has been documented in several types of cancers, including prostate, the role of these GPCRs in prostate cancer development and progression is yet to be examined. Interestingly, several studies have suggested potential roles in cellular invasion through the induction of cytoskeletal reorganisation and expression of basement membrane-degrading enzymes. Accordingly, this program of research focussed on the activation of the PARs by the prostate cancer associated enzyme KLK4, cellular processing of activated PARs and the expression pattern of receptor and agonist in prostate cancer. For these studies KLK4 was purified from the conditioned media of stably transfected Sf9 insect cells expressing a construct containing the complete human KLK4 coding sequence in frame with a V5 epitope and poly-histidine encoding sequences. The first aspect of this study was the further characterisation of this recombinant zymogen form of KLK4. The recombinant KLK4 zymogen was demonstrated to be activatable by the metalloendopeptidase thermolysin and amino terminal sequencing indicated that thermolysin activated KLK4 had the predicted N-terminus of mature active KLK4 (31IINED). Critically, removal of the pro-region successfully generated a catalytically active enzyme, with comparable activity to a previously published recombinant KLK4 produced from S2 insect cells. The second aspect of this study was the activation of the PARs by KLK4 and the initiation of signal transduction. This study demonstrated that KLK4 can activate PAR-1 and PAR-2 to mobilise intracellular Ca2+, but failed to activate PAR-4. Further, KLK4 activated PAR-1 and PAR-2 over distinct concentration ranges, with KLK4 activation and mobilisation of Ca2+ demonstrating higher efficacy through PAR-2. Thus, the remainder of this study focussed on PAR-2. KLK4 was demonstrated to directly cleave a synthetic peptide that mimicked the PAR-2 Nterminal activation sequence. Further, KLK4 mediated Ca2+ mobilisation through PAR-2 was accompanied by the initiation of the extra-cellular regulated kinase (ERK) cascade. The specificity of intracellular signaling mediated through PAR-2 by KLK4 activation was demonstrated by siRNA mediated protein depletion, with a reduction in PAR-2 protein levels correlating to a reduction in KLK4 mediated Ca2+mobilisation and ERK phosphorylation. The third aspect of this study examined cellular processing of KLK4 activated PAR- 2 in a prostate cancer cell line. PAR-2 was demonstrated to be expressed by five prostate derived cell lines including the prostate cancer cell line PC-3. It was also demonstrated by flow cytometry and confocal microscopy analyses that activation of PC-3 cell surface PAR-2 by KLK4 leads to internalisation of this receptor in a time dependent manner. Critically, in vivo relevance of the interaction between KLK4 and PAR-2 was established by the observation of the co-expression of receptor and agonist in primary prostate cancer and prostate cancer bone lesion samples by immunohistochemical analysis. Based on the results of this study a number of exciting future studies have been proposed, including, delineating differences in KLK4 cellular signaling via PAR-1 and PAR-2 and the role of PAR-1 and PAR-2 activation by KLK4 in prostate cancer cells and bone cells in prostate cancer progression.

Attitudes to Formal Business Training and Learning amongst Entrepreneurs in the Cultural Industries: Situated Business Learning through "Doing with Others."

Presents arguments supporting a social model of learning linked to situated learning and cultural capital. Critiques training methods used in cultural industries (arts, publishing, broadcasting, design, fashion, restaurants). Uses case study evidence to demonstrates inadequacies of formal training in this sector. (Contains 49 references.)

Performing with grid music systems

Grid music systems provide discrete geometric methods for simplified music-making by providing spatialised input to construct patterned music on a 2D matrix layout. While they are conceptually simple, grid systems may be layered to enable complex and satisfying musical results. Grid music systems have been applied to a range of systems from small portable devices up to larger systems. In this paper we will discuss the use of grid music systems in general and present an overview of the HarmonyGrid system we have developed as a new interactive performance system. We discuss a range of issues related to the design and use of larger-scale grid- based interactive performance systems such as the HarmonyGrid.

Employee engagement : the development of a three dimensional model of engagement; and an exploration of its relationship with affective leader behaviours

This study was designed to examine affective leader behaviours, and their impact on cognitive, affective and behavioural engagement. Researchers (e.g., Cropanzano & Mitchell, 2005; Moorman et al., 1998) have called for more research to be directed toward modelling and testing sets of relationships which better approximate the complexity associated with contemporary organisational experience. This research has attempted to do this by clarifying and defining the construct of engagement, and then by examining how each of the engagement dimensions are impacted by affective leader behaviours. Specifically, a model was tested that identifies leader behaviour antecedents of cognitive, affective and behavioural engagement. Data was collected from five public-sector organisations. Structural equation modelling was used to identify the relationships between the engagement dimensions and leader behaviours. The results suggested that affective leader behaviours had a substantial direct impact on cognitive engagement, which in turn influenced affective engagement, which then influenced intent to stay and extra-role performance. The results indicated a directional process for engagement, but particularly highlighted the significant impact of affective leader behaviours as an antecedent to engagement. In general terms, the findings will provide a platform from which to develop a robust measure of engagement, and will be helpful to human resource practitioners interested in understanding the directional process of engagement and the importance of affective leadership as an antecedent to engagement.

Providing youth with skills, training and employment opportunities through ICT Initiatives

Youth population is increasing explosively particularly in developing countries as a result of rapid urbanization. This increase is bringing large number of social and economic problems. For instance the impacts of job and training availability, and the physical, social and cultural quality of urban environment on young people are enormous, and affect their health, lifestyles, and well-being (Gleeson and Sipe 2006). Besides this, globalization and technological developments are affecting youth in urban areas in all parts of the world, both positively and negatively (Robertson 1995). The rapidly advancing information and communications technologies (ICTs) helps in addressing social and economic problems caused by the rapid growth of urban youth populations in developing countries. ICTs offer opportunities to young people for learning, skill development and employment. But there are downsides: young people in many developing countries lack of having broad access to these new technologies, they are vulnerable to global market changes, and ICTs link them into global cultures which promote consumer goods, potentially eroding local cultures and community values (Manacorda and Petrongolo 1999). However we believe that the positives outweigh such negatives. At the beginning of the twenty-first century, the world’s young population number more than they ever have. There are over a billion young people between the ages of 15 and 24, which 85 per cent of them live in developing countries and mainly in urban environments. Many of these young people are in the process of making, or have already made, the transition from school to work. During the last two decades all around the world, these young people, as new workers, have faced a number of challenges associated with globalization and technological advances on labour markets (United Nations 2004). The continuous decrease in the manufacturing employment is made many of the young people facing three options: getting jobs in the informal economy with insecurity and poor wages and working conditions, or getting jobs in the low-tier service industries, or developing their vocational skills to benefit from new opportunities in the professional and advanced technical/knowledge sectors. Moreover in developing countries a large portion of young people are not even lucky enough to choose among any of these options, and consequently facing long-term unemployment, which makes them highly vulnerable. The United Nations’ World Youth Employment report (2004) indicates that in almost all countries, females tend to be far more vulnerable than males in terms of long-term unemployment, and young people who have advanced qualifications are far less likely to experience long-term unemployment than others. In the limited opportunities of the formal labour market, those with limited vocational skills resort to forced entrepreneurship and selfemployment in the informal economy, often working for low pay under hazardous conditions, with only few prospects for the future (United Nations 2005a). The International Labour Organization’s research (2004) revealed that the labour force participation rates for young people decreased by almost four per cent (which is equivalent of 88 million young people) between 1993 and 2003. This is largely as a result of the increased number of young people attending school, high overall unemployment rates, and the fact that some young people gave up any hope of finding work and dropped out of the labour market. At the regional level, youth unemployment was highest in Middle East and North Africa (MENA) (25.6%) and sub-Saharan Africa (21%) and lowest in East Asia (7%) and the industrialized economies(13.4%) (International Labour Organization 2004). The youth in economically disadvantaged regions (e.g. the MENA region) face many challenges in education and training that delivers them the right set of skills and knowledge demanded by the labour market. As a consequence, the transition from school to work is mostly unsuccessful and young population end up either unemployed or underemployed in the informal sectors (United Nations 2005b). Unemployment and lack of economic prospects of the urban youth are pushing many of them into criminal acts, excessive alcohol use, substance addiction, and also in many cases resulting in processes of social or political violence (Fernandez-Maldonado 2004; United Nations 2005a). Long-term unemployment leads young people in a process of marginalisation and social exclusion (United Nations 2004). The sustained high rates of long-term youth unemployment have a number of negative effects on societies. First, it results in countries failing to take advantage of the human resources to increase their productive potential, at a time of transition to a globalized world that inexorably demands such leaps in productive capacity. Second, it reinforces the intergenerational transmission of poverty. Third, owing to the discrepancy between more education and exposure to the mass media and fewer employment opportunities, it may encourage the spread of disruptive behaviours, recourse to illegal alternatives for generating income and the loss of basic societal values, all of which erode public safety and social capital. Fourth, it may trigger violent and intractable political conflicts. And lastly, it may exacerbate intergenerational conflicts when young people perceive a lack of opportunity and meritocracy in a system that favours adults who have less formal education and training but more wealth, power and job stability (Hopenhayn 2002). To assist in addressing youth’s skill training and employment problems this paper scrutinises useful international practices, policies, initiatives and programs targeting youth skill training, particularly in ICTs. The MENA national governments and local authorities could consider implementing similar initiative and strategies to address some of the youth employment issues. The broader aim of this paper is to investigate the successful practice and strategies for the information and communication related income generation opportunities for young people to: promote youth entrepreneurship; promote public-private partnerships; target vulnerable groups of young people; narrow digital divide; and put young people in charge. The rest of this paper is organised in five parts. First, the paper provides an overview of the literature on the knowledge economy, skill, education and training issues. Secondly, it reviews the role of ICTs for vocational skill development and employability. Thirdly, it discusses the issues surrounding the development of the digital divide. Fourthly, the paper underlines types and the importance of developing ICT initiatives targeting young people, and reviews some of the successful policy implementations on ICT-based initiatives from both developed and developing countries that offer opportunities to young people for learning, skill development and employment. Then the paper concludes by providing useful generalised recommendations for the MENA region countries and cities in: advocating possible opportunities for ICT generated employment for young people; and discussing how ICT policies could be modified and adopted to meet young people’s needs.

New Approach on Robust Delay-Dependent H∞ Control for Uncertain T-S Fuzzy Systems With Interval Time-Varying Delay

This paper investigates the robust H∞ control for Takagi-Sugeno (T-S) fuzzy systems with interval time-varying delay. By employing a new and tighter integral inequality and constructing an appropriate type of Lyapunov functional, delay-dependent stability criteria are derived for the control problem. Because neither any model transformation nor free weighting matrices are employed in our theoretical derivation, the developed stability criteria significantly improve and simplify the existing stability conditions. Also, the maximum allowable upper delay bound and controller feedback gains can be obtained simultaneously from the developed approach by solving a constrained convex optimization problem. Numerical examples are given to demonstrate the effectiveness of the proposed methods.

Generating rules with predicates, terms and variables from the pruned neural networks

Artificial neural networks (ANN) have demonstrated good predictive performance in a wide range of applications. They are, however, not considered sufficient for knowledge representation because of their inability to represent the reasoning process succinctly. This paper proposes a novel methodology Gyan that represents the knowledge of a trained network in the form of restricted first-order predicate rules. The empirical results demonstrate that an equivalent symbolic interpretation in the form of rules with predicates, terms and variables can be derived describing the overall behaviour of the trained ANN with improved comprehensibility while maintaining the accuracy and fidelity of the propositional rules.

Thai word segmentation with hidden Markov Model and decision tree

The Thai written language is one of the languages that does not have word boundaries. In order to discover the meaning of the document, all texts must be separated into syllables, words, sentences, and paragraphs. This paper develops a novel method to segment the Thai text by combining a non-dictionary based technique with a dictionary-based technique. This method first applies the Thai language grammar rules to the text for identifying syllables. The hidden Markov model is then used for merging possible syllables into words. The identified words are verified with a lexical dictionary and a decision tree is employed to discover the words unidentified by the lexical dictionary. Documents used in the litigation process of Thai court proceedings have been used in experiments. The results which are segmented words, obtained by the proposed method outperform the results obtained by other existing methods.

Different cognitive profiles for single compared with recurrent fallers without Dementia

Relationships between self-reported retrospective falls and cognitive measures (executive function, reaction time, processing speed, working memory, visual attention) were examined in a population based sample of older adults (n = 658). Two of the choice reaction time tests involved inhibiting responses to either targets of a specific color or location with hand and foot responses. Potentially confounding demographic variables, medical conditions and postural sway were controlled for in logistic regression models, excluding participants with possible cognitive impairment. A factor analysis of cognitive measures extracted factors measuring reaction time, accuracy and inhibition, and visual search. Single fallers did not differ from non-fallers in terms of health, sway or cognitive function, except that they performed worse on accuracy and inhibition. In contrast, recurrent fallers performed worse than non-fallers on all measures. Results suggest that occasional falls in late life may be associated with subtle age-related changes in the pre-frontal cortex leading to failures of executive control, whereas recurrent falling may result from more advanced brain ageing that is associated with generalized cognitive decline.

Subjective fit with organizational culture : an investigation of moderating effects in the work stressor-employee adjustment relationship

Occupational stress has been a concern for human resource managers in light of research investigating the work stressor-employee adjustment relationship. This research has consistently demonstrated many negative effects between stressors in the workplace and employee adjustment. A considerable amount of literature also describes potential moderators of this relationship. Subjective fit with organizational culture has been established as a significant predictor of employee job-related attitudes; however, research has neglected investigation of the potential moderating effect of subjective fit in the work stressor-employee adjustment process. It was predicted that perceptions of subjective fit with the organization’s values and goals would mitigate the negative effect of work stressors on employee adjustment in an employee sample from three organizations (N ¼ 256). Hierarchical multiple regression analyses revealed support for the stress-buffering effects of high subjective fit in the prediction of physical symptoms, job satisfaction, and intentions to leave. The theoretical and practical implications of the results are discussed.

Enhancing digital road map with lane details extracted from large-scale stereo aerial imagery using object-oriented image analysis

Precise, up-to-date and increasingly detailed road maps are crucial for various advanced road applications, such as lane-level vehicle navigation, and advanced driver assistant systems. With the very high resolution (VHR) imagery from digital airborne sources, it will greatly facilitate the data acquisition, data collection and updates if the road details can be automatically extracted from the aerial images. In this paper, we proposed an effective approach to detect road lane information from aerial images with employment of the object-oriented image analysis method. Our proposed algorithm starts with constructing the DSM and true orthophotos from the stereo images. The road lane details are detected using an object-oriented rule based image classification approach. Due to the affection of other objects with similar spectral and geometrical attributes, the extracted road lanes are filtered with the road surface obtained by a progressive two-class decision classifier. The generated road network is evaluated using the datasets provided by Queensland department of Main Roads. The evaluation shows completeness values that range between 76% and 98% and correctness values that range between 82% and 97%.

Control and protection of a microgrid with converter interfaced micro sources

This paper describes protection and control of a microgrid with converter interfaced micro sources. The proposed protection and control scheme consider both grid connected and autonomous operation of the microgrid. A protection scheme, capable of detecting faults effectively in both grid connected and islanded operations is proposed. The main challenge of the protection, due to current limiting state of the converters is overcome by using admittance relays. The relays operate according to the inverse time characteristic based on measured admittance of the line. The proposed scheme isolates the fault from both sides, while downstream side of the microgrid operates in islanding condition. Moreover faults can be detected in autonomous operation. In grid connected mode distributed generators (DG) supply the rated power while in absence of the grid, DGs share the entire power requirement proportional to rating based on output voltage angle droop control. The protection scheme ensures minimum load shedding with isolating the faulted network and DG control provides a smooth islanding and resynchronization operation. The efficacy of coordinated control and protection scheme has been validated through simulation for various operating conditions.

Power sharing and stability enhancement of an autonomous microgrid with inertial and non-inertial DGs with DSTATCOM

This paper proposes a method of enhancing system stability with a distribution static compensator (DSTATCOM) in an autonomous microgrid with multiple distributed generators (DG). It is assumed that there are both inertial and non-inertial DGs connected to the microgrid. The inertial DG can be a synchronous machine of smaller rating while inertia less DGs (solar) are assumed as DC sources. The inertia less DGs are connected through Voltage Source Converter (VSC) to the microgrid. The VSCs are controlled by either state feedback or current feedback mode to achieve desired voltage-current or power outputs respectively. The power sharing among the DGs is achieved by drooping voltage angle. Once the reference for the output voltage magnitude and angle is calculated from the droop, state feedback controllers are used to track the reference. The angle reference for the synchronous machine is compared with the output voltage angle of the machine and the error is fed to a PI controller. The controller output is used to set the power reference of the synchronous machine. The rate of change in the angle in a synchronous machine is restricted by the machine inertia and to mimic this nature, the rate of change in the VSCs angles are restricted by a derivative feedback in the droop control. The connected distribution static compensator (DSTATCOM) provides ride through capability during power imbalance in the microgrid, especially when the stored energy of the inertial DG is not sufficient to maintain stability. The inclusion of the DSATCOM in such cases ensures the system stability. The efficacies of the controllers are established through extensive simulation studies using PSCAD.

Generating Flash files of Your Lectures: Good Practice Strategies Helping Students Engage with Their Learning

Our students come from diverse backgrounds. They need flexibility in their learning. First year students tend to worry when they miss lectures or part of lectures. Having the lecture as an on line resource allows students to miss a lecture without stressing about it and to be more relaxed in the lecture, knowing that anything they may miss will be available later. The resource: The Windows based program from Blueberry Software (not Blackberry!) - BB Flashback - allows the simultaneous recording of the computer screen together with the audio, as well as Webcam recording. Editing capabilities include adding pause buttons, graphics and text to the file before exporting it in a flash file. Any diagrams drawn on the board or shown via visualiser can be photographed and easily incorporated. The audio from the file can be extracted if required to be posted as podcast. Exporting modes other than Flash are also available, allowing vodcasting if you wish. What you will need: - the recording software: it can be installed on the lecture hall computer just prior to lecture if needed - a computer: either the ones in lecture halls, especially if fitted with audio recording, or a laptop (I have used audio recording via Bluetooth for mobility). Feedback from students has been positive and will be presented on the poster.