Unravelling metabolism of Leishmania by metabolomics

The leishmaniases are neglected tropical diseases with an urgent need for effective drugs. Better understanding of the metabolism of the causative parasites will hopefully lead to development of new compounds targeted at critical points of the parasite’s biochemical pathways. In my work I focused on the pentose phosphate pathway of Leishmania, specifically on transketolase, sugar utilisation, and comparison between insect and mammalian infective stages of the parasites. The pentose phosphate pathway (PPP) is the major cellular source of NADPH, an agent critical for oxidative stress defence. The PPP uses glucose, reduces the NADP+ cofactor and produces various sugar phosphates by mutual interconversions. One of the enzymes involved in this latter part is transketolase (TKT). A Leishmania mexicana cell line deleted in transketolase (Δtkt) was assessed regarding viability, sensitivity to a range of drugs, changes in metabolism, and infectivity. The Δtkt cell line had no obvious growth defect in the promastigote stage, but it was more sensitive to an oxidative stress inducing agent and most of the drugs tested. Most importantly, the Δtkt cells were not infective to mice, establishing TKT as a new potential drug target. Metabolomic analyses revealed multiple changes as a consequence of TKT deletion. Levels of the PPP intermediates upstream of TKT increased substantially, and were diverted into additional reactions. The perturbation triggered further changes in metabolism, resembling the ‘stringent metabolic response’ of amastigotes. The Δtkt cells consumed less glucose and glycolytic intermediates were decreased indicating a decrease in flux, and metabolic end products were diminished in production. The decrease in glycolysis was possibly caused by inhibition of fructose-1,6-bisphosphate aldolase by accumulation of the PPP intermediates 6-phosphogluconate and ribose 5-phosphate. The TCA cycle was fuelled by alternative carbon sources, most likely amino acids, instead of glucose. It remains unclear why deletion of TKT is lethal for amastigotes, increased sensitivity to oxidative stress or drop in mannogen levels may contribute, but no definite conclusions can be made. TKT localisation indicated interesting trends too. The WT enzyme is present in the cytosol and glycosomes, whereas a mutant version, truncated by ten amino acids, but retaining a C-terminal targeting sequence, localised solely to glycosomes. Surprisingly, cells expressing purely cytosolic or glycosomal TKT did not have different phenotypes regarding growth, oxidative stress sensitivity or any detected changes in metabolism. Hence, control of the subcellular localisation remains unclear as well as its function. However, these data are in agreement with the presumed semipermeable nature of the glycosome. Further, L. mexicana promastigote cultures were grown in media with different combinations of labelled glucose and ribose and their incorporation into metabolism was followed. Glucose was the preferred carbon source, but when not available, it could be fully replaced with ribose. I also compared metabolic profiles from splenic amastigotes, axenic amastigotes and promastigotes of L. donovani. Metabolomic analysis revealed a substantial drop in amino acids and other indications coherent with a stringent metabolic response in amastigotes. Despite some notable differences, axenic and splenic amastigotes demonstrated fairly similar results both regarding the total metabolic profile and specific metabolites of interest.

Guidelines on building design and operation to minimize air quality impacts from major roads in transit oriented development

Poor air quality has a huge detrimental effect, both economic and on the quality of life, in Australia. Transit oriented design (TOD), which aims to minimise urban sprawl and lower dependency on vehicles, leads to an increasing number of buildings close to transport corridors. This project aims at providing guidelines that are appropriate to include within City Plan to inform future planning along road corridors, and provide recommendations on when mitigation measures should be utilised.

A comparative analysis of major ERP lifecycle implementation, management and support issues in Queensland Government

This paper reports on a study of ERP lifecycle major issues from the perspectives of individuals with substantial and diverse involvement with SAP Financials in Queensland Government. A survey was conducted of 117 ERP system project participants in five closely related state government agencies. A modified Delphi technique identified, rationalized and weighed perceived major issues in ongoing ERP life cycle implementation, management and support. The five agencies each implemented SAP Financials simultaneously using a common implementation partner. The three survey rounds of the Delphi technique, together with coding and synthesizing procedures, resulted in a set of 10 major issue categories with 38 sub-issues. Relative scores of issue importance are compared across government agencies, roles (client vs implementation partner) and organizational levels (strategic, technical and operational). Study findings confirm the importance of this finer partitioning of the data, and distinctions identified reflect the circumstances of ERP lifecycle implementation, management and support among the stakeholder groups. The study findings should also be of interest to stakeholders who seek to better understand the issues surrounding ERP systems and to better realise the benefits of ERP.

Achieving better stewardship of major infrastructure assets through configuration of governance arrangements utilising Stewardship Theory

Major infrastructure assets are often governed by a mix of public and private organizations, each fulfilling a specific and separate role i.e. policy, ownership, operation or maintenance. This mix of entities is a legacy of Public Choice Theory influenced NPM reforms of the late 20th century. The privatization of the public sector has resulted in agency theory based ‘self-interest’ relationships and governance arrangements for major infrastructure assets which emphasize economic efficiency but which do not do not advance non-economic public values and the collective Public Interest. The community is now requiring that governments fulfill their stewardship role of also satisfying non-economic public values such as sustainability and intergenerational responsibility. In the 21st century governance arrangements which minimize individual self-interest alone and look to also pursue the interests of other stakeholders have emerged. Relational contracts, Public-Private Partnerships (PPP’s) and hybrid mixes of organizations from the state, market and network modes (Keast et al 2006) provide options for governance which better meet the interests of contractors, government and the community there is emerging a body of research which extends the consideration of the immediate governance configuration to the metagovernance environment constituted by hierarchy, regulation, industry standards, trust, culture and values. Stewardship theory has reemerged as a valuable aid in the understanding of the features of governance configurations which establish relationships between principal and agent which maximize the agent acting in the interests of the principal, even to the detriment of the agent. This body of literature suggests that an improved stewardship outcome from infrastructure governance configurations can be achieved by the application of the emerging options as to the immediate governance configuration, and the surrounding metagovernance environment. Stewardship theory provides a framework for the design of the relationships within that total governance environment, focusing on the achievement of a better, complete stewardship outcome. This paper explores the directions future research might take in seeking to improve the understanding of the design of the governance of major, critical infrastructure assets.

Driving and licensing experiences of learner drivers in two Australian states prior to major changes in the licensing laws

The learner licence is an important component of the graduated driver licensing system. This research describes the driving and licensing experiences of learner drivers in Queensland and New South Wales licensed prior to the changes made to the system in mid-2007. The sample consisted of 392 participants who completed a telephone interview just after they obtained their provisional licence. The results suggest that learner drivers in the two states had many similar experiences when they were obtaining a learner licence. However, once a learner licence was obtained, there were differences in the amount of practice, the supervisor learners practised with, the type of vehicle they used and the amount of unlicensed driving. This paper provides important baseline descriptive data that can be used to measure the impact of the changes that were introduced to the learner licence phase in mid-2007 in both of these states.

Developing within-company information and communication technologies (ICT) innovation diffusion networks : a study of three Australian major contractors

The innovation diffusion and knowledge management literature strongly supports the importance of communities of practice (COP) for enabling knowledge about how to use and adopt innovation initiatives. One of the most powerful tools for innovation diffusion is word-of-mouth wisdom from committed individuals who mentor and support each other. Close proximity for face-to-face interaction is highly effective, however, many organisations are geographically dispersed with projects being virtual linked sub-organisations using ICT to communicate. ICT has also introduced a useful facilitating technology for developing knowledge networks. This paper presents findings from a research program concentrating on ICT innovation diffusion in the Australian construction industry. One way in which ICT diffusion is taking place was found to be through within-company communities of practice. We undertook in-depth unstructured interviews with three of the major 10 to 15 contractors in Australia to discuss their ICT diffusion strategies. We discovered that in all three cases,within company networked communities of practice was a central strategy. Further, effective diffusion of ICT groupware tools can be critical in developing COP where they are geographically dispersed.

St. John’s wort and Kava in treating major depressive disorder with comorbid anxiety : a randomised double-blind placebo-controlled pilot trial

Objective - We report the first randomised controlled trial (RCT) using a combination of St. John’s wort (SJW) and Kava for the treatment of major depressive disorder (MDD) with comorbid anxiety. Methods - Twenty-eight adults with MDD and co-occurring anxiety were recruited for a double-blind RCT. After a placebo run-in of 2 weeks, the trial had a crossover design testing SJW and Kava against placebo over two controlled phases, each of 4 weeks. The primary analyses used intention-to-treat and completer analyses. Results - On both intention-to-treat ( p¼0.047) and completer analyses ( p¼0.003), SJW and Kava gave a significantly greater reduction in self-reported depression on the Beck Depression Inventory (BDI-II) over placebo in the first controlled phase. However, in the crossover phase, a replication of those effects in the delayed medication group did not occur. Nor were there significant effects on anxiety or quality of life. Conclusion - There was some evidence of antidepressant effects using SJW and Kava in a small sample with comorbid anxiety. Possible explanations for the absence of anxiolysis may include a potential interaction with SJW, the presence of depression, or an inadequate dose of Kava.

Major depressive disorder and nutritional medicine : a review of monotherapies and adjuvant treatments

A literature review was conducted to examine the evidence for nutritional interventions in depression. It revealed a number of significant conclusions. Interestingly, more positive clinical trials were found to support adjuvant, rather than monotherapeutic, use of nutrients to treat depression. Much evidence exists in the area of adjuvant application of folic acid, S-adenosyl-methionine, omega-3, and L-tryptophan with antidepressants. Current evidence does not support omega-3 as an effective monotherapy to treat depression. However, this may be due, at least in part, to olive oil being used as the control intervention, some studies using docosahexaenoic acid alone or a higher docosahexaenoic acid to eicosapentaenoic acid ratio, and significant heterogeneity regarding depressive populations. Nevertheless, adjunctive prescription of omega-3 with antidepressants, or in people with dietary deficiency, may be beneficial. Inositol lacks evidence as an effective antidepressant and cannot be currently recommended. Evidence on the use of L-trytophan for depression is inconclusive and additional studies utilizing a more robust methodology are required.

Value-mapping for major economic infrastructure projects

The establishment of corporate objectives regarding economic, environmental, social, and ethical responsibilities, to inform business practice, has been gaining credibility in the business sector since the early 1990’s. This is witnessed through (i) the formation of international forums for sustainable and accountable development, (ii) the emergence of standards, systems, and frameworks to provide common ground for regulatory and corporate dialogue, and (iii) the significant quantum of relevant popular and academic literature in a diverse range of disciplines. How then has this move towards greater corporate responsibility become evident in the provision of major urban infrastructure projects? The gap identified, in both academic literature and industry practice, is a structured and auditable link between corporate intent and project outcomes. Limited literature has been discovered which makes a link between corporate responsibility; project performance indicators (or critical success factors) and major infrastructure provision. This search revealed that a comprehensive mapping framework, from an organisation’s corporate objectives through to intended, anticipated and actual outcomes and impacts has not yet been developed for the delivery of such projects. The research problem thus explored is ‘the need to better identify, map and account for the outcomes, impacts and risks associated with economic, environmental, social and ethical outcomes and impacts which arise from major economic infrastructure projects, both now, and into the future’. The methodology being used to undertake this research is based on Checkland’s soft system methodology, engaging in action research on three collaborative case studies. A key outcome of this research is a value-mapping framework applicable to Australian public sector agencies. This is a decision-making methodology which will enable project teams responsible for delivering major projects, to better identify and align project objectives and impacts with stated corporate objectives.