Proteasome inhibitors as anti-cancer agents

The ubiquitin (Ub)-proteasome pathway is the major nonlysosomal pathway of proteolysis in human cells and accounts for the degradation of most short-lived, misfolded or damaged proteins. This pathway is important in the regulation of a number of key biological regulatory mechanisms. Proteins are usually targeted for proteasome-mediated degradation by polyubiquitinylation, the covalent addition of multiple units of the 76 amino acid protein Ub, which are ligated to 1-amino groups of lysine residues in the substrate. Polyubiquitinylated proteins are degraded by the 26S proteasome, a large, ATP-dependent multicatalytic protease complex, which also regenerates monomeric Ub. The targets of this pathway include key regulators of cell proliferation and cell death. An alternative form of the proteasome, termed the immunoproteasome, also has important functions in the generation of peptides for presentation by MHC class I molecules. In recent years there has been a great deal of interest in the possibility that proteasome inhibitors, through elevation of the levels of proteasome targets, might prove useful as a novel class of anti-cancer drugs. Here we review the progress made to date in this area and highlight the potential advantages and weaknesses of this approach.

Adolescent involvement in anti-social and delinquent behaviours : predicting future injury risk

The purpose of this study was to challenge the broadly based focus of injury prevention strategies towards concern with the needs of young adolescents who engage in multiple anti-social and delinquent behaviours. Five hundred and forty 13-14 year olds reported on injuries and truancy, violence, illegal road behaviours, drug, and alcohol use. Engagement in these behaviours was found to contribute to the likelihood of an injury. Those engaging in the most anti-social and delinquent behaviours were around five times more likely to report medically-treated injuries in the past three months. Their likelihood of future injury was 1.8 times more likely when they were followed up three months later. The engagement in multiple delinquent and illegal behaviours thus significantly increased the likelihood of injury and identifies a particularly vulnerable group. The findings also suggest that reaching these young people represents a key target for change strategies in injury prevention programs.

A hierarchical evolutionary algorithmic design (HEAD) system for generating and evolving building design models

This thesis develops a detailed conceptual design method and a system software architecture defined with a parametric and generative evolutionary design system to support an integrated interdisciplinary building design approach. The research recognises the need to shift design efforts toward the earliest phases of the design process to support crucial design decisions that have a substantial cost implication on the overall project budget. The overall motivation of the research is to improve the quality of designs produced at the author's employer, the General Directorate of Major Works (GDMW) of the Saudi Arabian Armed Forces. GDMW produces many buildings that have standard requirements, across a wide range of environmental and social circumstances. A rapid means of customising designs for local circumstances would have significant benefits. The research considers the use of evolutionary genetic algorithms in the design process and the ability to generate and assess a wider range of potential design solutions than a human could manage. This wider ranging assessment, during the early stages of the design process, means that the generated solutions will be more appropriate for the defined design problem. The research work proposes a design method and system that promotes a collaborative relationship between human creativity and the computer capability. The tectonic design approach is adopted as a process oriented design that values the process of design as much as the product. The aim is to connect the evolutionary systems to performance assessment applications, which are used as prioritised fitness functions. This will produce design solutions that respond to their environmental and function requirements. This integrated, interdisciplinary approach to design will produce solutions through a design process that considers and balances the requirements of all aspects of the design. Since this thesis covers a wide area of research material, 'methodological pluralism' approach was used, incorporating both prescriptive and descriptive research methods. Multiple models of research were combined and the overall research was undertaken following three main stages, conceptualisation, developmental and evaluation. The first two stages lay the foundations for the specification of the proposed system where key aspects of the system that have not previously been proven in the literature, were implemented to test the feasibility of the system. As a result of combining the existing knowledge in the area with the newlyverified key aspects of the proposed system, this research can form the base for a future software development project. The evaluation stage, which includes building the prototype system to test and evaluate the system performance based on the criteria defined in the earlier stage, is not within the scope this thesis. The research results in a conceptual design method and a proposed system software architecture. The proposed system is called the 'Hierarchical Evolutionary Algorithmic Design (HEAD) System'. The HEAD system has shown to be feasible through the initial illustrative paper-based simulation. The HEAD system consists of the two main components - 'Design Schema' and the 'Synthesis Algorithms'. The HEAD system reflects the major research contribution in the way it is conceptualised, while secondary contributions are achieved within the system components. The design schema provides constraints on the generation of designs, thus enabling the designer to create a wide range of potential designs that can then be analysed for desirable characteristics. The design schema supports the digital representation of the human creativity of designers into a dynamic design framework that can be encoded and then executed through the use of evolutionary genetic algorithms. The design schema incorporates 2D and 3D geometry and graph theory for space layout planning and building formation using the Lowest Common Design Denominator (LCDD) of a parameterised 2D module and a 3D structural module. This provides a bridge between the standard adjacency requirements and the evolutionary system. The use of graphs as an input to the evolutionary algorithm supports the introduction of constraints in a way that is not supported by standard evolutionary techniques. The process of design synthesis is guided as a higher level description of the building that supports geometrical constraints. The Synthesis Algorithms component analyses designs at four levels, 'Room', 'Layout', 'Building' and 'Optimisation'. At each level multiple fitness functions are embedded into the genetic algorithm to target the specific requirements of the relevant decomposed part of the design problem. Decomposing the design problem to allow for the design requirements of each level to be dealt with separately and then reassembling them in a bottom up approach reduces the generation of non-viable solutions through constraining the options available at the next higher level. The iterative approach, in exploring the range of design solutions through modification of the design schema as the understanding of the design problem improves, assists in identifying conflicts in the design requirements. Additionally, the hierarchical set-up allows the embedding of multiple fitness functions into the genetic algorithm, each relevant to a specific level. This supports an integrated multi-level, multi-disciplinary approach. The HEAD system promotes a collaborative relationship between human creativity and the computer capability. The design schema component, as the input to the procedural algorithms, enables the encoding of certain aspects of the designer's subjective creativity. By focusing on finding solutions for the relevant sub-problems at the appropriate levels of detail, the hierarchical nature of the system assist in the design decision-making process.

Disobedient Citizens : Press Depictions of Striking School Teachers in NSW and Anti-Vietnam War Demonstrators in NSW and Victoria in 1968

Across Australia in 1968, students demonstrating against the Vietnam War engaged in confrontational behaviour. The metropolitan daily newspapers,the most important source of news for most people, enthusiastically reported the scenes. The demonstrations were exciting. Sensational headlines and photographs captured the interest of readers and influenced their opinions. But radical opposition to government policies at the time was not limited to university students opposing the Vietnam War. Teachers had become increasingly critical of conditions in schools, with Victorian secondary school teachers having stopped work on a number of occasions since 1965. In October 1968, both primary and secondary school teachers in New South Wales participated in eastern Australia’s first state-wide teachers’ strike. As Sydney’s Sun commented on 1 October 1968, “The teachers’ strike threw the ... education system into chaos ... A huge proportion of the State’s 2764 schools were silent and empty.” Similarities with the anti-war demonstrations were obvious. Although not as confrontational, the New South Wales teachers’ strike was a publicity-seeking action. This examination of the teachers’ more restrained, but more effective, approach to challenging government policies provides a new voice and vision to our understandings of the diverse nature of radicalism in Australia in the 1960s.

Tolerance, Freedom, Justice and Peace?: Britain, Australia and anti-Muslim Racism in the UK and Australia before 11 September 2001

Since 11 September 2001, Muslim minorities have experienced intensive "othering" in “Western” countries, above all in those US-led anglophone nations which invaded Afghanistan and Iraq to prosecute their "war on terror". This paper examines the cases of Britain and Australia, where whole communities of Muslims have been criminalised as "evil" and a "fifth column" enemy within by media, politicians, the security services and the criminal justice system. Although constituted by disparate ethnic groups, the targeted communities in each of these nations have experienced similar treatment in the State's anti-terrorist measures, as well as ideological responses and everyday racism, making comparable the two cases.

Combination of MEK-ERK inhibitor and hyaluronic acid has a synergistic effect on anti-hypertrophic and pro-chondrogenic activities in osteoarthritis treatment

We hypothesised that a potentially disease-modifying osteoarthritis (OA) drug such as hyaluronic acid (HA) given in combination with anti-inflammatory signalling agents such as mitogen-activated protein kinase kinase–extracellular signal-regulated kinase (MEK-ERK) signalling inhibitor (U0126) could result in additive or synergistic effects on preventing the degeneration of articular cartilage. Chondrocyte differentiation and hypertrophy were evaluated using human OA primary cells treated with either HA or U0126, or the combination of HA + U0126. Cartilage degeneration in menisectomy (MSX) induced rat OA model was investigated by intra-articular delivery of either HA or U0126, or the combination of HA + U0126. Histology, immunostaining, RT-qPCR, Western blotting and zymography were performed to assess the expression of cartilage matrix proteins and hypertrophic markers. Phosphorylated ERK (pERK)1/2-positive chondrocytes were significantly higher in OA samples compared with those in healthy control suggesting the pathological role of that pathway in OA. It was noted that HA + U0126 significantly reduced the levels of pERK, chondrocyte hypertrophic markers (COL10 and RUNX2) and degenerative markers (ADAMTs5 and MMP-13), however, increased the levels of chondrogenic markers (COL2) compared to untreated or the application of HA or U0126 alone. In agreement with the results in vitro, intra-articular delivery of HA + U0126 showed significant therapeutic improvement of cartilage in rat MSX OA model compared with untreated or the application of HA or U0126 alone. Our study suggests that the combination of HA and MEK-ERK inhibition has a synergistic effect on preventing cartilage degeneration.

First international workshop on theory and applications of process visualization

The representation of business process models has been a continuing research topic for many years now. However, many process model representations have not developed beyond minimally interactive 2D icon-based representations of directed graphs and networks, with little or no annotation for information over- lays. With the rise of desktop computers and commodity mobile devices capable of supporting rich interactive 3D environments, we believe that much of the research performed in computer human interaction, virtual reality, games and interactive entertainment has much potential in areas of BPM; to engage, pro- vide insight, and to promote collaboration amongst analysts and stakeholders alike. This initial visualization workshop seeks to initiate the development of a high quality international forum to present and discuss research in this field. Via this workshop, we intend to create a community to unify and nurture the development of process visualization topics as a continuing research area.

Things that fall over : Women's playwriting, poetics and the (anti-)musical

Abstract: This study explores the contradictions and ambivalences experienced by a working artist at a time when her age, her gender, and broader cultural shifts are all potential obstacles or liabilities to creative flourishing. It is the product of practice-led research into the creative process from the perspective of the female "late bloomer". In this phrase, I have in mind the mature-aged woman who is, in mid-life, suddenly seized with inspiration and fired with creative energy. At its heart is the question: If an Elizabeth Jolley were in our midst today, would we hear from her? The result is a full-length libretto and accompanying exegetical binoculars in the form of a Preface and an Afterword. The creative work, Things That Fall Over (TTFO) is conceived in two parts: a libretto and oratorio for performance. It begins as a play, but over three acts and into a coda, the work becomes something entirely other - an (anti-) musical. The work grew from a personal interest in the nexus between women, ageing and creative practice, via investigation into the oeuvre of two Australian artists, Elizabeth Jolley, author, first published at age 53, and Rosalie Gascoigne, sculptor, first exhibited at 58. A second strand of the research grew from a fascination for the stage musical, especially in its more alternative modes as in the hands of Stephen Sondheim, or in more provocative manifestations as witnessed in recent Tony Award winners Avenue Q and The Book of Mormon. Contextually, this research is conducted at a time when anecdotal evidence suggests that women’s work in the performing arts and in literature is being pushed to the margins after a late twentieth century Golden Age on page and stage. Using hybrid practice-led methodologies - bricolage, log-keeping - and working within queer and feminist paradigms, this study seeks to counter that push with a new work that is all-female, part-pantomime, part monstrous allegory. In illuminating the creative process of a mature-aged playwright it concludes that hybrid and interstitial forms still offer an inclusive and democratic space in which voices that may otherwise be muted will continue to be heard.

Patriarchy reasserted : fathers' rights and anti-VAWA activism

The backlash against gender-sensitive responses to women's victimization, offending, and imprisonment is inseparable from contemporary reaction against feminism and other progressive movements. The backlash against the American Violence Against Women Act (VAWA) provides a prime example of this resistance. Despite widespread support for VAWA and other policies designed to address violence against women, some constituencies object to their existence. The author investigates fathers' rights rhetoric on VAWA as an example of antifeminist backlash.

How males and females define speeding and how they’d feel getting caught for it : some implications for anti-speeding message development

Speeding represents a major contributor to road trauma, increasing crash frequency and severity. Antispeeding campaigns represent a key strategy aimed at discouraging individuals from speeding. This paper investigated salient beliefs underpinning male and female drivers’ travel speed behaviour, with the view to use such insight to, ultimately, inform the content of targeted anti-speeding messages. A survey of N = 751 (579 males, 16-79 years) drivers assessed what they regarded as speeding in 60km/hr and 100km/hr zones and their beliefs about how they would respond to receiving a speeding infringement. Participants responded to scales which extended up to 20km/hr above each respective speed limit, the lowest speed that they considered was speeding and the speed at which they would be willing to drive and still feel in control. For analyses, to enable greater scrutiny of potential gender differences regarding the speeds identified, participants’ responses to these items were categorised into 5km/hr increments and chi-square analyses conducted. For their responses to (beliefs about) the possibility of being caught speeding, drivers were asked how applicable various beliefs were to them (e.g., feeling unlucky). These beliefs were analysed via MANOVA. The results revealed that there was considerable variability in the speeds identified, thus supporting the value of categorising speeds. Within the 100km/hr zone, based on the categories, a significant difference was found regarding the speed that males would be willing to drive (and still feel in control) relative to females. Specifically, the greatest proportion of males (30.4%) identified speeds within the 106-110km/hr category whereas the greatest proportion of females (38.1%) identified a lower speed, within the 101-105km/hr category, as the speed they would be willing to drive. No other significant differences emerged, however, either in relation to the definition of speeding reported for 100km/hr zones (i.e., males and females tended to identify a similar speed as indicative of speeding) nor for these same items as assessed in relation to the 60km/hr zones. For their responses to the possibility of being caught, males were significantly more likely than females to report that, if caught, a likely response they would have would be to think that they had still been driving safely. In contrast, females were significantly more likely than males to report thinking that their speeding had been unsafe and that they should not have been speeding. Females were also significantly more likely to report feeling embarrassed to tell important others about having received a speeding infringement than males. The findings are discussed in terms of their implications for developing well-targeted advertising messages aimed at discouraging drivers’ from speeding.

Anti-infectives

18.1 Antibiotics 18.1.1 Introduction to bacteria 18.1.2 Introduction to antibiotics 18.1.3 Inhibitors of bacterial cell wall synthesis 18.1.3.1 β-Lactams 18.1.3.2 Glycopeptides 18.1.4 Inhibitors of bacterial protein synthesis 18.1.4.1 Tetracyclines 18.1.4.2 Aminoglycosides 18.1.4.3 Chloramphenicol 18.1.4.4 Macrolides 18.1.4.5 Lincosamides 18.1.4.6 Oxalazidones 18.1.5 Inhibitors of DNA synthesis 18.2. Anti-tuberculotic drugs 18.2.1 Introduction 18.2.2 Isoniazid 18.2.3 Ethambutol 18.2.4 Rifamycin 18.2.5 Pyrazinamide 18.3. Anti-viral drugs 18.3.1 Introduction to viruses 18.3.2 Drugs used to treat herpesviruses 18.3.3 Drugs used to treat the flu 18.3.4 Drugs used to treat HIV/AIDS 18.4. Antifungal drugs 18.4.1 Introduction to Fungi 18.4.2 Antifungal drugs