School of BioSciences - Research Publications
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ItemPI3K Activation in Neural Stem Cells Drives Tumorigenesis which can be Ameliorated by Targeting the cAMP Response Element Binding (CREB) Protein(Oxford University Press, 2018-10)BACKGROUND: Hyperactivation of phosphoinositide 3-kinase (PI3K) signaling is common in cancers, but the precise role of the pathway in glioma biology remains to be determined. Some understanding of PI3K signaling mechanisms in brain cancer comes from studies on neural stem/progenitor cells (NSPCs), where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate critical cell functions. METHODS: To investigate the role of the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a PIK3CAH1047A oncogenic mutant and deletion of the PI3K negative regulator, phosphatase and tensin homolog (PTEN), to NSPCs. RESULTS: Expression of a Pik3caH1047A was sufficient to generate tumors with oligodendroglial features, but simultaneous loss of PTEN was required for the development of invasive, high-grade glioma. Pik3caH1047A-PTEN mutant NSPCs exhibited enhanced neurosphere formation which correlated with increased Wnt signaling, while loss of cAMP response element binding protein (CREB) in Pik3caH1047A-Pten mutant tumors led to longer symptom-free survival in mice. CONCLUSION: Taken together, our findings present a novel mouse model for glioma demonstrating that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion.
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ItemInvestigating Neural Stem Cell and Glioma Stem Cell Self-renewal Potential Using Extreme Limiting Dilution Analysis (ELDA)(BIO-PROTOCOL, 2018-09-05)Glioma stem cells (GSC) grown as neurospheres exhibit similar characteristics to neural stem cells (NSC) grown as neurospheres, including the ability to self-renew and differentiate. GSCs are thought to play a role in cancer initiation and progression. Self-renewal potential of GSCs is thought to reflect many characteristics associated with malignancy, including tumor recurrence following cytotoxic therapy due to their proliferative dormancy and capacity to allow for the development of resistant tumor cell sub-clones due to mutations acquired during their differentiation. Here, we demonstrate that using extreme limiting dilution analysis (ELDA), subtle differences in the frequency of sphere-forming potential between PI3K-mutant oncogenic NSCs and non-oncogenic NSCs can be measured, in vitro. We further show how ELDA can be used on cells, before and after forced differentiation to amplify inherent differences in sphere-forming potential between mutant and control NSCs. Ultimately, ELDA exploits a difference in the ability of a single or a few seeded stem cells to self-renew, divide and form neurospheres. Importantly, the assay also allows a comparison between genetically distinct cells or between the same cells under different conditions, where the impact of target-specific drugs or other novel cancer stem cell therapies can be tested.
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ItemAssessment and management of reproduction in Australian monotremes and marsupials(CSIRO Publishing, 2019)
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ItemConserved Glu-47 and Lys-50 residues are critical for UDP-N-acetylglucosamine/UMP antiport activity of the mouse Golgi-associated transporter Slc35a3(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2019-06-28)Nucleotide sugar transporters (NSTs) regulate the flux of activated sugars from the cytosol into the lumen of the Golgi apparatus where glycosyltransferases use them for the modification of proteins, lipids, and proteoglycans. It has been well-established that NSTs are antiporters that exchange nucleotide sugars with the respective nucleoside monophosphate. Nevertheless, information about the molecular basis of ligand recognition and transport is scarce. Here, using topology predictors, cysteine-scanning mutagenesis, expression of GFP-tagged protein variants, and phenotypic complementation of the yeast strain Kl3, we identified residues involved in the activity of a mouse UDP-GlcNAc transporter, murine solute carrier family 35 member A3 (mSlc35a3). We specifically focused on the putative transmembrane helix 2 (TMH2) and observed that cells expressing E47C or K50C mSlc35a3 variants had lower levels of GlcNAc-containing glycoconjugates than WT cells, indicating impaired UDP-GlcNAc transport activity of these two variants. A conservative substitution analysis revealed that single or double substitutions of Glu-47 and Lys-50 do not restore GlcNAc glycoconjugates. Analysis of mSlc35a3 and its genetic variants reconstituted into proteoliposomes disclosed the following: (i) all variants act as UDP-GlcNAc/UMP antiporters; (ii) conservative substitutions (E47D, E47Q, K50R, or K50H) impair UDP-GlcNAc uptake; and (iii) substitutions of Glu-47 and Lys-50 dramatically alter kinetic parameters, consistent with a critical role of these two residues in mSlc35a3 function. A bioinformatics analysis revealed that an EXXK motif in TMH2 is highly conserved across SLC35 A subfamily members, and a 3D-homology model predicted that Glu-47 and Lys-50 are facing the central cavity of the protein.
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ItemUsing decision support tools in emergency animal disease planning and response: Foot and mouth disease (CEBRA Project 1404D), Technical Report prepared for the Department of Agriculture and Water Resources(University of Melbourne, 2016)Modelling studies both in Australia and overseas have shown that vaccination can be very effective in reducing the size and duration of an FMD outbreak. Vaccination is most effective in reducing the duration and size of an outbreak when used early and is less effective the longer you delay. However, a decision to vaccinate early in the outbreak may result in using vaccination in situations where it is not actually required, with consequent implications for post-outbreak surveillance, the management of vaccinated animals and the ability to regain FMD-free status and access to markets. Overall, the choice of control measure to adopt in an FMD outbreak will thus depend on the variable and potentially conflicting objectives of the control program. As an important component of disease planning and preparedness for the department, the project will report on key information that could be used in an FMD outbreak to infer the potential scale of an outbreak and information to support disease management decision-making.
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ItemIncorporating economic components in Australia's FMD modelling capability and evaluating post-outbreak management to support return to trade (CEBRA project 1608D), Technical Report for the Department of Agriculture, Water and Environment(University of Melbourne, 2017)Following an outbreak of FMD, surveillance will be required to demonstrate that infection has been eradicated from the population and enable any remaining movement restrictions to be lifted within the country. Proof of freedom will also be needed to satisfy trading partners and regain access to international markets. Although vaccination is increasingly being recognised as an important tool to assist in containing and eradicating FMD outbreaks, it will make achieving recognition of free status more difficult—keeping vaccinated animals in the population will delay the period until FMD-free status is regained under the World Organisation for Animal Health (OIE) guidelines and add additional complications to the postoutbreak surveillance program. There is no agreed approach to post-outbreak management of vaccinated animals in AUSVETPLAN with the options being to: (1) allow vaccinated animals to remain in the population to live out their normal commercial lives (vaccinate-to-live); (2) remove all vaccinated animals from the population (vaccinateand- remove). Under option 2, vaccinated animals could be subject to (a) slaughter to waste i.e. remove and dispose of vaccinated animals; or (b) slaughter and salvage i.e. attempt to sell either raw or processed product from vaccinated animals. For (b) there may be some residual value of products that could offset some of the costs. The project will bring together epidemiological and economic expertise from the Department, the Australian National University, and CEBRA to formally explore and establish a science-based and cost effective approach to regaining free-status after an FMD outbreak as expeditiously as possible. The project will expand the Department’s modelling capability as well as providing insights into postoutbreak FMD management and contribute to Australia’s FMD preparedness.
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ItemNational-level farm demographic data for preparedness of highly-infectious livestock disease epidemics. Review of data sources in New Zealand, approach to modelling populations and the effect of population uncertainty on disease modelling.(University of Melbourne, 2016)Isolation and strict biosecurity measures implemented by Australia and New Zealand have prevented the incursion of many organisms of biosecurity concern. The agricultural industry is a key part of the economy for both countries, and preventing the arrival of diseases of concern, including foot-and-mouth (FMD) disease, is crucial to maintaining access to international markets, reputation, and protecting the economy and industry. Early detection of, and a rapid, effective response to such diseases have a large impact on limiting the economic damage caused by epidemics. An acknowledged weakness of biosecurity preparedness and response to agricultural diseases in both countries is the lack of a single source of accurate, up-to-date farm livestock demographics information. This report reviews the use of animal counts for investigation of, preparedness for and response to exotic animal disease outbreaks, and analyses the available New Zealand datasets in depth. Gaps and weaknesses in the current data landscape are documented. The project objectives then focus on developing methodologies to estimate national-level farm demographic data and assess the use of modelled and inaccurate data in disease simulation models. There are nine key deliverables outlined in the report which were carried out over the two year duration of the project.
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ItemCost-benefit analysis of the yellow crazy ant eradication program. Technical Report prepared for the Wet Tropics Management Authority(Centre of Excellence for Biosecurity Risk Analysis, 2019)Yellow crazy ants (Anoplolepis gracilipes) (YCA) are one of the world’s 100 worst invasive species (Lowe et al. 2000). Previous assessments of YCA invasions have demonstrated that YCA can dramatically reduce native species richness in invaded areas, including in the Seychelles (Bos et al. 2008), Christmas Island (O'Dowd et al. 2003), and Hawaii (Plentovich et al. 2011). Native species losses include direct losses of competing invertebrate species and indirect losses resulting from ecological interdependencies, which can result in “ecological meltdown” in extreme cases such as Christmas Island (O'Dowd et al. 2003). YCA can also cause large losses to people living in infested areas through nuisance and health effects (Lach and Hoskin 2015) and can also adversely affect agricultural producers (Young et al. 2001) through reducing yields and/or increasing pesticide costs. YCA was first detected in Cairns and its southern suburbs in 2001, and an eradication program was initiated by the Department of Natural Resources and Mines (DNRM) and Biosecurity Queensland as part of a larger state-wide program. Later discoveries of YCA across the state, including in and around the WTWHA led to the state-wide eradication program being discontinued. An application was then made by WTMA to continue eradication efforts in and around the WTWHA. The program has been funded by the Australian Government and the Queensland Government in two overlapping projects, as described in the Executive Summary.
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ItemWidespread cis-regulatory convergence between the extinct Tasmanian tiger and gray wolf(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2019-10)The extinct marsupial Tasmanian tiger, or thylacine, and the eutherian gray wolf are among the most widely recognized examples of convergent evolution in mammals. Despite being distantly related, these large predators independently evolved extremely similar craniofacial morphologies, and evidence suggests that they filled similar ecological niches. Previous analyses revealed little evidence of adaptive convergence between their protein-coding genes. Thus, the genetic basis of their convergence is still unclear. Here, we identified candidate craniofacial cis-regulatory elements across vertebrates and compared their evolutionary rates in the thylacine and wolf, revealing abundant signatures of convergent positive selection. Craniofacial thylacine-wolf accelerated regions were enriched near genes involved in TGF beta (TGFB) and BMP signaling, both of which are key morphological signaling pathways with critical roles in establishing the identities and boundaries between craniofacial tissues. Similarly, enhancers of genes involved in craniofacial nerve development showed convergent selection and involvement in these pathways. Taken together, these results suggest that adaptation in cis-regulators of TGF beta and BMP signaling may provide a mechanism to explain the coevolution of developmentally and functionally integrated craniofacial structures in these species. We also found that despite major structural differences in marsupial and eutherian brains, accelerated regions in both species were common near genes with roles in brain development. Our findings support the hypothesis that, relative to protein-coding genes, positive selection on cis-regulatory elements is likely to be an essential driver of adaptive convergent evolution and may underpin thylacine-wolf phenotypic similarities.
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ItemInsect Antennal Morphology: The Evolution of Diverse Solutions to Odorant Perception(Yale University, 2018-12-01)Chemical communication involves the production, transmission, and perception of odors. Most adult insects rely on chemical signals and cues to locate food resources, oviposition sites or reproductive partners and, consequently, numerous odors provide a vital source of information. Insects detect these odors with receptors mostly located on the antennae, and the diverse shapes and sizes of these antennae (and sensilla) are both astonishing and puzzling: what selective pressures are responsible for these different solutions to the same problem - to perceive signals and cues? This review describes the selection pressures derived from chemical communication that are responsible for shaping the diversity of insect antennal morphology. In particular, we highlight new technologies and techniques that offer exciting opportunities for addressing this surprisingly neglected and yet crucial component of chemical communication.