Melbourne University Sport - Research Publications
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Aedes aegypti has spatially structured and seasonally stable populations in Yogyakarta, Indonesia
BACKGROUND: Dengue fever, the most prevalent global arboviral disease, represents an important public health problem in Indonesia. Control of dengue relies on the control of its main vector, the mosquito Aedes aegypti, yet nothing is known about the population history and genetic structure of this insect in Indonesia. Our aim was to assess the spatio-temporal population genetic structure of Ae. aegypti in Yogyakarta, a densely populated region on Java with common dengue outbreaks. METHODS: We used multiple marker systems (microsatellites, nuclear and mitochondrial genome-wide single nucleotide polymorphisms generated via Restriction-site Associated DNA sequencing) to analyze 979 Ae. aegypti individuals collected from the Yogyakarta city and the surrounding hamlets during the wet season in 2011 and the following dry season in 2012. We employed individual- and group-based approaches for inferring genetic structure. RESULTS: We found that Ae. aegypti in Yogyakarta has spatially structured and seasonally stable populations. The spatial structuring was significant for the nuclear and mitochondrial markers, while the temporal structuring was non-significant. Nuclear markers identified three main genetic clusters, showing that hamlets have greater genetic isolation from each other and from the inner city sites. However, one hamlet experienced unrestricted mosquito interbreeding with the inner city, forming a single genetic cluster. Genetic distance was poorly correlated with the spatial distance among mosquito samples, suggesting stronger influence of human-assisted gene flow than active mosquito movement on spatial genetic structure. A star-shaped mitochondrial haplotype network and a significant R(2) test statistic (R(2) = 0.0187, P = 0.001) support the hypothesis that Ae. aegypti in Yogyakarta originated from a small or homogeneous source and has undergone a relatively recent demographic expansion. CONCLUSION: We report the first insights into the spatio-temporal genetic structure and the underlying processes in the dengue fever mosquito from Yogyakarta, Indonesia. Our results provide valuable information on the effectiveness of local control measures as well as guidelines for the implementation of novel biocontrol strategies such as release of Wolbachia-infected mosquitoes.
Glucocorticoids promote apoptosis of proinflammatory monocytes by inhibiting ERK activity
(NATURE PUBLISHING GROUP, 2018-02-15)
Glucocorticoids (GCs) are potent anti-inflammatory drugs whose mode of action is complex and still debatable. One likely cellular target of GCs are monocytes/macrophages. The role of GCs in monocyte survival is also debated. Although both granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) are important regulators of macrophage lineage functions including their survival, the former is often associated with proinflammatory functions while the latter is important in lineage homeostasis. We report here that the GC, dexamethasone, induces apoptosis in GM-CSF-treated human monocytes while having no impact on M-CSF-induced monocyte survival. To understand how GCs, GM-CSF, and M-CSF are regulating monocyte survival and other functions during inflammation, we firstly examined the transcriptomic changes elicited by these three agents in human monocytes, either acting alone or in combination. Transcriptomic and Ingenuity pathway analyses found that dexamethasone differentially modulated dendritic cell maturation and TREM1 signaling pathways in GM-CSF-treated and M-CSF-treated monocytes, two pathways known to be regulated by ERK1/2 activity. These analyses led us to provide evidence that the GC inhibits ERK1/2 activity selectively in GM-CSF-treated monocytes to induce apoptosis. It is proposed that this inhibition of ERK1/2 activity leads to inactivation of p90 ribosomal-S6 kinase and Bad dephosphorylation leading in turn to enhanced caspase-3 activity and subsequent apoptosis. Furthermore, pharmacological inhibition of GC receptor activity restored the ERK1/2 signaling and prevented the GC-induced apoptosis in GM-CSF-treated monocytes. Increased tissue macrophage numbers, possibly from enhanced survival due to mediators such as GM-CSF, can correlate with inflammatory disease severity; also reduction in these numbers can correlate with the therapeutic benefit of a number of agents, including GCs. We propose that the ERK1/2 signaling pathway promotes survival of GM-CSF-treated proinflammatory monocytes, which can be selectively targeted by GCs as a novel mechanism to reduce local monocyte/macrophage numbers and hence inflammation.
Restrictive versus liberal fluid therapy in major abdominal surgery (RELIEF): rationale and design for a multicentre randomised trial
(BMJ PUBLISHING GROUP, 2017-02-01)
INTRODUCTION: The optimal intravenous fluid regimen for patients undergoing major abdominal surgery is unclear. However, results from many small studies suggest a restrictive regimen may lead to better outcomes. A large, definitive clinical trial evaluating perioperative fluid replacement in major abdominal surgery, therefore, is required. METHODS/ANALYSIS: We designed a pragmatic, multicentre, randomised, controlled trial (the RELIEF trial). A total of 3000 patients were enrolled in this study and randomly allocated to a restrictive or liberal fluid regimen in a 1:1 ratio, stratified by centre and planned critical care admission. The expected fluid volumes in the first 24 hour from the start of surgery in restrictive and liberal groups were ≤3.0 L and ≥5.4 L, respectively. Patient enrolment is complete, and follow-up for the primary end point is ongoing. The primary outcome is disability-free survival at 1 year after surgery, with disability defined as a persistent (at least 6 months) reduction in functional status using the 12-item version of the World Health Organisation Disability Assessment Schedule. ETHICS/DISSEMINATION: The RELIEF trial has been approved by the responsible ethics committees of all participating sites. Participant recruitment began in March 2013 and was completed in August 2016, and 1-year follow-up will conclude in August 2017. Publication of the results of the RELIEF trial is anticipated in early 2018. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT01424150.
Global optimisation of chiller sequencing and load balancing using Shuffled Complex Evolution
(International Building Performance Simulation Association & AIRAH, 2017-11-15)
A new model has been developed to optimise the sequencing and load balancing of chillers in the central plants of commercial buildings with multiple water-cooled chillers. The model uses the Shuffled Complex Evolution optmisation algorithm to minimise the total energy consumptions of chillers and pumps by maximising the whole system (central plant) coefficient of performance under a known discrete cooling load. Two commercial buildings in Melbourne’s CBD were simulated as case studies to assess the validity and effectiveness of the model. The control strategies identified by the model performed better than the existing configuration in both cases, reducing energy consumption by 12.2% and 16.6% when compared to the observed energy data for 2016.