Natural and engineered plasmin inhibitors : applications and design strategies

Plasmin is the primary enzyme responsible for dissolution of fibrin in the circulatory system. Plasminogen, the zymogen of plasmin is expressed ubiquitously in the human body [1], with the predominant source being the liver [2, 3]. Plasminogen is produced as an 810 amino acid protein with a 19 amino acid leader peptide, which is cleaved during secretion to produce the mature 791 amino acid one-chain zymogen. This is converted to plasmin by cleavage of the Arg561 - Val562 scissile bond [4], resulting in an active protease consisting of two disulfide linked chains. The amino-terminal heavy chain (residues Glu1-Arg561) is comprised of a plasminogen/apple/nematode (PAN) domain [5] and five kringle domains of approximately equal size [6] while the light chain (residues Val562-Asn791) contains a serine protease domain homologous to trypsin with a catalytic triad comprising His603, Asp646 and Ser741 [7]. Both plasmin and plasminogen occur in two forms, full length and a Lys77-Lys78 activated variant produced through self catalysis (Figure 1). The former exists in a tight conformation through binding of Lys50 and/or Lys62 to kringle domain 5 [8, 9] while Lys78-plasminogen assumes a more relaxed conformation rendering it more susceptible to plasmin conversion [10, 11].

The role of motivation and motivational strategies in Saudi students' communicative competence in English

This study explored how motivation and motivational strategies influence the communicative competence of students from Saudi Arabia. Participants included Saudi students enrolled in English courses in Australian educational institutions, and Saudi students living in Saudi Arabia studying in English language institutes in Saudi Arabia. Phase One involved interviews with16 participants. In Phase Two, 279 participants completed a questionnaire. Findings included differences between participants’ measured and self-reported communicative competence, with the Australian group having higher levels of measured and self-reported communicative competence. In addition, motivation teaching strategies were found to affect students’ motivation, but not their communicative competence.

The health effects of temperature : current estimates, future projections, and adaptation strategies

Climate change is expected to be one of the biggest global health threats in the 21st century. In response to changes in climate and associated extreme events, public health adaptation has become imperative. This thesis examined several key issues in this emerging research field. The thesis aimed to identify the climate-health (particularly temperature-health) relationships, then develop quantitative models that can be used to project future health impacts of climate change, and therefore help formulate adaptation strategies for dealing with climate-related health risks and reducing vulnerability. The research questions addressed by this thesis were: (1) What are the barriers to public health adaptation to climate change? What are the research priorities in this emerging field? (2) What models and frameworks can be used to project future temperature-related mortality under different climate change scenarios? (3) What is the actual burden of temperature-related mortality? What are the impacts of climate change on future burden of disease? and (4) Can we develop public health adaptation strategies to manage the health effects of temperature in response to climate change? Using a literature review, I discussed how public health organisations should implement and manage the process of planned adaptation. This review showed that public health adaptation can operate at two levels: building adaptive capacity and implementing adaptation actions. However, there are constraints and barriers to adaptation arising from uncertainty, cost, technologic limits, institutional arrangements, deficits of social capital, and individual perception of risks. The opportunities for planning and implementing public health adaptation are reliant on effective strategies to overcome likely barriers. I proposed that high priorities should be given to multidisciplinary research on the assessment of potential health effects of climate change, projections of future health impacts under different climate and socio-economic scenarios, identification of health cobenefits of climate change policies, and evaluation of cost-effective public health adaptation options. Heat-related mortality is the most direct and highly-significant potential climate change impact on human health. I thus conducted a systematic review of research and methods for projecting future heat-related mortality under different climate change scenarios. The review showed that climate change is likely to result in a substantial increase in heatrelated mortality. Projecting heat-related mortality requires understanding of historical temperature-mortality relationships, and consideration of future changes in climate, population and acclimatisation. Further research is needed to provide a stronger theoretical framework for mortality projections, including a better understanding of socioeconomic development, adaptation strategies, land-use patterns, air pollution and mortality displacement. Most previous studies were designed to examine temperature-related excess deaths or mortality risks. However, if most temperature-related deaths occur in the very elderly who had only a short life expectancy, then the burden of temperature on mortality would have less public health importance. To guide policy decisions and resource allocation, it is desirable to know the actual burden of temperature-related mortality. To achieve this, I used years of life lost to provide a new measure of health effects of temperature. I conducted a time-series analysis to estimate years of life lost associated with changes in season and temperature in Brisbane, Australia. I also projected the future temperaturerelated years of life lost attributable to climate change. This study showed that the association between temperature and years of life lost was U-shaped, with increased years of life lost on cold and hot days. The temperature-related years of life lost will worsen greatly if future climate change goes beyond a 2 °C increase and without any adaptation to higher temperatures. The excess mortality during prolonged extreme temperatures is often greater than the predicted using smoothed temperature-mortality association. This is because sustained period of extreme temperatures produce an extra effect beyond that predicted by daily temperatures. To better estimate the burden of extreme temperatures, I estimated their effects on years of life lost due to cardiovascular disease using data from Brisbane, Australia. The results showed that the association between daily mean temperature and years of life lost due to cardiovascular disease was U-shaped, with the lowest years of life lost at 24 °C (the 75th percentile of daily mean temperature in Brisbane), rising progressively as temperatures become hotter or colder. There were significant added effects of heat waves, but no added effects of cold spells. Finally, public health adaptation to hot weather is necessary and pressing. I discussed how to manage the health effects of temperature, especially with the context of climate change. Strategies to minimise the health effects of high temperatures and climate change can fall into two categories: reducing the heat exposure and managing the health effects of high temperatures. However, policy decisions need information on specific adaptations, together with their expected costs and benefits. Therefore, more research is needed to evaluate cost-effective adaptation options. In summary, this thesis adds to the large body of literature on the impacts of temperature and climate change on human health. It improves our understanding of the temperaturehealth relationship, and how this relationship will change as temperatures increase. Although the research is limited to one city, which restricts the generalisability of the findings, the methods and approaches developed in this thesis will be useful to other researchers studying temperature-health relationships and climate change impacts. The results may be helpful for decision-makers who develop public health adaptation strategies to minimise the health effects of extreme temperatures and climate change.

Monitoring policy and actions on food environments : rationale and outline of the INFORMAS policy engagement and communication strategies

The International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support (INFORMAS) proposes to collect performance indicators on food policies, actions and environments related to obesity and non-communicable diseases. This paper reviews existing communications strategies used for performance indicators and proposes the approach to be taken for INFORMAS. Twenty-seven scoring and rating tools were identified in various fields of public health including alcohol, tobacco, physical activity, infant feeding and food environments. These were compared based on the types of indicators used and how they were quantified, scoring methods, presentation and the communication and reporting strategies used. There are several implications of these analyses for INFORMAS: the ratings/benchmarking approach is very commonly used, presumably because it is an effective way to communicate progress and stimulate action, although this has not been formally evaluated; the tools used must be trustworthy, pragmatic and policy-relevant; multiple channels of communication will be needed; communications need to be tailored and targeted to decision-makers; data and methods should be freely accessible. The proposed communications strategy for INFORMAS has been built around these lessons to ensure that INFORMAS's outputs have the greatest chance of being used to improve food environments.

It's just an old apron : aprons, artefacts and art - representations of personal and private 'her-stories', as public histories

This paper examines art and artefact in the representation and recollection of deeply personal WWII women’s experiences as POW’s under the Japanese. This kind of treatment of internees in the Tjideng Women and Children’s internment camp (and others) in Batavia under the Japanese in WWII, stands in stark and brutal contrast to the idyllic life lived by many families up to that time in what was then known as the Dutch East Indies (Indonesia). The deprivation and brutality of the Japanese incarceration of these women and children evoked responses - not military, but certainly militant, if muted. Representations of those responses – as both art and artefact - may be found in the most unlikely places and unexpected forms - and are still being unearthed to this day. However close we might personally be to these artists and artisans, can we, as observers from a distance, ever truly comprehend through spoken or written words alone, the day-today realities of those extraordinary times?

Establishing research in a palliative care clinical setting : perceived barriers and implemented strategies

There are many challenges in developing research projects in research-naïve clinical settings, especially palliative care where resistance to participate in research has been identified. These challenges to the implementation of research are common in nursing practice and are associated with attitudes towards research participation, and some lack of understanding of research as a process to improve clinical practice. This is despite the professional nursing requirement to conduct research into issues that influence palliative care practice. The purpose of this paper is to describe the process of implementing a clinical research project in collaboration with the clinicians of a palliative care community team and to reflect on the strategies implemented to overcome the challenges involved. The challenges presented here demonstrate the importance of proactively implementing engagement strategies from the inception of a research project in a clinical setting.

An analysis of ranking principles and retrieval strategies

The assumptions underlying the Probability Ranking Principle (PRP) have led to a number of alternative approaches that cater or compensate for the PRP’s limitations. All alternatives deviate from the PRP by incorporating dependencies. This results in a re-ranking that promotes or demotes documents depending upon their relationship with the documents that have been already ranked. In this paper, we compare and contrast the behaviour of state-of-the-art ranking strategies and principles. To do so, we tease out analytical relationships between the ranking approaches and we investigate the document kinematics to visualise the effects of the different approaches on document ranking.

Developing a framework of effective prevention and response strategies in workplace sexual harassment

Sexual harassment remains a widespread workplace phenomenon, despite laws that proscribe it. Drawing initially on a typology from the violence prevention literature that conceptualizes prevention and response approaches according to when they occur, the paper synthesizes strategies identified in literature addressing workplace sexual harassment, as well as other workplace injustices or grievances. The paper utilizes this previous research to develop a framework of sexual harassment prevention strategies along two dimensions: functions and timing. The framework offers a research-informed set of organization-wide preventative and remedial approaches, a systemic approach to what is often seen as an individual problem, and a means to better focus interventions that are often disparate and unco-ordinated. The paper also highlights important areas for future research including a stronger focus on longer-term (tertiary) corrective actions.

An analysis of ranking principles and retrieval strategies

The assumptions underlying the Probability Ranking Principle (PRP) have led to a number of alternative approaches that cater or compensate for the PRP’s limitations. All alternatives deviate from the PRP by incorporating dependencies. This results in a re-ranking that promotes or demotes documents depending upon their relationship with the documents that have been already ranked. In this paper, we compare and contrast the behaviour of state-of-the-art ranking strategies and principles. To do so, we tease out analytical relationships between the ranking approaches and we investigate the document kinematics to visualise the effects of the different approaches on document ranking.

Managing growth and entry strategies across borders

Should the firm move successfully into a growth or expansion phase the owner manager will be required to increase the scale and scope of its operations. Part of this expansion will involve hiring additional employees, and increasing the overall complexity of the firm's activities. It is likely that the need for greater levels of professional management will be required to operate the firm, along with the need for enhanced planning and the introduction of systems to support the new levels of complexity. The transition from a small, owner-managed firm to a large systems-managed business will require the development of a team-based management approach with greater specialisation within the management team. Corporate governance is also likely to change as the growth cycle takes place. As it grows, the business will become more formalised in its accounting, management and other systems. The need for greater quantities of capital is likely to lead the business towards equity finance. As new equity partner are taken into the company the original owner managers may find their level of control diminished. The larger the firm becomes the more likely its management structure will become decentralised with greater separation between the owner and the firm in terms of operational and financial matters.

Tetraspanins as regulators of the tumour microenvironment : implications for metastasis and therapeutic strategies

One of the hallmarks of cancer is the ability to activate invasion and metastasis (Hanahan et al., 2011). Cancer morbidity and mortality are largely related to the spread of the primary, localised tumour to adjacent and distant sites (Pantel et al., 2004). Appropriate management and treatment decisions of predicting metastatic disease at the time of diagnosis is thus crucial, which supports better understanding of the metastatic process. There are common events that occur during metastasis: dissociation from the primary tumour mass, reorganisation/remodelling of extracellular matrix, cell migration, recognition and transversal of endothelial cells and the vascular circulation and lodgement and proliferation within ectopic stroma (Wells, 2006). One of the key and initial events is the increased capability of cancer cells to move, escaping the regulation of normal physiological control. The cellular cytoskeleton plays an important role in cancer cell motility and active cytoskeletal rearrangement can result in metastatic disease. This active change in cytoskeletal dynamics results in manipulation of plasma membrane and cellular balance between cellular adhesion and motility which in turn determines cancer cell movement. Members of the tetraspanins play important roles in regulation of cancer migration and cancer-endothelial cell interactions, which are critical for cancer invasion and metastasis. Their involvements in active cytoskeletal dynamics, cancer metastasis and potential clinical application will be discussed in this review. In particular, tetraspanin member, CD151, is highlighted for its major role in cancer invasion and metastasis

Environmental, personal, and genetic determinants of response to vitamin D supplementation in older adults

CONTEXT AND OBJECTIVE: Suboptimal vitamin D status can be corrected by vitamin D supplementation, but individual responses to supplementation vary. We aimed to examine genetic and nongenetic determinants of change in serum 25-hydroxyvitamin D (25(OH)D) after supplementation. DESIGN AND PARTICIPANTS: We used data from a pilot randomized controlled trial in which 644 adults aged 60 to 84 years were randomly assigned to monthly doses of placebo, 30 000 IU, or 60 000 IU vitamin D3 for 12 months. Baseline characteristics were obtained from a self-administered questionnaire. Eighty-eight single-nucleotide polymorphisms (SNPs) in 41 candidate genes were genotyped using Sequenom MassArray technology. Serum 25(OH)D levels before and after the intervention were measured using the Diasorin Liaison platform immunoassay. We used linear regression models to examine associations between genetic and nongenetic factors and change in serum 25(OH)D levels. RESULTS: Supplement dose and baseline 25(OH)D level explained 24% of the variability in response to supplementation. Body mass index, self-reported health status, and ambient UV radiation made a small additional contribution. SNPs in CYP2R1, IRF4, MC1R, CYP27B1, VDR, TYRP1, MCM6, and HERC2 were associated with change in 25(OH)D level, although only CYP2R1 was significant after adjustment for multiple testing. Models including SNPs explained a similar proportion of variability in response to supplementation as models that included personal and environmental factors. CONCLUSION: Stepwise regression analyses suggest that genetic variability may be associated with response to supplementation, perhaps suggesting that some people might need higher doses to reach optimal 25(OH)D levels or that there is variability in the physiologically normal level of 25(OH)D.

Predicting Australian adults' sun-safe behaviour : examining the role of personal and social norms

Objectives To address the scarcity of comprehensive, theory-based research in the Australian context, this study, using a theory of planned behaviour (TPB) framework, investigated the role of personal and social norms to identify the key predictors of adult Australians' sun-safe intentions and behaviour. Design The study used a prospective design with two waves of data collection, 1 week apart. Methods Participants were 816 adults (48.2% men) aged between 18 and 88 years recruited from urban, regional, and rural areas of Australia. At baseline, participants completed a questionnaire assessing the standard TPB predictors (attitude, subjective norm, and perceived behavioural control [PBC]), past behaviour, behavioural intention, and additional measures of group norm for the referent groups of friends and family, image norm, personal norm, personal choice/responsibility, and Australian identity. Seventy-one per cent of the participants (n = 577) reported on their sun-safe behaviour in the subsequent week. Results Via path modelling, past behaviour, attitude, group norm (friends), personal norm, and personal choice/responsibility emerged as independent predictors of intentions which, in turn, predicted sun-safe behaviour prospectively. Past behaviour, but not PBC, had direct effects on sun-safe behaviour. The model explained 61.6% and 43.9% of the variance in intention and behaviour, respectively. Conclusions This study provides support for the use of a comprehensive theoretical decision-making model to explain Australian adults' sun-safe intentions and behaviours and identifies viable targets for health-promoting messages in this high-risk context.

Using DNA as a drug - bioprocessing and delivery strategies

DNA may take a leading role in a future generation of blockbuster therapeutics. DNA has inherent advantages over other biomolecules such as protein, RNA and virus-like particles including safety, production simplicity and higher stability at ambient temperatures. Vaccination is the principal measure for preventing influenza and reducing the impact of pandemics; however, vaccines take up to 8-9 months to produce, and the global production capacity is woefully low. With production times as short as 2 weeks, improved safety and stability, bioprocess engineering developments, and the ability to perform numerous therapeutic roles, DNA has the potential to meet the demands of emerging and existing diseases. DNA is experiencing sharp growths in demand as indicated by its use in gene therapy trials and DNA vaccine related patents. Of particular interest for therapeutic use is plasmid DNA (pDNA), a form of non-genomic DNA that makes use of cellular machinery to express proteins or antigens. The production stages of fermentation and downstream purification are considered in this article. Forward looking approaches to purifying and delivering DNA are reported, including affinity chromatography and nasal inhalation. The place that pDNA may take in the preparation for and protection against pandemics is considered. If DNA therapeutics and vaccines prove to be effective, the ultimate scale of production will be huge which shall require associated bioprocess engineering research and development for purification of this large, unique biomolecule.

Evolutionary optimization and game strategies for advanced multi-disciplinary design : applications to aeronautics and UAV design

Many complex aeronautical design problems can be formulated with efficient multi-objective evolutionary optimization methods and game strategies. This book describes the role of advanced innovative evolution tools in the solution, or the set of solutions of single or multi disciplinary optimization. These tools use the concept of multi-population, asynchronous parallelization and hierarchical topology which allows different models including precise, intermediate and approximate models with each node belonging to the different hierarchical layer handled by a different Evolutionary Algorithm. The efficiency of evolutionary algorithms for both single and multi-objective optimization problems are significantly improved by the coupling of EAs with games and in particular by a new dynamic methodology named “Hybridized Nash-Pareto games”. Multi objective Optimization techniques and robust design problems taking into account uncertainties are introduced and explained in detail. Several applications dealing with civil aircraft and UAV, UCAV systems are implemented numerically and discussed. Applications of increasing optimization complexity are presented as well as two hands-on test cases problems. These examples focus on aeronautical applications and will be useful to the practitioner in the laboratory or in industrial design environments. The evolutionary methods coupled with games presented in this volume can be applied to other areas including surface and marine transport, structures, biomedical engineering, renewable energy and environmental problems.