Melbourne Medical School Collected Works - Research Publications

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    Evolution and transmission of antibiotic resistance is driven by Beijing lineage Mycobacterium tuberculosisin Vietnam
    Silcocks, M ; Chang, X ; Thuong, NTT ; Qin, Y ; Ha, DTM ; Thai, PVK ; Vijay, S ; Thu, DDA ; Ha, VTN ; Nhung, HN ; Lan, NH ; Nhu, NTQ ; Edwards, D ; Nath, A ; Pham, K ; Bang, ND ; Chau, TTH ; Thwaites, G ; Heemskerk, AD ; Chuen Khor, C ; Teo, YY ; Inouye, M ; Ong, RT-H ; Caws, M ; Holt, KE ; Dunstan, SJ ; Neyrolles, O (AMER SOC MICROBIOLOGY, 2023-12-12)
    Drug-resistant tuberculosis (TB) infection is a growing and potent concern, and combating it will be necessary to achieve the WHO's goal of a 95% reduction in TB deaths by 2035. While prior studies have explored the evolution and spread of drug resistance, we still lack a clear understanding of the fitness costs (if any) imposed by resistance-conferring mutations and the role that Mtb genetic lineage plays in determining the likelihood of resistance evolution. This study offers insight into these questions by assessing the dynamics of resistance evolution in a high-burden Southeast Asian setting with a diverse lineage composition. It demonstrates that there are clear lineage-specific differences in the dynamics of resistance acquisition and transmission and shows that different lineages evolve resistance via characteristic mutational pathways.
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    Gold-iron oxide nanoparticle: A unique multimodal theranostic approach for thrombosis
    Fithri, NA ; Wu, Y ; Cowin, G ; Akther, F ; Tran, HDN ; Tse, B ; Holthe, NWV ; Moonshi, SS ; Peter, K ; Wang, X ; Truong, NP ; Ta, HT (ELSEVIER, 2023-04)
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    Characterizing and predicting ccRCC-causing missense mutations in Von Hippel-Lindau disease
    Serghini, A ; Portelli, S ; Troadec, G ; Song, C ; Pan, Q ; Pires, DE ; Ascher, DB (OXFORD UNIV PRESS, 2024-01-20)
    BACKGROUND: Mutations within the Von Hippel-Lindau (VHL) tumor suppressor gene are known to cause VHL disease, which is characterized by the formation of cysts and tumors in multiple organs of the body, particularly clear cell renal cell carcinoma (ccRCC). A major challenge in clinical practice is determining tumor risk from a given mutation in the VHL gene. Previous efforts have been hindered by limited available clinical data and technological constraints. METHODS: To overcome this, we initially manually curated the largest set of clinically validated VHL mutations to date, enabling a robust assessment of existing predictive tools on an independent test set. Additionally, we comprehensively characterized the effects of mutations within VHL using in silico biophysical tools describing changes in protein stability, dynamics and affinity to binding partners to provide insights into the structure-phenotype relationship. These descriptive properties were used as molecular features for the construction of a machine learning model, designed to predict the risk of ccRCC development as a result of a VHL missense mutation. RESULTS: Analysis of our model showed an accuracy of 0.81 in the identification of ccRCC-causing missense mutations, and a Matthew's Correlation Coefficient of 0.44 on a non-redundant blind test, a significant improvement in comparison to the previous available approaches. CONCLUSION: This work highlights the power of using protein 3D structure to fully explore the range of molecular and functional consequences of genomic variants. We believe this optimized model will better enable its clinical implementation and assist guiding patient risk stratification and management.
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    Bioengineered Vascular Model of Foam Cell Formation
    Zhou, Y ; Sekar, NC ; Thurgood, P ; Needham, S ; Peter, K ; Khoshmanesh, K ; Baratchi, S (AMER CHEMICAL SOC, 2023-11-29)
    Foam cell formation is a complex blood vessel pathology, which is characterized by a series of events, including endothelium dysfunction, inflammation, and accumulation of immune cells underneath the blood vessel walls. Novel bioengineered models capable of recapitulating these events are required to better understand the complex pathological processes underlying the development of foam cell formation and, consequently, advanced bioengineered platforms for screening drugs. Here, we generated a microfluidic blood vessel model, incorporating a three-dimensional (3D) extracellular matrix coated with an endothelial layer. This system enables us to perform experiments under a dynamic microenvironment that recapitulates the complexities of the native vascular regions. Using this model, we studied the effectors that regulate monocyte adhesion and migration, as well as foam cell formation inside vessel walls. We found that monocyte adhesion and migration are regulated by both the endothelium and monocytes themselves. Monocytes migrated into the extracellular matrix only when endothelial cells were cultured in the vessel model. In addition, the exposure of an endothelial layer to tumor necrosis factor α (TNF-α) and low shear stress both increased monocyte migration into the subendothelial space toward the matrix. Furthermore, we demonstrated the process of foam cell formation, 3 days after transmigration of peripheral blood mononuclear cells (PBMCs) into the vessel wall. We showed that pre-exposure of PBMCs to high shear rates increases their adhesion and migration through the TNF-α-treated endothelium but does not affect their capacity to form foam cells. The versatility of our model allows for mechanistic studies on foam cell formation under customized pathological conditions.
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    A Broad-Spectrum α-Glucosidase of Glycoside Hydrolase Family 13 from Marinovum sp., a Member of the Roseobacter Clade
    Li, J ; Mui, JW-Y ; da Silva, BM ; Pires, DEV ; Ascher, DB ; Soler, NM ; Goddard-Borger, ED ; Williams, SJ (SPRINGER, 2024-01-05)
    Glycoside hydrolases (GHs) are a diverse group of enzymes that catalyze the hydrolysis of glycosidic bonds. The Carbohydrate-Active enZymes (CAZy) classification organizes GHs into families based on sequence data and function, with fewer than 1% of the predicted proteins characterized biochemically. Consideration of genomic context can provide clues to infer possible enzyme activities for proteins of unknown function. We used the MultiGeneBLAST tool to discover a gene cluster in Marinovum sp., a member of the marine Roseobacter clade, that encodes homologues of enzymes belonging to the sulfoquinovose monooxygenase pathway for sulfosugar catabolism. This cluster lacks a gene encoding a classical family GH31 sulfoquinovosidase candidate, but which instead includes an uncharacterized family GH13 protein (MsGH13) that we hypothesized could be a non-classical sulfoquinovosidase. Surprisingly, recombinant MsGH13 lacks sulfoquinovosidase activity and is a broad-spectrum α-glucosidase that is active on a diverse array of α-linked disaccharides, including maltose, sucrose, nigerose, trehalose, isomaltose, and kojibiose. Using AlphaFold, a 3D model for the MsGH13 enzyme was constructed that predicted its active site shared close similarity with an α-glucosidase from Halomonas sp. H11 of the same GH13 subfamily that shows narrower substrate specificity.
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    AI-driven GPCR analysis, engineering, and targeting
    Velloso, JPL ; Kovacs, AS ; Pires, DEV ; Ascher, DB (ELSEVIER SCI LTD, 2024-02)
    This article investigates the role of recent advances in Artificial Intelligence (AI) to revolutionise the study of G protein-coupled receptors (GPCRs). AI has been applied to many areas of GPCR research, including the application of machine learning (ML) in GPCR classification, prediction of GPCR activation levels, modelling GPCR 3D structures and interactions, understanding G-protein selectivity, aiding elucidation of GPCRs structures, and drug design. Despite progress, challenges in predicting GPCR structures and addressing the complex nature of GPCRs remain, providing avenues for future research and development.
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    An Ultrasound‐Responsive Theranostic Cyclodextrin‐Loaded Nanoparticle for Multimodal Imaging and Therapy for Atherosclerosis (Small 31/2022)
    Mehta, S ; Bongcaron, V ; Nguyen, TK ; Jirwanka, Y ; Maluenda, A ; Walsh, APG ; Palasubramaniam, J ; Hulett, MD ; Srivastava, R ; Bobik, A ; Wang, X ; Peter, K (Wiley, 2022-08)
    In article number 2200967, Xiaowei Wang, Karlheinz Peter, and co-workers show that theranostic nanoparticles made of air can deliver a near-infrared fluorescence dye, cyclodextrin, to be used as a contrast agent for ultrasound and fluorescence imaging and as ultrasound-responsive anti-atherosclerotic drug, achieving reduction of cholesterol in plaques after ingestion of nanoparticle by monocytes/macrophages.
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    3D‐Printed Micro Lens‐in‐Lens for In Vivo Multimodal Microendoscopy (Small 17/2022)
    Li, J ; Thiele, S ; Kirk, RW ; Quirk, BC ; Hoogendoorn, A ; Chen, YC ; Peter, K ; Nicholls, SJ ; Verjans, JW ; Psaltis, PJ ; Bursill, C ; Herkommer, AM ; Giessen, H ; McLaughlin, RA (Wiley, 2022-04)
    In article number 2107032, Jiawen Li and co-workers use two-photon 3D printing to develop a 330 micron diameter lens optimized for both fluorescence imaging and optical coherence tomography. This lens-in-lens design is incorporated in an intravascular imaging catheter offering improved performance for heart disease detection.
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    Understanding Exercise Capacity: From Elite Athlete to HFpEF
    Rowe, SJ ; Paratz, ED ; Foulkes, SJ ; Janssens, K ; Spencer, LW ; Fahy, L ; D'Ambrosio, P ; Haykowsky, MJ ; La Gerche, A (ELSEVIER SCIENCE INC, 2023-11)
    Exercise capacity is a spectrum that reflects an individual's functional capacity and the dynamic nature of cardiac remodelling along with respiratory and skeletal muscle systems. The relationship of increasing physical activity, increased cardiac mass and volumes, and improved cardiorespiratory fitness (CRF) is well established in the endurance athlete. However, less emphasis has been placed on the other end of the spectrum, which includes individuals with a more sedentary lifestyle and small hearts who are at increased risk of functional disability and poor clinical outcomes. Reduced CRF is an independent predictor of all-cause mortality and cardiovascular events determined by multiple inter-related exogenous and endogenous factors. In this review, we explore the relationship of physical activity, cardiac remodelling, and CRF across the exercise spectrum, emphasising the critical role of cardiac size in determining exercise capacity. In contrast to the large compliant left ventricle of the endurance athlete, an individual with a lifetime of physical inactivity is likely to have a small, stiff heart with reduced cardiac reserve. We propose that this might contribute to the development of heart failure with preserved ejection fraction in certain individuals, and is key to understanding the link between low CRF and increased risk of heart failure.