Bio21 Institute

Parkville, Australia

Bio21 Institute

Parkville, Australia
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Mitchell K.A.,Bio21 Institute | Mitchell K.A.,University of Melbourne | Sgro C.M.,Monash University | Hoffmann A.A.,Bio21 Institute | Hoffmann A.A.,University of Melbourne
Functional Ecology | Year: 2011

Acclimation and hardening represent examples of phenotypic plasticity, the extent to which phenotypes produced by the same genotype vary under different environments. Widespread species are expected to differ in thermal plasticity from narrowly distributed tropical species, but this has rarely been tested particularly when species are reared under the same conditions. We investigated acclimation and hardening responses of 11 widespread or tropically restricted Drosophila species from Australia using estimates of heat resistance where temperatures were increased suddenly (static measure) or slowly (ramping measure), and after controlling for phylogenetic relatedness. We predicted that restricted species would show little acclimation regardless of the method used, whilst widespread species would respond well after a hardening treatment (35°C for 1h) particularly under ramping. These predictions were partially supported. There was a tendency for the tropically restricted species to be less plastic than the widespread species, although variation among species within the two groups was generally greater than between the groups. For acclimation and stress resistance measured under ramping acclimation, there was an association between the southernmost latitude at which species were found (reflecting variability in climatic conditions they encountered) and knockdown resistance after controlling for phylogeny. There was also evidence of significant divergence from the ancestral state in the ramping trait, likely reflecting a history of direct or indirect selection for ramping knockdown resistance in Drosophila. There was a significant negative association between basal resistance and hardening capacity for static acclimation in the widespread species, suggesting a limit to the extent that plastic responses vary independently of basal resistance. The reduced plastic response in tropically restricted species and negative association between hardening and basal resistance suggest a limit to the effectiveness of plastic responses in changing upper thermal limits for countering increases in thermal stress under future climate change. © 2010 The Authors. Functional Ecology © 2010 British Ecological Society.

Dearnley M.K.,Bio21 Institute | Dearnley M.K.,University of Melbourne | Yeoman J.A.,La Trobe University | Hanssen E.,University of Melbourne | And 8 more authors.
Journal of Cell Science | Year: 2012

The most virulent of the human malaria parasites, Plasmodium falciparum, undergoes a remarkable morphological transformation as it prepares itself for sexual reproduction and transmission via mosquitoes. Indeed P. falciparum is named for the unique falciform or crescent shape of the mature sexual stages. Once the metamorphosis is completed, the mature gametocyte releases from sequestration sites and enters the circulation, thus making it accessible to feeding mosquitoes. Early ultrastructural studies showed that gametocyte elongation is driven by the assembly of a system of flattened cisternal membrane compartments underneath the parasite plasma membrane and a supporting network of microtubules. Here we describe the molecular composition and origin of the sub-pellicular membrane complex, and show that it is analogous to the inner membrane complex, an organelle with structural and motor functions that is well conserved across the apicomplexa. We identify novel crosslinking elements that might help stabilize the inner membrane complex during gametocyte development. We show that changes in gametocyte morphology are associated with an increase in cellular deformability and postulate that this enables the gametocytes to circulate in the bloodstream without being detected and removed by the mechanical filtering mechanisms in the spleen of the host. © 2012.

PubMed | Baker IDI Heart and Diabetes Institute, University of Melbourne and Bio21 Institute
Type: Journal Article | Journal: Atherosclerosis | Year: 2015

We previously reported a negative association of circulating plasmalogens (phospholipids with proposed atheroprotective properties) with coronary artery disease. Plasmalogen modulation was previously demonstrated in animals but its effect on atherosclerosis was unknown. We assessed the effect of plasmalogen enrichment on atherosclerosis of murine models with differing levels of oxidative stress.Six-week old ApoE- and ApoE/glutathione peroxidase-1 (GPx1)-deficient mice were fed a high-fat diet with/without 2% batyl alcohol (precursor to plasmalogen synthesis) for 12 weeks. Mass spectrometry analysis of lipids showed that batyl alcohol supplementation to ApoE- and ApoE/GPx1-deficient mice increased the total plasmalogen levels in both plasma and heart. Oxidation of plasmalogen in the treated mice was evident from increased level of plasmalogen oxidative by-product, sn-2 lysophospholipids. Atherosclerotic plaque in the aorta was reduced by 70% (P=5.69E-07) and 69% (P=2.00E-04) in treated ApoE- and ApoE/GPx1-deficient mice, respectively. A 40% reduction in plaque (P=7.74E-03) was also seen in the aortic sinus of only the treated ApoE/GPx1-deficient mice. Only the treated ApoE/GPx1-deficient mice showed a decrease in VCAM-1 staining (-28%, P=2.43E-02) in the aortic sinus and nitrotyrosine staining (-78%, P=5.11E-06) in the aorta.Plasmalogen enrichment via batyl alcohol supplementation attenuated atherosclerosis in ApoE- and ApoE/GPx1-deficient mice, with a greater effect in the latter group. Plasmalogen enrichment may represent a viable therapeutic strategy to prevent atherosclerosis and reduce cardiovascular disease risk, particularly under conditions of elevated oxidative stress and inflammation.

PubMed | Baker IDI Heart and Diabetes Institute, University of Western Australia, Victoria University of Melbourne and Bio21 Institute
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2015

Oxidised low density lipoprotein (oxLDL) contributes to atherosclerosis, whereas high density lipoprotein (HDL) is known to be atheroprotective due, at least in part, to its ability to remove oxidised lipids from oxLDL. The molecular details of the lipid transfer process are not fully understood. We aimed to identify major oxidised lipid species of oxLDL and investigate their transfer upon co-incubation with HDL with varying levels of oxidation.A total of 14 major species of oxidised phosphatidylcholine and oxidised cholesteryl ester from oxLDL were identified using an untargeted mass spectrometry approach. HDL obtained from pooled plasma of normolipidemic subjects (N=5) was oxidised under mild and heavy oxidative conditions. Non-oxidised (native) HDL and oxidised HDL were co-incubated with oxLDL, re-isolated and lipidomic analysis was performed. Lipoprotein surface lipids, oxidised phosphatidylcholines and oxidised cholesterols (7-ketocholesterol and 7-hydroxycholesterol), but not internal oxidised cholesteryl esters, were effectively transferred to native HDL. Saturated and monounsaturated lyso-phosphatidylcholines were also transferred from the oxLDL to native HDL. These processes were attenuated when HDL was oxidised under mild and heavy oxidative conditions. The impaired capacities were accompanied by an increase in a ratio of sphingomyelin to phosphatidylcholine and a reduction in phosphatidylserine content in oxidised HDL, both of which are potentially important regulators of the oxidised lipid transfer capacity of HDL.Our study has revealed the differential transfer efficiency of surface and internal oxidised lipids from oxLDL and their acceptance onto HDL. These capacities were modulated when HDL was itself oxidised.

Colinet H.,Catholic University of Louvain | Colinet H.,Bio21 Institute | Hoffmann A.,Bio21 Institute
Insect Biochemistry and Molecular Biology | Year: 2010

In Drosophila melanogaster, the sole member of the Bcl-2-associated anthanogene (BAG)-family proteins, called Starvin (Stv), has only been recently described. BAG proteins regulate a large range of physiological processes including life/death cell balance and stress response. The role of Stv has been poorly studied in the context of abiotic stress and particularly during and after cold stress. In this study we investigated the temporal expression of Stv gene and protein in adult flies during both the cold stress (up to 9 h at 0 °C) and the subsequent recovery phase (up to 8 h at 25 °C). Because BAG proteins can regulate positively and negatively the function of Hsp70/Hsc70, we also checked whether Stv expression was related to Hsp70 and Hsc70. Stv mRNA and Stv protein both showed a similar expression pattern: no modulation during the cold period followed by a significant up-regulation during the recovery period. A coordinated response of Stv and Hsp70 mRNA was observed, but not for Hsc70. Our findings indicate that Stv expression is part of a stress-induced program in D. melanogaster. It probably acts as a co-chaperone modulating the activity of Hsp70 chaperone machinery during recovery from cold stress. Finally our results support the suggestion that Stv and human BAG3 may be functional homologs. © 2010 Elsevier Ltd. All rights reserved.

Matthews K.,Deakin University | Kalanon M.,Deakin University | Chisholm S.A.,Deakin University | Sturm A.,University of Melbourne | And 11 more authors.
Molecular Microbiology | Year: 2013

Summary: 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. © 2013 John Wiley & Sons Ltd.

Crava C.M.,University of Valencia | Bel Y.,University of Valencia | Lee S.F.,Bio21 Institute | Manachini B.,University of Palermo | And 2 more authors.
Insect Biochemistry and Molecular Biology | Year: 2010

Aminopeptidases N (APNs) are a class of ectoenzymes present in lepidopteran larvae midguts, involved in the Bacillus thuringiensis (Bt) toxins mode of action. In the present work, seven aminopeptidases have been cloned from the midgut of Ostrinia nubilalis, the major Lepidopteran corn pest in the temperate climates. Six sequences were identified as APNs because of the presence of the HEXXH(X)18E and GAMEN motifs, as well as the signal peptide and the GPI-anchor sequences. The remaining sequence did not contain the two cellular targeting signals, indicating it belonged to the puromycin-sensitive aminopeptidase (PSA) family. An in silico analysis allowed us to find orthologous sequences in Bombyx mori. A phylogenetic study of lepidopteran aminopeptidase sequences resulted in their clustering into nine classes. Linkage analysis revealed that the onapn genes as well as all bmapn genes clustered in a single linkage group. O. nubilalis aminopeptidases were expressed in all larval instars. In 5th instar larvae tissues, apns transcripts were found mainly in midguts while apn8 was also highly expressed in Malpighian tubules, and psa showed an ubiquitous expression pattern in O. nubilalis and B. mori. The sequence homology and gene organization of apns suggest a single origin from an ancestral lepidopteran apn gene. © 2010 Elsevier Ltd.

PubMed | Burnet Institute, Deakin University and Bio21 Institute
Type: Journal Article | Journal: PloS one | Year: 2016

Pathogenesis of malaria infections is linked to remodeling of erythrocytes, a process dependent on the trafficking of hundreds of parasite-derived proteins into the host erythrocyte. Recent studies have demonstrated that the Plasmodium translocon of exported proteins (PTEX) serves as the central gateway for trafficking of these proteins, as inducible knockdown of the core PTEX constituents blocked the trafficking of all classes of cargo into the erythrocyte. However, the role of the auxiliary component PTEX88 in protein export remains less clear. Here we have used inducible knockdown technologies in P. falciparum and P. berghei to assess the role of PTEX88 in parasite development and protein export, which reveal that the in vivo growth of PTEX88-deficient parasites is hindered. Interestingly, we were unable to link this observation to a general defect in export of a variety of known parasite proteins, suggesting that PTEX88 functions in a different fashion to the core PTEX components. Strikingly, PTEX88-deficient P. berghei were incapable of causing cerebral malaria despite a robust pro-inflammatory response from the host. These parasites also exhibited a reduced ability to sequester in peripheral tissues and were removed more readily from the circulation by the spleen. In keeping with these findings, PTEX88-deficient P. falciparum-infected erythrocytes displayed reduced binding to the endothelial cell receptor, CD36. This suggests that PTEX88 likely plays a specific direct or indirect role in mediating parasite sequestration rather than making a universal contribution to the trafficking of all exported proteins.

News Article | September 13, 2016

The study, published today in Nature Microbiology, holds promise for a new treatment method against antibiotic-resistant bacteria (commonly known as superbugs). The star-shaped structures, are short chains of proteins called 'peptide polymers', and were created by a team from the Melbourne School of Engineering. The team included Professor Greg Qiao and PhD candidate Shu Lam, from the Department of Chemical and Biomolecular Engineering, as well as Associate Professor Neil O'Brien-Simpson and Professor Eric Reynolds from the Faculty of Medicine, Dentistry and Health Sciences and Bio21 Institute. Professor Qiao said that currently the only treatment for infections caused by bacteria is antibiotics. However, over time bacteria mutate to protect themselves against antibiotics, making treatment no longer effective. These mutated bacteria are known as 'superbugs'. "It is estimated that the rise of superbugs will cause up to ten million deaths a year by 2050. In addition, there have only been one or two new antibiotics developed in the last 30 years," he said. Professor Qiao and his team have been working with peptide polymers in the past few years. Recently, the team created a star-shaped peptide polymer that was extremely effective at killing Gram-negative bacteria – a major class of bacteria known to be highly prone to antibiotic resistance – while being non-toxic to the body. In fact, tests undertaken on red blood cells showed that the star-shaped polymer dosage rate would need to be increased by a factor of greater than 100 to become toxic. The star-shaped peptide polymer is also effective in killing superbugs when tested in animal models. Furthermore, superbugs showed no signs of resistance against these peptide polymers. The team discovered that their star-shaped peptide polymers can kill bacteria with multiple pathways, unlike most antibiotics which kill with a single pathway. They believe that this accounts for the superior performance of the star-shaped peptide polymers over antibiotics. One of these pathways includes 'ripping apart' the bacteria cell wall. (see image). While more research is needed, Professor Qiao and his team believe that their discovery is the beginning of unlocking a new treatment for antibiotic-resistant pathogens. More information: Shu J. Lam et al. Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers, Nature Microbiology (2016). DOI: 10.1038/nmicrobiol.2016.162

News Article | October 31, 2016

A female mosquito lays hundreds of eggs at a time, and within ten days newly minted adults are leaving their stagnant water homes to buzz around our ears and ankles. Victoria is braced for swarms of the things after late winter floods and warming spring temperatures created perfect breeding conditions, prompting public health warnings and forcing councils to start spraying breeding sites. But as Victorians stalk their bedrooms and hallways armed with insecticide cans, they should count their blessings that for now at least the Aedes albopictus mosquito remains in the Torres Strait. Nicknamed "Tiger" because of the bright white stripe on its back and the white bands on its legs, albopictus is a biting mosquito that can carry a variety of tropical diseases. And it doesn't mind a bit of chilly whether. Which means, if it crossed to the mainland it could cover much of the country, making once exotics tropical diseases into more common temperate ones. "Albopictus is one of our main quarantine pests," says Professor Ary Hoffmann of the Bio21 Institute at the University of Melbourne. "Its ability to withstand colder weather has allowed it to invade Europe and North America." And as far as Professor Hoffmann is concerned, despite our quarantine efforts it is likely a matter of when, not if, the Tiger makes it to the mainland. It was first reported in the Torres Strait islands in 2005. At the moment the rise in mosquito numbers in Victoria has prompted health warnings about comparatively rare mosquito-borne diseases such as the non-fatal Ross River Fever and Barmah Forest viruses, and the potentially fatal Murray Valley Encephalitis. But if albopictus arrives here Professor Hoffmann says we will have to add dengue fever, which is currently just limited to northern Queensland, as well as the zika and chikungunya viruses. Many mosquito breeds tend to be more active at dawn and dusk when the air is more humid and the insects are at less risk of drying out. But Professor Hoffmann says albopictus doesn't mind a bit of daylight. It means that albopictus is active and biting in the middle of the day. "It is regarded as a massive irritant as well as being a vector for diseases, making it a real nuisance for outdoor activities." Professor Hoffmann and colleagues have modelled the possible reach of albopictus if it does arrive, and they predict it could become widespread as far south as northern Tasmania. "It will go a long way," he says While their modelling suggests it would be concentrated on the coastal fringes of the continent, its spread so far in North America and elsewhere suggests forms of this mosquito could also travel further inland in Australia. Dengue fever is spreading rapidly elsewhere around the world as a direct result of albopictus migrating into more temperate climes and the ongoing spread of its sister species Aedes aegypti. Since 1970 the number of countries where dengue is endemic, that is it is present, has risen from just nine to now 100. And there are a rising number of outbreaks. The World Health Organization says 2015 was a particularly bad year with outbreaks of over 100,000 cases in the Philippines and Malaysia, representing a 60 per cent and 16 per cent increase respectively on the previous year. The number of cases in Brazil trebled to over 1.5 million, and Delhi in India reported its worst outbreak since 2006 with 15,000 cases. In 2014, China's Guangdong province near Hong Kong reported its worst outbreak with 45,000 reported cases and six confirmed deaths. WHO now warns that Europe is also at risk of possible outbreaks. Cases of local transmission were reported in France and Croatia in 2010. The main vector of dengue has been Aedes aegypti mosquito, which is limited to tropical climates including northern Australia. But the ability of albopictus to withstand cold temperatures means the disease is now spread more widely. It is believed to have travelled into northern climes by breeding in water puddles caught inside imported tyres and bamboo. Its eggs can survive temperatures below freezing. Dengue fever has similar symptoms to mosquito-borne malaria, but is less fatal. Dengue can cause severe flu-like symptoms, headaches and joint pain, as well as vomiting and rashes. Severe dengue fever, known as dengue haemorrhagic fever, is present in most Asian and Latin American countries, and with proper medical attention fatality rates from severe dengue can be kept below 1 per cent. It is estimated that every year abour 500,000 people are infected with severe dengue fever requiring hospitalisation, of which about 2.5 per cent die. In contrast, in 2015 there were 438,000 deaths from malaria. "Dengue isn't as deadly as malaria, but while the incidence of malaria is going down the incidence of dengue fever is going up, and the resulting economic impact can be massive because dengue can still really knock people around." "We hope albopictus won't hit the mainland but I think it is inevitable that it will at some stage, it is just a matter of time. And when it does you will certainly notice it." The odd temporary swarm of mosquitoes may be the least of our problems. Explore further: Dengue fever: what you need to know More information: Matthew P. Hill et al. Predicting the spread ofin Australia under current and future climates: Multiple approaches and datasets to incorporate potential evolutionary divergence, Austral Ecology (2014). DOI: 10.1111/aec.12105

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