Functional analysis of Plasmodium falciparum merozoite antigens : implications for erythrocyte invasion and vaccine development

Malaria is a major human health problem and is responsible for over 2 million deaths per year. It is caused by a number of species of the genus Plasmodium, and Plasmodium falciparum is the causative agent of the most lethal form. Consequently, the development of a vaccine against this parasite is a priority. There are a number of stages of the parasite life cycle that are being targeted for the development of vaccines. Important candidate antigens include proteins on the surface of the asexual merozoite stage, the form that invades the host erythrocyte. The development of methods to manipulate the genome of Plasmodium species has enabled the construction of gain-of-function and loss-of-function mutants and provided new strategies to analyse the role of parasite proteins. This has provided new information on the role of merozoite antigens in erythrocyte invasion and also allows new approaches to address their potential as vaccine candidates.

Regional integration 2.0 : facilitating regional integration and development with collaborative technologies

The current global economic instability and the vulnerability of small nations provide the impetus for greater integration between the countries of the South Pacific region. This exercise is critical for their survival. Past efforts of regional integration in the South Pacific have mostly failed. However, today’s IT collaborative capabilities provide the opportunity to develop a shared IT infrastructure to facilitate integration in the South Pacific. In developing an IT-backed model of regional integration, this study identifies and reports on the antecedents of the current stage for integration in the Pacific. We conducted interviews with twenty five individuals from various sectors and find that while most respondents were optimistic about the potential of IT-backed regional integration, significant challenges exists. The study identifies and discusses these challenges providing policy implications to stakeholders in the regional integration process. The findings will assist in suggesting a model of regional integration 2.0 for the Pacific region.

Establishment and development of a seabird colony : long-term trends in phenology, breeding success, recruitment, breeding density and demography

Few studies document long-term colony-level metrics from colony establishment to maturity (equilibrium) and few test predictions of general models of colony development. We describe long-term trends in a colony of Australasian Gannets (Morus serrator) which has been monitored from an early stage in its development. The colony at Pope’s Eye, within Port Phillip Bay, Victoria, Australia was established in 1984 on an artificial structure and the first nest count (25 nests) was conducted in the same year. The colony was then studied for 15 of 19 years between 1988 and 2006–2007. During the study, 2,516 eggs were recorded, resulting in 1,694 chicks hatching (67 % of eggs), of which 1,310 (77 % of those hatched) fledged. At least 184 (14 %) of fledged offspring returned to Pope’s Eye as breeding adults. Since establishment, the number and density of nests increased (number of nests increased 8.8 % annually), with density increasing at varying rates in different areas of the colony. Early recruitment involved birds from a nearby colony, but within 5 years post establishment the first natal recruits were breeding at Pope’s Eye and thereafter natal recruitment was the main source of new breeding adults (totalling 81.4 % of all recruits). Age of recruitment varied throughout the study, though not systematically, and there was no difference between the sexes. The pattern of rapid initial growth is typical of patterns reported for other seabird colonies. However, as the colony (and birds within it) aged, there was no increase in breeding success and egg laying did not become earlier, as was expected from general models of colony development.

The development of the institutional investor : the case of Australian life insurers 1945-85

This paper considers the post-war development of asset management practices among Australian life insurers, which have historically been among the largest institutional investors in Australia. A complex process of adaptation and organisational restructuring allowed life insurers to transform from basic investors of policy-holders’ funds to large multifaceted institutional investors in just three decades. Three stages in the development of investment practices are identified. These phases trace the process of expanding existing knowledge bases; diversification; and the acquisition of new skills; consolidation and the integration of these skills into institutional structures; thus completing one cycle of organisational learning and setting the stage for the next.

Caveolin-1 orchestrates the balance between glucose and lipid-dependent energy metabolism : implications for liver regeneration

Caveolin-1 (CAV1) is a structural protein of caveolae involved in lipid homeostasis and endocytosis. Using newly generated pure Balb/C CAV1 null (Balb/CCAV1−/−) mice, CAV1−/− mice from Jackson Laboratories (JAXCAV1−/−), and CAV1−/− mice developed in the Kurzchalia Laboratory (KCAV1−/−), we show that under physiological conditions CAV1 expression in mouse tissues is necessary to guarantee an efficient progression of liver regeneration and mouse survival after partial hepatectomy. Absence of CAV1 in mouse tissues is compensated by the development of a carbohydrate-dependent anabolic adaptation. These results were supported by extracellular flux analysis of cellular glycolytic metabolism in CAV1-knockdown AML12 hepatocytes, suggesting cell autonomous effects of CAV1 loss in hepatic glycolysis. Unlike in KCAV1−/− livers, in JAXCAV1−/− livers CAV1 deficiency is compensated by activation of anabolic metabolism (pentose phosphate pathway and lipogenesis) allowing liver regeneration. Administration of 2-deoxy-glucose in JAXCAV1−/− mice indicated that liver regeneration in JAXCAV1−/− mice is strictly dependent on hepatic carbohydrate metabolism. Moreover, with the exception of regenerating JAXCAV1−/− livers, expression of CAV1 in mice is required for efficient hepatic lipid storage during fasting, liver regeneration, and diet-induced steatosis in the three CAV1−/− mouse strains. Furthermore, under these conditions CAV1 accumulates in the lipid droplet fraction in wildtype mouse hepatocytes. Conclusion: Our data demonstrate that lack of CAV1 alters hepatocyte energy metabolism homeostasis under physiological and pathological conditions.

Role of multidrug resistance associated proteins in drug development

The Multidrug Resistance Associated Proteins (MRPI, MRP2, MRP3, MRp4, MRp5, MRP6, MRP7, MRPS and MRP9) belong to the ATP-binding cassette superfamily (ABCC family) of transporters expressed differentially in the liver, kidney, intestine and blood-brain barrier. MRps transport a structurally diverse array of endo- and xenobiotics and their metabolites (in particular conjugates) and are subject to induction and inhibition by a variety of compounds. An increased efflux of natural product anticancer drugs and other anticancer agents by MRPs in cancer cells is associated with tumor resistance. These transporting proteins play a role in the absorption, distribution and elimination of various compounds in the body. There are increased reports on the clinical impact of genetic mutations of genes encoding MRP1-9. Therefore, MRPs have an important role in drug development, since a better understanding of their function and regulating mechanism can help minimize and avoid drug toxicity, unfavorable drug-drug interactions, and to overcome drug resistance.

Sustainability evaluation, life cycle assessment and facilities management for Geelong Retail Development

Value management is a technique used during the design stage to justify cost and worth of a proposal. Designer must never center only to save capital expenditure but consider holistically the whole building life which will be sustainable. Therefore, sustainability evaluation must adopt a long term view and will properly include three crucial elements: economic, social and environmental. Lack of awareness of value management during the design stage of a building project will adversely impact on the life cycle assessment (LCA) and facilities management (FM). This paper provides a review of the sustainable elements that must be considered when designing and costing a new retail development in the Geelong region of Australia and how these factors influence the whole building life. The result of this research helps to create a greater understanding of the different attributes that will affect the LCA and FM decisions made on sustainable development in this and other regional Australian cities that are undergoing major population growth.

Preparing for WIL : online career development for IT students

This paper reports on an online unit that enhances IT students’ generic skills. Frequently IT students, even those with a strong technical background and a high academic record, can be unsuccessful at obtaining work placements as they stumble at the interview stage due to a lack of social or professional skills. A simulation was created that enables students to enhance their employability and to prepare for transition to work integrated learning (WIL) through realistic interview preparation. The simulation utilizes a synchronous communication tool to conduct behavioural group interviews with expert careers advisors. The impact of this new initiative is explored and feedback received from faculty, careers advisors and students during three trimesters is discussed. The findings suggest that incorporating WIL through the simulation has been a success by at least raising students’ awareness of the importance and significance of being well prepared for job interviews.

Loss of insulin-mediated microvascular perfusion in skeletal muscle is associated with the development of insulin resistance

Aim: The aetiology of the development of type 2 diabetes remains unresolved. In the present study, we assessed whether an impairment of insulin-mediated microvascular perfusion occurs early in the onset of insulin resistance. Materials and methods: Hooded Wistar rats were fed either a normal diet (ND) or a high-fat diet (HFD) for 4 weeks. Anaesthetized animals were subjected to an isoglycaemic hyperinsulinaemic clamp (3 or 10 mU/min/kg × 2 h), and measurements were made of glucose infusion rate (GIR), hindleg glucose uptake, muscle glucose uptake by 2-deoxy-d-glucose (R′g), glucose appearance (Ra), glucose disappearance (Rd), femoral blood flow (FBF) and hindleg 1-methylxanthine disappearance (1-MXD, an index of microvascular perfusion). Results: Compared with ND-fed animal, HFD feeding led to a mild increase in fasting plasma glucose and plasma insulin, without an increase in total body weight. During the clamps, HFD rats showed an impairment of insulin-mediated action on GIR, hindleg glucose uptake, R′g, Ra, Rd and FBF, with a greater loss of insulin responsiveness at 3 mU/min/kg than at 10 mU/min/kg. The HFD also impaired insulin-mediated microvascular perfusion as assessed by 1-MXD. Interestingly, 1-MXD was the only measurement that remained unresponsive to the higher dose of 10 mU/min/kg insulin. Conclusions: We conclude that the early stage of insulin resistance is characterized by an impairment of the insulin-mediated microvascular responses in skeletal muscle. This is likely to cause greater whole body insulin resistance by limiting the delivery of hormones and nutrients to muscle.

The role of lipogenesis in the development of obesity and diabetes in Israeli sand rats (Psammomys obesus)

Obesity and diabetes in Israeli sand rats, Psammomys obesus, occur with the sequential transition of animals from normal insulin sensitivity to impaired insulin sensitivity, accompanied by increased adiposity, prior to insulin resistance and obesity, in a manner similar to susceptible human populations. The current study was designed to examine the role of de novo lipid synthesis in the development of excessive weight gain in P. obesus. Sand rats were classified at 12 wk of age into three groups: A, normoglycemic normoinsulinemic; B, normoglycemic hyperinsulinemic; C, hyperglycemic hyperinsulinemic, based on glucose and insulin responses in fed sand rats. Body weight, liver weight, white adipose tissue (WAT) mass and food intake were significantly elevated in Group C compared to Group A (P < 0.05). Lipogenic rate was measured by the amount of 3H incorporated into subscapular brown adipose tissue (BAT), epidiymal WAT and liver per hour, from sand rats with and without access to food. No difference in lipogenic rate was found between the groups in BAT, indicating that this tissue is of minor importance in whole body lipogenesis in P. obesus. In the WAT there was a greater lipogenic rate with the development of obesity and hyperinsulinemia (Group B vs. Group A) but no difference in the liver. However, the onset of hyperglycemia (Group C) further stimulated WAT lipogenesis and initiated increased hepatic lipogenesis, both of which contributed to the pre-existing obesity. This study suggests that elevated lipogenesis is not the primary cause of obesity in P. obesus, as lipogenic rate only markedly increases after obesity is already present in hyperglycemic animals.

Development of a new best practice model for building projects

Time, cost and quality are the traditional determinants of project success. The level of client satisfaction is a newly defined measurement of project success. Often the satisfaction level of construction clients is not high. The reasons for this situation are twofold, firstly due to the temporary organizational structure of construction team and secondly, the inefficient construction process. The traditional procurement route, whilst still the most popular in the building sector, is probably subject to most criticism. The primary aim of this research is to develop a new best practice model for building projects. This will enable the client’s project manager to identify best practice under the traditional procurement route before the work is executed. Within this model, the sequence of construction activities, the responsibilities of the parties and the critical aspect of each phase of the project are identified. This model can then be utilized at both the design and/ or the construction stage in order to secure project success.

The Plasmodium translocon of exported proteins (PTEX) component thioredoxin-2 is important for maintaining normal blood-stage growth

Plasmodium parasites remodel their vertebrate host cells by translocating hundreds of proteins across an encasing membrane into the host cell cytosol via a putative export machinery termed PTEX. Previously PTEX150, HSP101 and EXP2 have been shown to be bona fide members of PTEX.

Here we validate that PTEX88 and TRX2 are also genuine members of PTEX and provide evidence that expression of PTEX components are also expressed in early gametocytes, mosquito and liver stages, consistent with observations that protein export is not restricted to asexual stages. Although amenable to genetic tagging, HSP101, PTEX150, EXP2 and PTEX88 could not be genetically deleted in Plasmodium berghei, in keeping with the obligatory role this complex is postulated to have in maintaining normal blood-stage growth.

In contrast, the putative thioredoxin-like protein TRX2 could be deleted, with knockout parasites displaying reduced grow-rates, both in vivo and in vitro, and reduced capacity to cause severe disease in a cerebral malaria model. Thus, while not essential for parasite survival, TRX2 may help to optimize PTEX activity. Importantly, the generation of TRX2 knockout parasites that display altered phenotypes provides a much-needed tool to dissect PTEX function.

Neighborhood environment walkability scale : validity and development of a short form

Purpose : The aim of this study was to examine the factorial and criterion validity of the Neighborhood Environment Walkability Scale (NEWS) and to develop an abbreviated version (NEWS-A).

Methods : A stratified two-stage cluster sample design was used to recruit 1286 adults. The sample was drawn from residential addresses within eight high- and eight low-walkable neighborhoods matched for socioeconomic status. Subjects completed the NEWS and reported weekly minutes of walking for transport and recreation using items from the International Physical Activity Questionnaire.

Results : Multilevel confirmatory factor analysis was used to develop measurement models of the NEWS and NEWS-A. Six individual-level and five blockgroup-level factors were identified. Factors/scales gauging presence of diversity of destinations, residential density, walking infrastructure, aesthetics, traffic safety, and crime were positively related to walking for transport. Aesthetics, mixed destinations, and residential density were associated with walking for recreation.

Conclusions : The NEWS and NEWS-A possess adequate levels of factorial and criterion validity. Alternative methods of scoring for different purposes are presented.

A global approach to dissecting lipid-induced impairment of liver gluconeogenesis

This thesis identified: 1) novel aspects of cholesterol metabolism, 2) a novel signalling lipid in the phosphatidylinositol class, and 3) a gene involved in regulating lipid breakdown, as being regulated in the reversal of a fatty acid induced diabetic liver. The identification of these targets may allow for future development of targeted therapies against type 2 diabetes with a specific focus on the liver.

Rapid development of non-alcoholic steatohepatitis in Psammomys obesus (Israeli Sand Rat)

Background and AimsA major impediment to establishing new treatments for non-alcoholic steatohepatitis is the lack of suitable animal models that accurately mimic the biochemical and metabolic characteristics of the disease. The aim of this study was to explore a unique polygenic animal model of metabolic disease as a model of non-alcoholic steatohepatitis by determining the effects of 2% dietary cholesterol supplementation on metabolic and liver endpoints in Psammomys obesus (Israeli sand rat).MethodsP. obesus were provided ad libitum access to either a standard rodent diet (20% kcal/fat) or a standard rodent diet supplemented with 2% cholesterol (w/w) for 4 weeks. Histological sections of liver from animals on both diets were examined for key features of non-alcoholic steatohepatitis. The expression levels of key genes involved in hepatic lipid metabolism were measured by real-time PCR.ResultsP. obesus fed a cholesterol-supplemented diet exhibited profound hepatomegaly and steatosis, and higher plasma transaminase levels. Histological analysis identified extensive steatosis, inflammation, hepatocyte injury and fibrosis. Hepatic gene expression profiling revealed decreased expression of genes involved in delivery and uptake of lipids, and fatty acid and triglyceride synthesis, and increased expression of genes involved in very low density lipoprotein cholesterol synthesis, triglyceride and cholesterol export.ConclusionsP. obesus rapidly develop non-alcoholic steatohepatitis when fed a cholesterol-supplemented diet that appears to be histologically and mechanistically similar to patients.