Using bioinformatics techniques for gene identification in drug discovery and development

As more and more evidence has become available, the link between gene and emergent disease has been made including cancer, heart disease and parkinsonism. Analyzing the diseases and designing drugs with respect to the gene and protein level obviously help to find the underlying causes of the diseases, and to improve their rate of cure. The development of modern molecular biology, biochemistry, data collection and analysis techniques provides the scientists with a large amount of gene data. To draw a link between genes and their relation to disease outcomes and drug discovery is a big challenge: How to analyze large datasets and extract useful knowledge? Combining bioinformatics with drug discovery is a promising method to tackle this issue. Most techniques of bioinformatics are used in the first two phases of drug discovery to extract interesting information and find important genes and/or proteins for speeding the process of drug discovery, enhancing the accuracy of analysis and reducing the cost. Gene identification is a very fundamental and important technique among them. In this paper, we have reviewed gene identification algorithms and discussed their usage, relationships and challenges in drug discovery and development.

Cardiovascular risk prediction model development and assessment

The aim of this article is to review the development and assessment of cardiovascular risk prediction models and to discuss the predictive value of a risk factor as well as to introduce new assessment methods to evaluate a risk prediction model. Many cardiovascular risk prediction models have been developed during the past three decades. However, there has not been consistent agreement regarding how to appropriately assess a risk prediction model, especially when new markers are added to an existing model. The area under the receiver operating characteristic (ROC) curve has traditionally been used to assess the discriminatory ability of a risk prediction model. However, recent studies suggest that this method has its limitations and cannot be the sole approach to evaluate the usefulness of a new marker. New assessment methods are being developed to appropriately assess a risk prediction model and they will be gradually used in clinical and epidemiological studies.

Development and use of a model system to monitor clubroot disease progression with an Australian field collection of Plasmodiophora brassicae

A modified sand–liquid culture method facilitated easy visualisation of the primary life cycle stages of Plasmodiophora brassicae within clean root hairs of the Arabidopsis host. Pathogen penetration occurred from day 4 onwards and then primary plasmodia developed within the host root. Several Arabidopsis ecotypes tested in varying growth conditions showed differences in disease expression. Defined growth cabinet conditions were found most suitable for studying disease progression in the ecotypes and for achieving uniform infection and disease development. Arabidopsis ecotypes Ta-0 and Tsu-0 known to be partially resistant to a German single-spore isolate of P. brassicae were susceptible to an Australian (Victorian) field population of P. brassicae. The European clubroot differential test was used to confirm virulence and describe the pathotype of the Victorian field population. Knowledge of the interaction of an Australian population of P. brassicae with its host will provide valuable information on a disease which is very difficult to control.

Evidence for healthy cities : reflections on practice, method and theory

The European Healthy Cities project can be characterized as a social movement that employs an extremely wide range of political, social and behavioural interventions for the development and sustenance of urban population health. At all of these levels, the movement is inspired by ideological, theoretical and evidence-based perspectives. The result of this stance is a dynamic, complex and diverse landscape of initiatives, plans, programmes and actions. In quantitative terms (the number of WHO designated cities and associated cities and communities through national networks), ‘Healthy Cities’ can be regarded as an extraordinary accomplishment and a credit for both WHO and cities in the movement. In qualitative terms, however, critics of the movement have maintained that little evidence on its success and effectiveness has been generated. This critique finds its foundations in the mere perceptions of evidence, the politics of science and urban governance, and perspectives on the preferred or professed utilities of evidence-based health notions. The article reviews the nature of evidence and its interface with politics and governance. Applying a conceptual framework combining insights from knowledge utilization theory, theoretical perspectives on (health) policy development, theory-based evaluations and planned intervention approaches, it demonstrates that, although the evidence is overwhelming, there are barriers to the implementation of such evidence that should be further addressed by ‘Healthy Cities’.

FEA simulation of contact and wear between non-metallic materials for accelerated new product development

The conventional approach ie laboratory life testing to examine the reliability of products takes long time and involves tremendous cost as samples are tested till failures. The accelerated life test (ALT) has recently been used as an alternative method. Although ALT reduces the cost of reliability testing through applying more severe environmental conditions than the normal ones, it is no longer sufficient as it does not describe the process of products’ failure explicitly and it is still highly dependent on physical testing. Consequently, novel practices need to be developed for better understanding of the products’ reliability. A novel Finite Element Analysis (FEA) model incorporating mathematical wear equations is developed in the current work and applied to polymer materials. Wear rate, a key parameter, is calculated by using a combinatorial formula that combines a conventional linear equation with a recently published exponential equation. The local wear is firstly calculated and then integrated over the sliding distance. The FEA simulation works in a loop and performs a series of simulation with updated surface geometries. The simulation is in good agreement with the physical testing result.

A method for evaluating workplace utility

Acquiring office buildings that provide the required level of utility, and maintaining the buildings in that state, should be a priority for any organisation. Failure to do so may give rise to increased churn, reduced productivity, higher employee turnover, increased staff absenteeism and rising health care costs related to heightened stress. There is, however, no single measure of office building utility. Discusses the development of a valid and reliable scale for measuring the utility of public sector office buildings. Data collection involved the use of focus groups and an online survey of 1,800 building occupants. The findings suggest that the utility of public sector office buildings can be measured using a 22-item scale comprising four dimensions. The potential applications of the scale and its use in current research are examined.

The structural and behaviourial barriers to sustainable real estate development

Sustainable real estate development appears, on literal translation of both terms, to be an oxymoron - however it is a concept that the real estate profession needs to embrace knowledgably. On one hand it can be argued that real estate development is required for continued economic growth and the adoption of sustainability measures is required to mitigate climate change and global warming. Over the last few years there has been growth in the number of sustainability tools available to designers and operators of buildings. For example, in the US the LEED scheme enables designers to assess the environmental impact of their design and to benchmark the sustainability of the design against industry recognised criteria. LEED follows a similar format to the UK’s Building Research Establishment Environmental Assessment Method (BREEAM) introduced in 1990 and the Australian ‘GreenStar’ introduced in 2004. Even though there are an increasing number of sustainability tools available to designers, it still remains that the degree of uptake of the tools has been sporadic. This paper discusses the barriers to sustainable real estate development. Firstly it identifies the barriers to uptake and secondly it establishes the structural barriers in the market which prevent the wider uptake of tools.

Processes influencing the development of graduate nurse capabilities in clinical risk management : an Australian study

Objectives: To explore and describe key processes influencing the development of graduate nurse capabilities in clinical risk management (CRM).

Methods: This study was undertaken using an exploratory descriptive case study method. Four sample units of analysis were used, notably: 2 cohorts of graduate nurses (n = 11) undertaking a 12-month graduate nurse transition program; key stakeholders (n = 34), that is, nurse unit managers, clinical teachers, preceptors, a quality manager, a librarian, and senior nurse administratiors employed by the participating health service; patient outcome data; and pertinent literature.

Results: Data strongly suggested that graduate nurse capabilities in CRM were most influenced not by their supposed lack of clinical knowledge and skills but by their lack of corporate knowledge. The failure to provide new graduate nurses with pertinent information on CRM at the beginning of their employment and thereafter at pertinent intervals during the graduate nurse year program aslo hindered the development of their capabilities to manage clinical risk.

Conclusions: Management and educational processes pertinent to informing and involving new graduate nurses in a hospital's local CRM program (including information about the organization's local policies and procedures) need to be implemented systematically at the very beginning of a new graduate's employment and thereafter throughout the remainder of the graduate nurse year.

Control of ovarian development in the yabby (Cherax destructor)

A study under controlled conditions of ovarian development and rematuration in the yabby (Cherax destructot) was undertaken. The purpose of the study was to improve fundamental understanding of the reproductive biology of the species and provide a basis for application to hatchery management in culture. A review was made of the current status of yabby culture in Australia and the present understanding of reproductive biology of decapod Crustacea. The review emphasised factors controlling several aspects of ovarian development, in particular the processes of vitellogenesis. The subsequent study was designed within the context of current hatchery practice and was based on existing knowledge of decapod reproduction, The sexual differentiation of the yabby after hatching was investigated by serial histological sections, and experiments were carried out to investigate the possibility of sex reversal of males. Most of this Investigation was concerned with removing the influence of the androgenic gland in directing male development, with the intent of observing the development of the elementary gonadal tissue into ovary. It was found that in contrast to other crustacean species, the sex of the yabby becomes fixed before the development of external secondary sexual characteristics, and before the androgenic gland can be discerned. Ovarian tissue developed in females at less than 8 weeks after hatching. A preliminary examination was undertaken for feminising parasites in gonadal tissue of a hermaphrodite yabby. Investigation of the ovary after spawning demonstrated that whilst the female was held under constant conditions of temperature and photoperiod, little rematuration occurred. Except for generation of previtellogenic oocytes during the first two days, the gonaciosomatic index remained low for up to 5 months after spawning. If the temperature of the female was reduced to 10°C and maintained constant, the previtellogenic oocytes were partially resorbed over a three week period. Rematuration then commenced, albeit at a low rate because of the reduced temperature, A method for standardising gonadosomatic indices was developed which took into account differences in hepatopancreatic nutrient reserves of individuals and loss of one or more appendages. This part of the study also considered constraints to rematuration and developed a method of accounting for differences in the ability of females to remature after spawning. Experiments were carried out to investigate the effect of crowding and temperature manipulation on initiating ovarian rematuration and to determine the rate of rematuration at 22°C once initiated. The duration of low temperature had no effect on rematuration; an overnight cooling was sufficient to initiate the process, Rematuration to the end of stage 2 vltellogenesis was substantially complete within 10 days. Crowding of females suppressed rematuration, but less than ideal water quality was not found to have any effect. The presence of a male initiated rematuration at a similar rate, but also led to stage 3 vitetlogenesis and spawning. A study was made of the pheromonal influence of the male through water borne factors without success. Rematuration could not be induced in ovigerous females. The literature review indicated that ovarian rematuration was under the control of an ovary stimulating hormone produced by the thoracic nerve ganglia. Attempts were therefore made to stimulate ovarian rematuration by incorporating the thoracic nerve into the diet of females. Attempts were also made to induce the release of ovary stimulating hormone from the thoracic nerve with 5-hydroxytryptamine, and also with octopamine. No effects were found, but a significant difference between the neurophysiology of the yabby and northern hemisphere crayfish was observed, and the implications of this finding are discussed. The study did not produce any conclusive evidence of an ovary stimulating hormone for the yabby. A model of ovarian rematuration which collects the findings of the experimental investigations was developed, and was used to suggest a hatchery broodstock management protocol. This model differs from existing models in that rematuration triggers and nutritional status are considered.

Role of leptin receptors in the development of obesity

The focus of this dissertation was leptin and the leptin receptor, and the role of these genes (OB and OB-R) in the development of obesity and type 2 diabetes in humans and Psammomys obesus, a polygenic rodent model of obesity and type 2 diabetes. Studies in humans showed that circulating leptin concentrations were positively associated with adiposity, and independently associated with circulating insulin and triglyceride concentrations. Analysis of two leptin receptor sequence polymorphisms in a Caucasian Australian population and a population of Nauruan males, with very high prevalence rates of obesity, showed no associations between sequence variation within the OB-R gene and obesity- or diabetes-related phenotypic measures. In addition, these two OB-R polymorphisms were not associated with longitudinal changes in body mass or composition in either of the populations examined. A unique analysis of the effects of multiple gene defects in the Nauruan population, demonstrated that the presence of sequence alterations in both the OB and OB-R genes were associated with insulin resistance. Psammomys obesus is regarded as an excellent rodent model in which to study the development of obesity and type 2 diabetes in humans. Examination of circulating leptin concentrations in Psammomys revealed that, as in humans, leptin concentrations were associated with adiposity, and independently associated with circulating insulin concentrations. This animal model was utilised to examine expression of OB-R, and the regulation of expression of this gene after dietary manipulation. OB-R is known to have several isoforms, and in particular, OB-RA and OB-RB gene expression were examined. OB-RB is the main signalling isoform of the leptin receptors. It has a long intracellular domain and has previously been shown to play an important role in energy balance and body weight regulation in rodents and humans. OB-RA is a much shorter isoform of OB-R, and although it lacks the long intracellular domain necessary to activate the JAK/STAT pathway, OB-RA is also capable of signalling, although to a lesser degree than OB-RB. OB-RA is found to be expressed almost ubiquitously throughout the body, and this isoform may be involved in transport of leptin into the cell, although its role remains unclear. OB-RA and OB-RB were both found to be expressed in a large number of tissues in Psammomys obesus. Interestingly, obese Psammomys were found to have lower levels of expression of OB-RA and OB-RB in the hypothalamus, compared to lean animals. This finding raises the possibility that decreased leptin signalling in the brain of obese, hyperleptinemic Psammomys obesus may contribute to the leptin resistance previously described in this animal model. However, the primary defect is unclear, as alternatively, increased circulating leptin concentrations may lead to down-regulation of leptin receptors. The effect of fasting on leptin concentrations and gene expression of OB-RA and OB-RB was also examined. A 24-hour fast resulted in no change in body weight, but a reduction in circulating leptin concentrations, and an increase in hypothalamic OB-RB gene expression in lean Psammomys. In obese animals, fasting again did not alter body weight, but resulted in an increase in both circulating leptin concentrations and hypothalamic OB-RB gene expression. In the liver, fasting resulted in a large increase in OB-RA gene expression in both lean and obese animals. These results highlighted the fact that regulation of leptin receptor gene expression in polygenic models of obesity and type 2 diabetes is complex, and not solely under the control of circulating leptin concentrations. Sucrose-feeding is an established method of inducing obesity and type 2 diabetes in rodents, and this experimental paradigm was utilised to examine the effects of longer term perturbations of energy balance on the leptin signalling pathway in Psammomys obesus. Addition of a 5% sucrose solution to the diet of lean and obese Psammomys resulted in increased body weight in both groups of animals, however only obese Psammomys showed increased fat mass and the development of type 2 diabetes. The changes in body mass and composition with sucrose-feeding were accompanied by decreased circulating leptin concentrations in both groups of animals, as well as a range of changes in leptin receptor gene expression. Sucrose-feeding increased hypothalamic OB-RB gene expression in obese Psammomys only, while in the liver there was evidence of a reduction in OB-RA and OB-RB gene expression in both lean and obese animals. The direct effects of sucrose on the leptin signalling pathway are unclear, however it is possible to speculate that the effect of sucrose to decrease leptin concentrations may have been involved in the exacerbation of obesity and the development of type 2 diabetes in obese Psammomys, From these studies, it appears that sequence variation in the OB and OB-R genes is unlikely to be a major factor in the etiology of obesity in human populations. The ability to examine regulation of expression of these genes in Psammomys obesus, however, has demonstrated that the effects of nutritional modifications on leptin receptor gene expression need closer attention. The role of the OB and OB-R genes in metabolism and the development of type 2 diabetes also warrants further examination, with particular attention on the differential effects of dietary modifications on leptin receptor gene expression across a range of tissues.

Incorporating design explanation within formal object-oriented method (FOOM)

Requirements engineering is a commencing phase in the development of either software applications or information systems. It is concerned with understanding and specifying the customer's requirements of the system to be delivered. Throughout the literature, this is agreed to be one of the most crucial and, unfortunately, problematic phases in development. Despite the diversity of research directions, approaches and methods, the question of process understanding and management is still limited. Among contemporary approaches to the improvement of the current practice of Requirements Engineering, Formal Object-Oriented Method (FOOM) has been introduced as a new promising solution. The FOOM approach to requirements engineering is based on a synthesis of socio-organisational theory, the object-oriented approach, and mathematical formal specification. The entire FOOM specification process is evolutionary and involves a large volume of changes in requirements. During this process, requirements evolve through various forms of informal, semi-formal, and formal while maintaining a semantic link between these forms and, most importantly, conforming to the customer's requirements. A deep understanding of the complexity of the requirements model and its dynamics is critical in improving requirements engineering process management. This thesis investigates the benefits of documenting both the evolution of the requirements model and the rationale for that evolution. Design explanation explains and justifies the deliberations of, and decisions made during, the design activity. In this thesis, design explanation is used to describe the requirements engineering process in order to improve understandability of, and traceability within, the evolving requirements specification. The design explanation recorded during this research project is also useful in assisting the researcher in gaining insights into the creativity and opportunistic characteristics of the requirements engineering process. This thesis offers an interpretive investigation into incorporating design explanation within FOOM in order to extend and advantage the method. The researcher's interpretation and analysis of collected data highlight an insight-driven and opportunistic process rather than a strictly and systematically predefined one. In fact, the process was not smoothly evolutionary, but involved occasional 'crisis' points at which the model was reconceptualised, simplified and restructured. Therefore, contributions of the thesis lie not only in an effective incorporation of design explanation within FOOM, but also a deep understanding of the dynamic process of requirements engineering. The new understanding of the complexity of the requirements model and its dynamics suggests new directions for future research and forms a basis for a new approach to process management.

Where and when to revegetate : a quantitative method for scheduling landscape reconstruction

Restoration of native vegetation is required in many regions of the world, but determining priority locations for revegetation is a complex problem. We consider the problem of determining spatial and temporal priorities for revegetation to maximize habitat for 62 bird species within a heavily cleared agricultural region, 11 000 km2 in area. We show how a reserve-selection framework can be applied to a complex, large-scale restoration-planning problem to account for multi-species objectives and connectivity requirements at a spatial extent and resolution relevant to management. Our approach explicitly accounts for time lags in planting and development of habitat resources, which is intended to avoid future population bottlenecks caused by delayed provision of critical resources, such as tree hollows. We coupled species-specific models of expected habitat quality and fragmentation effects with the dynamics of habitat suitability following replanting to produce species-specific maps for future times. Spatial priorities for restoration were determined by ranking locations (150-m grid cells) by their expected contribution to species habitat through time using the conservation planning tool, ‘‘Zonation.’’ We evaluated solutions by calculating expected trajectories of habitat availability for each species. We produced a spatially explicit revegetation schedule for the region that resulted in a balanced increase in habitat for all species. Priority areas for revegetation generally were clustered around existing vegetation, although not always. Areas on richer soils and with high rainfall were more highly ranked, reflecting their potential to support high-quality habitats that have been disproportionately cleared for agriculture. Accounting for delayed development of habitat resources altered the rank-order of locations in the derived revegetation plan and led to improved expected outcomes for fragmentation-sensitive species. This work demonstrates the potential for systematic restoration planning at large scales that accounts for multiple objectives, which is urgently needed by land and natural resource managers.

Development of material models to predict the crashworthiness of tubes

Metallic tubes have been extensively studied for their crashworthiness as they closely resemble automotive crash rails. Recently, the demand to produce light weight yet safer vehicles has led to the need to understand the behaviour of novel materials such as composites, metallic foams and sandwich structures durign a crash. This paper presents a method to predict the crashworthiness of structural components using material modes. The material factors that most affect the crushing response are determined and quantified by developing and validating the crushing of a square tube model in Abaqus. The inputs from the model are used to construct a simple, physically realistic constitutive model and new test methods for predicting the material behaviour at high strain rates using low test speeds. These material models enable a designer to predict the crash behaviour of a structure without the need to perform extensive physical tests, thus reducing the time and cost of development.

Is phase-specific, community-oriented treatment of early psychosis- an economically viable method of improving outcome?

Objective: The Early Psychosis Prevention and Intervention Centre (EPPIC) provides a comprehensive 'real-world' model of early intervention to young people experiencing an emerging psychotic disorder. A prospective study has already provided evidence of improved clinical outcome at 12 months after entry. The present study examined whether the service was also cost-effective.

Method: A cost-effectiveness analysis compared EPPIC with its immediate precursor service, from the perspective of the government funding agency. Only direct costs were included.

Results: EPPIC proved to be more cost-effective. The weighted average cost per patient for the first 12 months was cheaper (by äD 7110 per patient), while treatment outcomes were superior. The savings were due to the marked reduction in in-patient costs outweighing substantial increases in the costs of community care.

Conclusion: These results, while encouraging in terms of the further development of integrated, phase-specific intervention programmes for early psychosis, are not conclusive, and further research is required.