Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides

Tissue damage resulting from the extracellular production of HOCl (hypochlorous acid) by the MPO (myeloperoxidase)-hydrogen peroxide-chloride system of activated phagocytes is implicated as a key event in the progression of a number of human inflammatory diseases. Consequently, there is considerable interest in the development of therapeutically useful MPO inhibitors. Nitroxides are well established antioxidant compounds of low toxicity that can attenuate oxidative damage in animal models of inflammatory disease. They are believed to exert protective effects principally by acting as superoxide dismutase mimetics or radical scavengers. However, we show here that nitroxides can also potently inhibit MPO-mediated HOCl production, with the nitroxide 4-aminoTEMPO inhibiting HOCl production by MPO and by neutrophils with IC50 values of approx. 1 and 6 μM respectively. Structure–activity relationships were determined for a range of aliphatic and aromatic nitroxides, and inhibition of oxidative damage to two biologically-important protein targets (albumin and perlecan) are demonstrated. Inhibition was shown to involve one-electron oxidation of the nitroxides by the compound I form of MPO and accumulation of compound II. Haem destruction was also observed with some nitroxides. Inhibition of neutrophil HOCl production by nitroxides was antagonized by neutrophil-derived superoxide, with this attributed to superoxide-mediated reduction of compound II. This effect was marginal with 4-aminoTEMPO, probably due to the efficient superoxide dismutase-mimetic activity of this nitroxide. Overall, these data indicate that nitroxides have considerable promise as therapeutic agents for the inhibition of MPO-mediated damage in inflammatory diseases.

A method for evaluating lean assembly process at design stage

Lean product design has the potential to reduce the overall product development time and cost and can improve the quality of a product. However, it has been found that no or little work has been carried out to provide an integrated framework of "lean design" and to quantitatively evaluate the effectiveness of lean practices/principles in product development process. This research proposed an integrated framework for lean design process and developed a dynamic decision making tool based on Methods Time Measurement (MTM) approach for assessing the impact of lean design on the assembly process. The proposed integrated lean framework demonstrates the lean processes to be followed in the product design and assembly process in order to achieve overall leanness. The decision tool consists of a central database, the lean design guidelines, and MTM analysis. Microsoft Access and C# are utilized to develop the user interface to use the MTM analysis as decision making tool. MTM based dynamic tool is capable of estimating the assembly time, costs of parts and labour of various alternatives of a design and hence is able to achieve optimum design. A case study is conducted to test and validate the functionality of the MTM Analysis as well as to verify the lean guidelines proposed for product development.

Bear With Me

This project investigates musicalisation and intermediality in the writing and devising of composed theatre. Its research question asks “How does the narrative of a musical play differ when it emerges from a setlist of original songs?”, the aim being to create performance event that is neither music nor theatre. This involves composition of lyrics, music, action and spoken text, projected image: gathered in a script and presented in performance. Scholars such as Kulezic-Wilson(in Kendrick, L and Roesner, D 2011:34) outline the acoustic dimension to the ‘performative turn’ (Mungen, Ernst and Bentzweizer, 2012) as heralding “…a shift of emphasis on how meaning is created (and veiled) and how the spectrum of theatrical creation and reception is widened.” Rebstock and Roesner (2012) capture approaches similar to this, building on Lehmann’s work in the post-dramatic under the new term ‘composed theatre’. This practice led research draws influence from these new theoretical frames, pushing beyond ‘the musical’. Springing from a set of original songs in dialogue with performed narrative, Bear with Me is a 45 minute music driven work for children, involving projected image and participatory action. Bear with Me’s intermedial hybrid of theatrical, screen and concert presentations shows that a simple setlist of original songs can be the starting point for the structure of a complex intermedial performance. Bear with Me was programmed into the Queensland Performing Arts Centre’s Out of the Box Festival. It was first performed in the Tony Gould Gallery at the Queensland in June 2012. The season sold out. A masterclass on my playwriting methodology was presented at the Connecting The Dots Symposium which ran alongside the festival.

Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

Foreword

In 1978, three years after the publication of Foucault’s book Discipline and Punish, which famously introduced Bentham’s notion of the Panopticon to a wide audience, the French historian Jacques Léonard remarked that ‘it would need a squadron of competent historians to sort out the mass of interpretations’ offered by Foucault’s work. In response, Foucault said that he wanted his work to provide a workshop which would allow both himself and others to undertake further work and experiment with different approaches. He also cheerfully noted that he was encouraged by the ‘irritating effect’ that his work produced on others. The present book, which comprehensively treats the work of Bentham both in the wake of and against Foucault’s work, is a cogent testimony to the continued currency of these observations.

Architecture and affect

Invited Lecture for Interdisciplinary seminar, Yale School of Architecture. Seminar investigates architectural techniques of affect; topics included Adrian Stokes, Freud on aggression, Spinoza, German aesthetics, viscerality, Guattari and “concrete machines”; Other Invited guests: Peggy Deamer, Brian Massumi, Gary Genosko, Ernst Prelinger, Elizabeth Grosz, Ed Mitchell.

Factor Five : Transforming the Global Economy through 80% Improvements in Resource Productivity

The 21st century will see monumental change. Either the human race will use its knowledge and skills and change the way it interacts with the environment, or the environment will change the way it interacts with its inhabitants. In the first case, the focus of this book, we would see our sophisticated understanding in areas such as physics, chemistry, engineering, biology, planning, commerce, business and governance accumulated over the last 1,000 years brought to bear on the challenge of dramatically reducing our pressure on the environment. The second case however is the opposite scenario, involving the decline of the planet’s ecosystems until they reach thresholds where recovery is not possible, and following which we have no idea what happens. For instance, if we fail to respond to Sir Nicolas Stern’s call to meet appropriate stabilisation trajectories for greenhouse gas emissions, and we allow the average temperature of our planets surface to increase by 4-6 degrees Celsius, we will see staggering changes to our environment, including rapidly rising sea level, withering crops, diminishing water reserves, drought, cyclones, floods… allowing this to happen will be the failure of our species, and those that survive will have a deadly legacy. In this update to the 1997 International Best Seller, Factor Four, Ernst von Weizsäcker again leads a team to present a compelling case for sector wide advances that can deliver significant resource productivity improvements over the coming century. The purpose of this book is to inspire hope and to then inform meaningful action in the coming decades to respond to the greatest challenge our species has ever faced – that of living in harmony with our planet and its other inhabitants.

Decoupling 2 : technologies, opportunities and policy options

This report was produced by the Decoupling Working Group of the International Resource Panel. It explores technological possibilities and opportunities for both developing and developed countries to accelerate decoupling and reap the environmental and economic benefits of increased resource productivity. It also examines several policy options that have proved to be successful in helping different countries to improve resource productivity in various sectors of their economy, avoiding negative impacts on the environment. It does not seem possible for a global economy based on the current unsustainable patterns of resource use to continue into the future. The economic consequences of these patterns are already apparent in three areas: increases in resource prices, increased price volatility and disruption of environmental systems. The environment impacts of resource use are also leading to potentially irreversible changes to the world’s ecosystems, often with direct effects on people and the economy – for example through damage to health, water shortages, loss of fish stocks or increased storm damage. But there are alternatives to these scary patterns. Many decoupling technologies and techniques that deliver resource productivity increases as high as 5 to 10-fold are already available, allowing countries to pursue their development strategies while significantly reducing their resource footprint and negative impacts on the environment. This report shows that much of the policy design “know-how” needed to achieve decoupling is present in terms of legislation, incentive systems, and institutional reform. Many countries have tried these out with tangible results, encouraging others to study and where appropriate replicate and scale up such practices and successes.

Evolving a synergistic approach to road safety : an appraisal of the project management, stakeholder engagement and change facilitation (PSC) approach by means of two case studies

Existing research and best practice were utilized to develop the Project Management, Stakeholder Engagement and Change Facilitation (PSC) approach to road safety infrastructure projects. Two case studies involving Queensland Transport and Main Roads demonstrated that use of the PSC has potential to create synergies for projects undertaken by multi-disciplinary road safety groups, and to complement Safe System projects and philosophy. The case studies were the North West Road Safety Alliance project, and the implementation of Road Safety Audit policy, and utilised a mix of qualitative and quantitative methods including interviews and surveys.