Research, Innovation and Commercialisation - Research Publications
Permanent URI for this collection
Search Results
1 - 10 of 55
-
Item
-
ItemNo Preview AvailableAre NKT cells a useful predictor of COVID-19 severity?(CELL PRESS, 2022-02-08)
-
ItemNo Preview AvailableStructural biology of cell surface receptors implicated in Alzheimer's disease.(Springer Science and Business Media LLC, 2022-02)Alzheimer's disease is a common and devastating age-related disease with no effective disease-modifying treatments. Human genetics has implicated a wide range of cell surface receptors as playing a role in the disease, many of which are involved in the production or clearance of neurotoxins in the brain. Amyloid precursor protein, a membrane-bound signaling molecule, is at the very heart of the disease: hereditary mutations in its gene are associated with a greatly increased risk of getting the disease. A proteolytic breakdown product of amyloid precursor protein, the neurotoxic Aβ peptide, has been the target for many drug discovery efforts. Antibodies have been designed to target Aβ production with some success, although they have not proved efficacious in clinical trials with regards to cognitive benefits to date. Many of the recently identified genes associated with late-onset Alzheimer's disease risk are integral to the innate immune system. Some of these genes code for microglial proteins, such as the strongest genetic risk factor for the disease, namely APOE, and the cell surface receptors CD33 and TREM2 which are involved in clearance of the Aβ peptide from the brain. In this review, we show how structural biology has provided key insights into the normal functioning of these cell surface receptors and provided a framework for developing novel treatments to combat Alzheimer's disease.
-
ItemAnionic Phospholipid Interactions of the Prion Protein N Terminus Are Minimally Perturbing and Not Driven Solely by the Octapeptide Repeat Domain(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010-10-15)Although the N terminus of the prion protein (PrP(C)) has been shown to directly associate with lipid membranes, the precise determinants, biophysical basis, and functional implications of such binding, particularly in relation to endogenously occurring fragments, are unresolved. To better understand these issues, we studied a range of synthetic peptides: specifically those equating to the N1 (residues 23-110) and N2 (23-89) fragments derived from constitutive processing of PrP(C) and including those representing arbitrarily defined component domains of the N terminus of mouse prion protein. Utilizing more physiologically relevant large unilamellar vesicles, fluorescence studies at synaptosomal pH (7.4) showed absent binding of all peptides to lipids containing the zwitterionic headgroup phosphatidylcholine and mixtures containing the anionic headgroups phosphatidylglycerol or phosphatidylserine. At pH 5, typical of early endosomes, quartz crystal microbalance with dissipation showed the highest affinity binding occurred with N1 and N2, selective for anionic lipid species. Of particular note, the absence of binding by individual peptides representing component domains underscored the importance of the combination of the octapeptide repeat and the N-terminal polybasic regions for effective membrane interaction. In addition, using quartz crystal microbalance with dissipation and solid-state NMR, we characterized for the first time that both N1 and N2 deeply insert into the lipid bilayer with minimal disruption. Potential functional implications related to cellular stress responses are discussed.
-
ItemBiparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2(CELL PRESS, 2022-11-18)The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.
-
ItemNo Preview AvailableRising to the challenge of teaching Chinese students( 2020-05-23)
-
ItemBasic income: trade-offs and bottom lines(Brotherhood of St Laurence, 2017-11-01)In 2016, Professor Brian Howe, University of Melbourne academic and former Deputy Prime Minister and Minister for Social Security in the Hawke Labor Government, recognised the opportunity to celebrate the 50 plus year legacy of Professor Ronald Henderson, the inaugural director of the Melbourne Institute of Applied Economic and Social Research at the University of Melbourne. Professor Henderson led the National Poverty Inquiry (1972–1975), which resulted in the Henderson Poverty Line as well as a proposal for a Basic Income. The crucial role of social security in mitigating the negative impact of poverty was also considered in the poverty inquiry. Professor Howe, together with Professor Shelley Mallett, General Manager of the Brotherhood of St Laurence’s Research and Policy Centre, and the Melbourne Institute have partnered in a program of activities throughout 2016 and 2017 that honour Professor Henderson’s work on poverty, social security and basic income. This working paper was commissioned by the partners to review existing proposals and trials of basic income and inform discussion of the strengths and weaknesses of basic income approaches, especially in relation to income adequacy. Further papers on basic income will be developed by a range of authors as part of the Henderson Program.
-
Item
-
ItemNo Preview AvailableDiversion Ahead? Change Is Needed but That Doesn’t Mean That Basic Income Is the Answer(Palgrave Macmillan, Cham, 2019)Using an expanded version of De Wispelaere and Stirton’s 2004 framework for assessing basic income policies, we examine selected past and recent trials. The trials have all produced inconclusive results, in part because of the political contexts in which they have been implemented. As a result, they do little to progress policy reforms to address the challenges of economic insecurities and inequalities. Basic income proposals can act as beacons for change, but because they often lack detail, they risk distracting attention from the challenges and opportunities for social security reform. Our expanded framework enables detailed assessment of the dimensions of proposals for change. It also enables the identification of the elements of basic income proposals that can be incorporated into progressive efforts to reclaim social security.
-
ItemRecombinant influenza virus expressing HIV-1 p24 capsid protein induces mucosal HIV-specific CD8 T-cell responses(ELSEVIER SCI LTD, 2016-02-24)Influenza viruses are promising mucosal vaccine vectors for HIV but their use has been limited by difficulties in engineering the expression of large amounts of foreign protein. We developed recombinant influenza viruses incorporating the HIV-1 p24 gag capsid into the NS-segment of PR8 (H1N1) and X31 (H3N2) influenza viruses with the use of multiple 2A ribosomal skip sequences. Despite the insertion of a sizable HIV-1 gene into the influenza genome, recombinant viruses were readily rescued to high titers. Intracellular expression of p24 capsid was confirmed by in vitro infection assays. The recombinant influenza viruses were subsequently tested as mucosal vaccines in BALB/c mice. Recombinant viruses were attenuated and safe in immunized mice. Systemic and mucosal HIV-specific CD8 T-cell responses were elicited in mice that were immunized via intranasal route with a prime-boost regimen. Isolated HIV-specific CD8 T-cells displayed polyfunctional cytokine and degranulation profiles. Mice boosted via intravaginal route induced recall responses from the distal lung mucosa and developed heightened HIV-specific CD8 T-cell responses in the vaginal mucosa. These findings demonstrate the potential utility of recombinant influenza viruses as vaccines for mucosal immunity against HIV-1 infection.