Melbourne Medical School Collected Works - Research Publications

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http://hdl.handle.net/11343/220

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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.
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)
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.
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.
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.
Lipidomic signatures for APOE genotypes provides new insights about mechanisms of resilience in Alzheimer’s disease

Wang, T ; Huynh, K ; Giles, C ; Lim, WLF ; Duong, T ; Mellett, NA ; Smith, A ; Olshansky, G ; Drew, BG ; Cadby, G ; Melton, PE ; Hung, J ; Beilby, J ; Watts, GF ; Chatterjee, P ; Martins, I ; Laws, SM ; Bush, AI ; Rowe, CC ; Villemagne, VL ; Ames, D ; Masters, CL ; Arnold, M ; Kastenmüller, G ; Nho, K ; Saykin, AJ ; Baillie, R ; Han, X ; Martins, RN ; Moses, E ; Kaddurah‐Daouk, RF ; Meikle, PJ (Wiley, 2021-12)

Background The apolipoprotein E gene (APOE) genotype is the first and strongest genetic risk factor for late‐onset Alzheimer’s disease and has emerged as a novel therapeutic target for AD. The encoded protein (Apolipoprotein E, APOE) is well‐known to be involved in lipoprotein transport and metabolism, but its effect on lipid metabolic pathways and the potential mediating effect of these on disease risk have not been fully defined. Method We performed lipidomic analysis on three independent cohorts (AIBL, n = 693; ADNI, n=207; BHS, n=4,384) and defined the association between APOE polymorphisms (ε4 and ε2) and plasma lipid species. To identify associations independent of lipoprotein metabolism, the analyses was performed with adjustment for clinical lipids (total cholesterol, HDL‐C and triglycerides). Causal mediation analysis was performed to estimate the proportion of risk in the outcome model explained by a direct effect of APOE genotype on prevalent AD — the average direct effect (ADE) — and the proportion that was mediated by lipid species or lipidomic risk models — the average causal mediation effect (ACME). Result We identified multiple associations of species from lipid classes such as ceramide, hexosylceramide, sphingomyelin, plasmalogens, alkyldiacylglycerol and cholesteryl esters with APOE polymorphisms (ε4 and ε2) that were independent of clinical lipoprotein measurements. There were 104 and 237 lipid species associated with APOE ε4 and ε2 respectively which were largely discordant. Of these 116 were also associated with Alzheimer’s disease. Individual lipid species (notably the alkyldiacylglycerol subspecies) or lipidomic risk models of APOE genotypes mediated up to 10% and 30% of APOE ε4 and ε2 treatment effect on AD risks respectively. Conclusion We demonstrate a strong relationship between APOE polymorphisms and peripheral lipid species. Lipids species mediate a proportion of the effects of APOE genotypes in risk of AD, particularly resilience with e2. Our results highlight the involvement of lipids in how APOE e2 mediates its resilience to AD and solidify their involvement with the disease pathway.
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.
Uncovering the Molecular Drivers of NHEJ DNA Repair-Implicated Missense Variants and Their Functional Consequences

Al-Jarf, R ; Karmakar, M ; Myung, Y ; Ascher, DB (MDPI, 2023-10)

Variants in non-homologous end joining (NHEJ) DNA repair genes are associated with various human syndromes, including microcephaly, growth delay, Fanconi anemia, and different hereditary cancers. However, very little has been done previously to systematically record the underlying molecular consequences of NHEJ variants and their link to phenotypic outcomes. In this study, a list of over 2983 missense variants of the principal components of the NHEJ system, including DNA Ligase IV, DNA-PKcs, Ku70/80 and XRCC4, reported in the clinical literature, was initially collected. The molecular consequences of variants were evaluated using in silico biophysical tools to quantitatively assess their impact on protein folding, dynamics, stability, and interactions. Cancer-causing and population variants within these NHEJ factors were statistically analyzed to identify molecular drivers. A comprehensive catalog of NHEJ variants from genes known to be mutated in cancer was curated, providing a resource for better understanding their role and molecular mechanisms in diseases. The variant analysis highlighted different molecular drivers among the distinct proteins, where cancer-driving variants in anchor proteins, such as Ku70/80, were more likely to affect key protein-protein interactions, whilst those in the enzymatic components, such as DNA-PKcs, were likely to be found in intolerant regions undergoing purifying selection. We believe that the information acquired in our database will be a powerful resource to better understand the role of non-homologous end-joining DNA repair in genetic disorders, and will serve as a source to inspire other investigations to understand the disease further, vital for the development of improved therapeutic strategies.
Acute effects of single and repeated mild traumatic brain injury on levels of neurometabolites, lipids, and mitochondrial function in male rats.

Allen, J ; Pham, L ; Bond, ST ; O'Brien, WT ; Spitz, G ; Shultz, SR ; Drew, BG ; Wright, DK ; McDonald, SJ (Frontiers Media SA, 2023)

INTRODUCTION: Mild traumatic brain injuries (mTBIs) are the most common form of acquired brain injury. Symptoms of mTBI are thought to be associated with a neuropathological cascade, potentially involving the dysregulation of neurometabolites, lipids, and mitochondrial bioenergetics. Such alterations may play a role in the period of enhanced vulnerability that occurs after mTBI, such that a second mTBI will exacerbate neuropathology. However, it is unclear whether mTBI-induced alterations in neurometabolites and lipids that are involved in energy metabolism and other important cellular functions are exacerbated by repeat mTBI, and if such alterations are associated with mitochondrial dysfunction. METHODS: In this experiment, using a well-established awake-closed head injury (ACHI) paradigm to model mTBI, male rats were subjected to a single injury, or five injuries delivered 1 day apart, and injuries were confirmed with a beam-walk task and a video observation protocol. Abundance of several neurometabolites was evaluated 24 h post-final injury in the ipsilateral and contralateral hippocampus using in vivo proton magnetic resonance spectroscopy (1H-MRS), and mitochondrial bioenergetics were evaluated 30 h post-final injury, or at 24 h in place of 1H-MRS, in the rostral half of the ipsilateral hippocampus. Lipidomic evaluations were conducted in the ipsilateral hippocampus and cortex. RESULTS: We found that behavioral deficits in the beam task persisted 1- and 4 h after the final injury in rats that received repetitive mTBIs, and this was paralleled by an increase and decrease in hippocampal glutamine and glucose, respectively, whereas a single mTBI had no effect on sensorimotor and metabolic measurements. No group differences were observed in lipid levels and mitochondrial bioenergetics in the hippocampus, although some lipids were altered in the cortex after repeated mTBI. DISCUSSION: The decrease in performance in sensorimotor tests and the presence of more neurometabolic and lipidomic abnormalities, after repeated but not singular mTBI, indicates that multiple concussions in short succession can have cumulative effects. Further preclinical research efforts are required to understand the underlying mechanisms that drive these alterations to establish biomarkers and inform treatment strategies to improve patient outcomes.
Factors Associated with Participation in a Multidomain Web-Based Dementia Prevention Trial: Evidence from Maintain Your Brain (MYB)

Welberry, HJ ; Chau, T ; Heffernan, M ; San Jose, JC ; Jorm, LR ; Singh, MF ; Sachdev, PS ; Anstey, KJ ; Lautenschlager, NT ; Valenzuela, M ; McNeil, JJ ; Brodaty, H ; Fairley, A (IOS PRESS, 2023)

BACKGROUND: The Maintain Your Brain (MYB) trial aims to prevent cognitive decline and dementia through multidomain, web-based risk-reduction. To facilitate translation, it is important to understand drivers of participation. OBJECTIVE: To describe characteristics associated with participation in MYB. METHODS: This was an observational ancillary study of MYB, a randomized controlled trial nested within the 45 and Up Study in New South Wales, Australia. We linked 45 and Up Study survey and MYB participation data. The study cohort comprised 45 and Up Study participants, aged 55-77 years at 1 January 2018, who were invited to participate in MYB. 45 and Up Study participant characteristics and subsequent MYB consent and participation were examined. RESULTS: Of 98,836 invited, 13,882 (14%) consented to participate and 6,190 participated (6%). Adjusting for age and sex, a wide range of factors were related to participation. Higher educational attainment had the strongest relationship with increased MYB participation (university versus school non-completion; AdjOR = 5.15; 95% CI:4.70-5.64) and lower self-rated quality of life with reduced participation (Poor versus Excellent: AdjOR = 0.19; 95% CI:0.11-0.32). A family history of Alzheimer's disease was related to increased participation but most other dementia risk factors such as diabetes, obesity, stroke, high blood pressure, and current smoking were associated with reduced participation. CONCLUSION: Higher socio-economic status, particularly educational attainment, is strongly associated with engagement in online dementia prevention research. Increasing population awareness of dementia risk factors, and better understanding the participation barriers in at-risk groups, is necessary to ensure online interventions are optimally designed to promote maximum participation.

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