ORCID Profile
0000-0002-7799-3683
Current Organisation
Monash Institute of Pharmaceutical Sciences
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Pharmacology and Pharmaceutical Sciences | Biochemistry and cell biology | Basic pharmacology | Structural biology (incl. macromolecular modelling) | Receptors and membrane biology | Basic Pharmacology | Receptors and Membrane Biology | Structural Biology (incl. Macromolecular Modelling) |
Human Pharmaceutical Treatments (e.g. Antibiotics) | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences
Publisher: Public Library of Science (PLoS)
Date: 18-06-2015
Publisher: American Association for the Advancement of Science (AAAS)
Date: 25-03-2022
Abstract: Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), AMY
Publisher: Proceedings of the National Academy of Sciences
Date: 31-03-2016
Abstract: Influenza is a rapidly spreading acute respiratory infection that causes profound morbidity and mortality. Established CD8 + T-lymphocyte (CTL) immunity directed at conserved viral regions provides protection against distinct influenza A viruses (IAVs). In this study, we show that public T-cell receptors (TCRs) specific for the most prominent human CTL epitope (M1 58–66 restricted by HLA-A*0201) are capable of recognizing sporadically emerging variant IAVs. We also identify the structural mechanisms that enable promiscuous TCR recognition in this context. Our analysis suggests that preexisting cross-reactive TCRs may limit the spread of newly emerging pandemic IAVs.
Publisher: Wiley
Date: 16-09-2022
Publisher: Elsevier BV
Date: 11-2017
Publisher: American Chemical Society (ACS)
Date: 08-03-2021
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 10-04-2018
Publisher: Bioscientifica
Date: 03-2022
DOI: 10.1530/JME-21-0263
Abstract: Loss-of-function calcium-sensing receptor (CaSR) mutations cause the mineral metabolism disorders familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism,and increase the risk of femoral fracture, chronic kidney disease, coronary heart disease, and other diseases. In severe cases, CaSR mutations are lethal. Off-label use of the CaSR positive allosteric modulator (PAM), cinacalcet, corrects hypercalcemia in some patients with CaSR mutations. However, other patients remain unresponsive to cinacalcet, attesting to the need for novel treatments. Here we compared the effects of cinacalcet to two other clinically approved synthetic CaSR activators, evocalcet and etelcalcetide, as well as a novel PAM, 1-(2,4-dimethylphenyl)-1-(4,5-dimethylthiazol-2-yl)ethan-1-ol (MIPS-VD-836-108) on clinically relevant CaSR mutations. We assessed the compounds in CaSR-expressing HEK293 cells for correction of mutation-induced impairments in intracellular calcium (Ca2+i) mobilization and cell surface expression. While cinacalcet, MIPS-VD-836-108 and evocalcet rescued the signaling of cell surface-expressed mutants, albeit to varying degrees, etelcalcetide was ineffective. Cinacalcet and evocalcet, but not MIPS-VD-836-108 or etelcalcetide, restored expression of a R680H mutant. However, no compound rescued expression of I81K and C582R mutants or a receptor missing 77 amino acids in the extracellular domain mimicking deletion of CASR exon 5, which impairs CaSR function. These data suggest specific compounds may be clinically effective in some patients with CaSR mutations, but other patients will remain refractory to treatment with currently available CaSR-targeting activators, highlighting the need for new generation drugs to rescue both the signaling and expression of mutant CaSRs.
Publisher: Springer Science and Business Media LLC
Date: 21-12-2018
DOI: 10.1038/S41467-018-07815-5
Abstract: Newly-emerged and vaccine-mismatched influenza A viruses (IAVs) result in a rapid global spread of the virus due to minimal antibody-mediated immunity. In that case, established CD8 + T-cells can reduce disease severity. However, as mutations occur sporadically within immunogenic IAV-derived T-cell peptides, understanding of T-cell receptor (TCRαβ) cross-reactivity towards IAV variants is needed for a vaccine design. Here, we investigate TCRαβ cross-strain recognition across IAV variants within two immunodominant human IAV-specific CD8 + T-cell epitopes, HLA-B*37:01-restricted NP 338-346 (B37-NP 338 ) and HLA-A*01:01-restricted NP 44-52 (A1-NP 44 ). We find high abundance of cross-reactive TCRαβ clonotypes recognizing distinct IAV variants. Structures of the wild-type and variant peptides revealed preserved conformation of the bound peptides. Structures of a cross-reactive TCR-HLA-B37-NP 338 complex suggest that the conserved conformation of the variants underpins TCR cross-reactivity. Overall, cross-reactive CD8 + T-cell responses, underpinned by conserved epitope structure, facilitates recognition of distinct IAV variants, thus CD8 + T-cell-targeted vaccines could provide protection across different IAV strains.
Publisher: The American Association of Immunologists
Date: 15-04-2016
Abstract: Prior work has demonstrated that HIV-1–specific CD8 T cells can cross-recognize variant epitopes. However, most of these studies were performed in the context of chronic infection, where the presence of viral quasispecies makes it difficult to ascertain the true nature of the original antigenic stimulus. To overcome this limitation, we evaluated the extent of CD8 T cell cross-reactivity in patients with acute HIV-1 clade B infection. In each case, we determined the transmitted founder virus sequence to identify the autologous epitopes restricted by in idual HLA class I molecules. Our data show that cross-reactive CD8 T cells are infrequent during the acute phase of HIV-1 infection. Moreover, in the uncommon instances where cross-reactive responses were detected, the variant epitopes were poorly recognized in cytotoxicity assays. Molecular analysis revealed that similar antigenic structures could be cross-recognized by identical CD8 T cell clonotypes mobilized in vivo, yet even subtle differences in a single TCR-accessible peptide residue were sufficient to disrupt variant-specific reactivity. These findings demonstrate that CD8 T cells are highly specific for autologous epitopes during acute HIV-1 infection. Polyvalent vaccines may therefore be required to provide optimal immune cover against this genetically labile pathogen.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2013
Publisher: Portland Press Ltd.
Date: 14-02-2014
DOI: 10.1042/BJ20131386
Abstract: The peroxidase activity of cytochrome c may play a key role in the release of cytochrome c from the mitochondrial intermembrane space in the intrinsic apoptosis pathway. Induction of the peroxidase activity of cytochrome c is ascribed to partial unfolding and loss of axial co-ordination between the haem Fe and Met80, and is thought to be triggered by interaction of cytochrome c with cardiolipin (diphosphatidylglycerol) in vivo. However, the reaction mechanism for the peroxidase activity of either native or cardiolipin-bound cytochrome c is uncertain. In the present study we analyse the peroxidase activity of human and mouse cytochrome c residue 41 variants and demonstrate that stimulation of peroxidase activity can occur without prior loss of Fe–Met80 co-ordination or partial unfolding. The effects of cardiolipin and mutation of residue 41 are not additive, suggesting that cardiolipin stimulates peroxidase activity by the same mechanism as residue 41 mutation. Consistent with this, mutation of residue 41 did not enhance apoptotic release of cytochrome c from mitochondria. We propose that mutation of residue 41, and interaction with cardiolipin, increase peroxidase activity by altering the 40–57 Ω loop and its hydrogen bond network with the propionate of haem ring A. These changes enhance access of hydrogen peroxide and substrate to the haem.
Publisher: Walter de Gruyter GmbH
Date: 28-08-2017
Abstract: It has widely been accepted that major histocompatibility complex class I molecules (MHC-I) are limited to binding small peptides of 8–10 residues in length. However, this consensus has recently been challenged with the identification of longer peptides (≥11 residues) that can also elicit cytotoxic CD8 + T cell responses. Indeed, a growing number of studies demonstrate that these non-canonical epitopes are important targets for the immune system. As long epitopes represent up to 10% of the peptide repertoire bound to MHC-I molecules, here we review their impact on antigen presentation by MHC-I, TCR recognition, and T cell immunity.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-04-2021
Abstract: G protein–coupled receptors (GPCRs) coordinate a complex information flow between the outside and inside of a cell. An increasing number of GPCR structures provide insight into function. However, the dynamics that link extracellular sensing to intracellular signaling are not completely understood, because GPCRs used in structure determination are generally modified to constrain their dynamics. Josephs et al. succeeded in determining the structures of an unmodified calcitonin gene–related peptide receptor, which is implicated in migraines, both alone and bound to its neuropeptide ligand. Based on the structures and data from complementary biophysical techniques, they show that initial binding of the peptide causes only minor conformational changes of the GPCR, but dynamically causes changes at the intracellular side that facilitate G protein binding and activation. Science , this issue p. eabf7258
Publisher: Elsevier BV
Date: 11-2016
Publisher: Wiley
Date: 29-07-2021
Abstract: The calcium-sensing receptor (CaSR) is a clinical target in the treatment of hyperparathyroidism and related diseases. However, clinical use of approved CaSR-targeting drugs such as cinacalcet is limited due to adverse side effects including hypocalcaemia, nausea and vomiting, and in some instances, a lack of efficacy. The CaSR agonist and positive allosteric modulator (ago-PAM), AC265347, is chemically distinct from clinically-approved CaSR PAMs. AC265347 potently suppressed parathyroid hormone (PTH) release in rats with a lower propensity to cause hypocalcaemia compared to cinacalcet and may therefore offer benefits over current CaSR PAMs. Here we report a structure activity relationship (SAR) study seeking to optimise AC265347 as a drug candidate and disclose the discovery of AC265347-like compounds with erse pharmacology and improved physicochemical and drug-like properties.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 28-05-2020
Publisher: Wiley
Date: 12-02-2020
DOI: 10.1111/BPH.14961
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.IMMUNI.2016.09.007
Abstract: The anti-viral T cell response is drawn from the naive T cell repertoire. During influenza infection, the CD8
Publisher: Bioscientifica
Date: 08-2007
DOI: 10.1677/JOE-07-0158
Abstract: Adipokines, which are expressed and secreted from white adipose tissue (WAT), are potential factors that could contribute to the changes in energy homeostasis that occurs in pregnancy and lactation to meet the nutrient demands of fetal growth and milk production. The aim was to identify adipokines that could be involved by measuring the pattern of their mRNA expression in adipose tissue. Adipokine mRNAs were measured by quantitative RT-PCR in RNA isolated from white and brown adipose tissue (BAT) of rats at days 7, 14 and 21 of pregnancy, day 7 of lactation and virgin at dioestrus phase. The results for leptin, adiponectin and resistin expression in WAT essentially confirmed previous studies and it is unlikely that they are directly involved in the metabolic adaptations. The relative amounts of the mRNAs of the adipokines in BAT were comparable with those in WAT, but the patterns of expression did not follow those in WAT, except for apelin. Visfatin mRNA in WAT was elevated 2.5-fold only at day 21 of pregnancy. Apelin mRNA in WAT was increased 2.2-fold at day 7 of pregnancy. Retinol-binding protein 4 mRNA in WAT decreased to 46% of control at day 14 of pregnancy. Fasting-induced adipose factor (FIAF) mRNA in WAT was 2.2- to 2.5-fold higher throughout pregnancy and lactation. The marked induction of FIAF identifies this adipokine as a potential regulator of the metabolic adaptations that occur during pregnancy and lactation.
Location: Australia
Start Date: 2021
End Date: 2024
Funder: Australian Research Council
View Funded ActivityStart Date: 2023
End Date: 2025
Funder: Australian Research Council
View Funded ActivityStart Date: 2021
End Date: 2025
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2023
End Date: 12-2025
Amount: $776,880.00
Funder: Australian Research Council
View Funded ActivityStart Date: 06-2021
End Date: 12-2023
Amount: $645,190.00
Funder: Australian Research Council
View Funded Activity