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Programmed cell death licensed by iNOS: dissecting its role in inflammatory bowel disease and SARS-CoV-2 pathogenesis
No full text© 2025 Jiyi PangCell death is a fundamental process in health and disease, influencing tissue homeostasis, immune responses, and pathological conditions. Based on the requirements for distinct signalling molecules and effectors, several types of regulated cell death (RCD), including apoptosis, necroptosis and pyroptosis, have been characterised. RCD is intricately linked to inflammation. During inflammatory processes, RCD pathways are activated to eliminate damaged or infected cells, maintaining tissue homeostasis and preventing the spread of infection. However, excessive or dysregulated RCD can exacerbate inflammation by releasing damage-associated molecular patterns (DAMPs) and cytokines, or impairing tissue integrity, driving immune cell recruitment and amplifying inflammatory responses. These functions of RCD underscore its importance in both resolving inflammation and contributing to inflammatory conditions, such as inflammatory bowel disease (IBD) and COVID-19, where its regulation is likely disrupted.
Inducible nitric oxide synthase (iNOS) is an enzyme that produces nitric oxide (NO), a versatile signaling molecule involved in physiological and pathological processes. Unlike its constitutively expressed counterparts, endothelial NOS (eNOS) and neuronal NOS (nNOS), iNOS expression is induced by pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interferon-gamma. During inflammatory processes, iNOS-derived NO serves dual roles: it can act as a protective agent by promoting vasodilation, antimicrobial activity, and immune cell recruitment, or excessive iNOS signalling can lead to tissue damage through the generation of reactive nitrogen species (RNS), oxidative stress, or the triggering of cell death. This dual functionality makes iNOS an important player in balancing the inflammatory responses.
My PhD investigates the intricate mechanisms and implications of RCD and iNOS in inflammatory bowel disease and SARS-CoV-2 infection. In the study of IBD, my findings identify that apoptotic caspase-3 activation in IBD tissue correlates with TNF and interferon-gamma signaling. Using human-derived three-dimensional intestinal organoids, I demonstrate that interferon-gamma primes cells for cell death by upregulating apoptotic, pyroptotic, and necroptotic machinery. Notably, using CRISPR/Cas9 gene editing, I show that iNOS-mediated mitochondrial apoptosis is critical for interferon-gamma and TNF-induced colonocyte death, while intestinal stem cell apoptosis occurs independent of iNOS and is mediated by the pro-apoptotic BH3-only protein PUMA. These results delineate how cytokine-driven RCD can contribute to increased intestinal cell death in IBD.
My thesis also examines the role of RCD and iNOS in SARS-CoV-2 infection, particularly its age-dependent effects. Utilizing a SARS-CoV-2 mouse model, I observed increased apoptosis in lung tissue of SARS-CoV-2 infected young, but not aged, mice. This was despite higher viral loads in the latter. TNF-induced iNOS expression was shown to facilitate apoptosis of infiltrating immune cells in young mice, reducing macrophage numbers and impairing antiviral responses. In contrast, aged mice exhibit diminished iNOS activity and a reduced apoptotic capacity, potentially enabling viral replication. These findings highlight the complex age-dependent interplay between iNOS, apoptosis, and immune responses in SARS-CoV-2 pathogenesis.
Collectively, my PhD thesis advances our understanding of iNOS in cytokine-regulated cell death in inflammatory diseases, uncovering novel mechanisms that underlie IBD and COVID-19 pathologies. These insights provide an important knowledge foundation for developing targeted therapies aimed at modulating cell death to improve disease outcomes
Assessing patterns of chronic kidney disease care in Australian primary care: a retrospective cohort study of a national general practice dataset
No full textBACKGROUND: Chronic kidney disease (CKD) monitoring and cardiovascular risk management are essential in reducing disease progression and cardiovascular events. This study aimed to understand CKD monitoring and management practices in Australian primary care. METHODS: We conducted a retrospective, population-based cohort study of adults who attended general practices participating in MedicineInsight between 1 January 2011 and 30 June 2020 and met diagnostic criteria for CKD. Care quality was assessed in the 18-months following identification of CKD. Core monitoring was defined as at least one assessment of all the following measurements: blood pressure, estimated glomerular filtration rate (eGFR), urine albumin creatinine ratio (UACR), lipid profile, and HbA1c in patients with diabetes. Cardiovascular risk management comprised medication prescription (ACEi/ARB and statin), blood pressure target achievement and LDL cholesterol <2 mmol/L. Modified Poisson regression models adjusted for socio-demographic and clinical characteristics were used to identify patient factors associated with completion of monitoring and medication prescription. FINDINGS: CKD was identified in 140,780 patients, of which 34.2% received core monitoring within 18 months of CKD identification. Measurement of the individual components of the core monitoring outcome varied: blood pressure (88.7%), eGFR (86.0%), UACR (41.1%), lipids (70.9%) and HbA1c (85.5%). ACEi/ARB were prescribed in 65.2% of the cohort and 54.4% were prescribed a statin. Blood pressure targets of <140/90 mmHg and <130/80 mmHg were achieved in 57.9% and 29.3% of patients, respectively. LDL target of <2 mmol/L was achieved in 38.8% of patients. Older age, comorbid diabetes and hypertension were associated with a greater likelihood of monitoring and medication prescription. INTERPRETATION: In this large, population-based study, we observed substantial variation in CKD risk monitoring and the management of cardiovascular risk in patients with CKD. We identified several priority areas for CKD management in primary care including need for improvement in albuminuria monitoring. FUNDING: University of New South Wales Scientia Program and Boehringer Ingelheim Eli Lilly Alliance
Feasibility and effects of cognitive training on cognition and psychosocial function in Huntington’s disease: a randomised pilot trial
No full textBACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disease that causes progressive cognitive, physical, and psychiatric symptoms. Computerised cognitive training (CCT) is a novel intervention that aims to improve and maintain cognitive functions through repeated practice. The effects of CCT have yet to be established in HD. This randomised pilot trial examined the feasibility of a large scale trial to assess efficacy of multidomain CCT in pre-manifest and early-stage HD. METHODS: 28 participants were randomised to either at-home CCT (2 × 60 min sessions per week for 12 weeks; n = 13) or lifestyle education through monthly newsletters (n = 15). Participants completed cognitive tasks and questionnaires at baseline and follow up, either in person (n = 18) or via video teleconferencing (n = 10). RESULTS: All participants were retained at follow up, and adherence to CCT ranged from 96 to 100%, with 11/13 participants completing all sessions. Preliminary analyses showed evidence of a large effect of CCT on task switching and response inhibition, compared to lifestyle education. There was no evidence of specific benefit to other cognitive domains (processing speed, basic and divided attention, working memory), or psychosocial functions (subjective cognition, mood, health-related quality of life). DISCUSSION: Whilst retention and adherence rates were high, recruitment rates were low, suggesting that a large scale trial may be feasible with some modifications to increase recruitment rates, such as by reducing time burden associated with the study, and using a multi-site trial design. Potential effects on cognitive functioning warrant further investigation. CLINICAL TRIAL REGISTRATION: The trial was prospectively registered on the Australian New Zealand Clinical Trials Registry (ACTRN12622000908730)
Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics
No full textOxidative phosphorylation defects result in now intractable mitochondrial diseases (MD) with cardiac involvement markedly affecting prognosis. The mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear. Here, we used spatially resolved transcriptomics and single-nucleus RNA sequencing (snRNA-seq) on the heart of a patient with mitochondrial cardiomyopathy (MCM), combined with an MCM mouse model with cardiac-specific Ndufs6 knockdown (FS6KD). Cardiomyocytes demonstrated the most heterogeneous expression landscape among cell types caused by metabolic perturbation, and pseudotime trajectory analysis revealed dynamic cellular states transitioning from compensation to severe compromise. This progression coincided with the transient up-regulation of a transcription factor, ATF3. Genetic ablation of Atf3 in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of ATF3 in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression
Transformative musical futures:Building tomorrow's virtual performances together
No full textAbstract (Trendsetter Presentation)
This presentation will provide an overview of the work being conducted around the use of virtual simulation technology to assist performance preparation. Our research addresses challenges in music performance training, including performance anxiety and limited access to realistic performance conditions.
By investigating immersive performance technologies during the COVID-19 lockdowns, our research demonstrated the potential to simulate the psychological and physiological markers of performance anxiety while facilitating remote teaching of performance psychology skills. Building on this work, we have now developed a VR application that simulates a concert hall environment. This virtual performance application offers a realistic environment for students to experience challenging scenarios with the aim to develop their resilience and confidence in a safe, controlled setting.
Our recent research with music students from the Faculty of Fine Arts and Music provides valuable insights into the performer experience. This participant feedback has enabled iterative improvements to the VR application’s realism and effectiveness within a design-based research framework. Key areas of development have focussed on realistic hall environment and lighting, enhancing audio with reverb and environmental sounds, the incorporation of performance distractions, and simulating the backstage to onstage transition.
Students have reported that the virtual environment successfully induces performance-related nervousness while indicating a strong interest in using the application to further their performance training. Future developments include exploring more creative aspects of the virtual space, incorporating gamification, mixed reality experiences, biometric capture and generative AI feedback. Our virtual performance research aims to improve performance preparation by re-imagining how the next generation of musicians train, create, and engage with audiences
Polyphenol-Enabled Drug Carriers: Nanoengineering and Organ Selective Delivery
No full text© 2025 Yuang GuDrug delivery systems are designed to enhance the efficacy and safety of therapeutics by precisely controlling the rate, timing, and site of drug release within the body. Among the various drug delivery systems platforms, nanoparticles (NPs) have emerged as one of the most promising carriers due to their ability to traverse biological barriers, protect labile therapeutics such as proteins and nucleic acids, and improve accumulation at the target sites. Despite these advantages, most NP systems are designed for specific cargo types or applications. There remains a need to develop a generalizable NP platform that can (i) immobilize a wide array of therapeutic agents, and (ii) efficiently deliver them to the target tissues/organs. Polyphenols, renowned for their universal binding affinity to a diverse array of metal ions and biomolecules, afford the generation of a versatile and modular delivery platform capable of accommodating a wide range of therapeutic cargos and enabling tuneable physicochemical properties.
This thesis presents three research chapters centred on polyphenol-enabled drug delivery strategies. Chapter 2 focuses on broadening the application of lipid nanoparticles for protein delivery using polyphenols. Nucleic acids have a relatively well-defined structure and strong negative charges, which facilitate facile encapsulation into lipid nanoparticles via electrostatic interactions. However, proteins display significant variability in size, isoelectric point, and chemical specificity, presenting a critical bottleneck for achieving efficient encapsulation within lipid nanoparticles. In this chapter, phenolic ligands are introduced to negate protein charge and drive the formation of biofunctional lipid–phenolic nanocomposites (b-LPNs). b-LPNs afford over 90% encapsulation efficiency of proteins and preservation of their bioactivity. This lipid-phenolic delivery platform not only expands the library of current lipid-based delivery systems but also provides a viable approach for integrating biofunctionality into lipidic matrices.
In Chapter 3, an alternative mRNA delivery system is developed whereby mRNA is incorporated into a poly(ethylene glycol)–polyphenol network stabilized by metal ions, forming mRNA-encapsulated metal-organic nanoparticles (mRNA-MPN NPs). Unlike most of current mRNA delivery platforms that rely on cationic components for encapsulation, these mRNA–MPN NPs are composed of sustainable materials and exhibit an overall negative charge. This feature reduces membrane-associated toxicity and the risk of inflammation. Following extensive formulation screening, a lead formulation is identified and enables robust mRNA transfection both in vitro and in mice. Notably, the organ tropism of mRNA expression can be readily modulated by varying NP composition, suggesting potential for targeted mRNA delivery.
Chapter 4 is built on the concept of modulating organ tropism demonstrated in Chapter 3. In this chapter, MPN formations are further developed to enhance the organ selectivity and tropism tunability, and more importantly, to improve their adaptability to existing drug delivery modalities. By exploring a wide range of polyphenol, metal ion, and polymer building blocks, the organ deposition of MPN NPs can be tuned towards the liver, lung, kidney, heart, and brain. Moreover, the universal adherence of polyphenol enables the engineering of organ-tropic MPNs as a coating material on diverse existing established drug delivery platforms, (re)-programming/redirecting their organ deposition selectivity based on the composition–selectivity correlation revealed by MPN NPs. This study provides a generalizable approach for developing next-generation organ-targeting nanotechnology, underscoring the potential to advance nanoparticle-mediated treatment and diagnostics.
In summary, this thesis develops polyphenol-enabled carriers and explores their applications in therapeutic delivery. Specifically, polyphenols are engineered into lipid-phenolic complexes and metal–phenolic networks. These polyphenol-enabled drug carriers are highly biocompatible, afford above 90% therapeutic loading efficiency, and enable organ-selective delivery via compositional tuning. These studies present a versatile polyphenol-based platform for therapeutic delivery, with the potential to shape the landscape of hybrid materials and advanced delivery technologies
Understanding the effects of mining and processing parameters on Life Cycle Assessment of Greenbushes Spodumene production
No full textThe rapid transition to clean energy has intensified demand for lithium, a critical element for battery production, yet lithium extraction imposes substantial environmental burdens. While the Life Cycle Assessment (LCA) provides a snapshot of environmental impacts, it does not account for dynamic changes in mining and processing operations, such as declining ore grade. This study conducts comprehensive LCAs of Spodumene ore and concentrate production from 2009 to 2023 at the Greenbushes project, empirically analysing how variable parameters influence environmental impacts. Regression analysis identifies the waste-to-ore ratio as the most significant factor affecting most of the mining-related impacts, while ore grade and yield play a dominant role in processing operations for most of the impact categories. Consequently, the global warming potential of producing Spodumene concentrate increased by almost 42.7 % between 2011 and 2023. Moreover, electricity and grinding media consistently contributed the most to the carbon footprint throughout the study period, though their combined share declined from 81.1 % to 57.1 %, whereas diesel consumption rose from 3 % to nearly 20.1 %, mainly due to site expansion
Transcriptomic changes including p53 dysregulation prime DNMT3A mutant cells for transformation
No full textDNMT3A mutations are prevalent in haematologic malignancies. In our mouse model the murine homologue (R878H) of the human 'hotspot' R882H mutation is introduced into the mouse Dnmt3a locus. This results in globally reduced DNA methylation in all tissues. Mice with heterozygous R878H DNMT3A mutations develop γ-radiation induced thymic lymphoma more rapidly than control mice, suggesting a vulnerability to stress stimuli in Dnmt3aR878H/+ cells. In competitive transplantations, Dnmt3aR878H/+ Lin-Sca-1+Kit+ (LSK) haematopoietic stem/progenitor cells (HSPCs) have a competitive advantage over WT HSPCs, indicating a self-renewal phenotype at the expense of differentiation. RNA sequencing of Dnmt3aR878H/+ LSKs exposed to low dose γ-radiation shows downregulation of the p53 pathway compared to γ-irradiated WT LSKs. Accordingly, reduced PUMA expression is observed by flow cytometry in the bone marrow of γ-irradiated Dnmt3aR878H/+ mice due to impaired p53 signalling. These findings provide new insights into how DNMT3A mutations cause subtle changes in the transcriptome of LSK cells which contribute to their increased self-renewal and propensity for malignant transformation
High-throughput method characterizes hundreds of previously unknown antibiotic resistance mutations
No full textA fundamental obstacle to tackling the antimicrobial resistance crisis is identifying mutations that lead to resistance in a given genomic background and environment. We present a high-throughput technique - Quantitative Mutational Scan sequencing (QMS-seq) - that enables quantitative comparison of which genes are under antibiotic selection and captures how genetic background influences resistance evolution. We compare four E. coli strains exposed to ciprofloxacin, cycloserine, or nitrofurantoin and identify 812 resistance mutations, many in genes and regulatory regions not previously associated with resistance. We find that multi-drug and antibiotic-specific resistance are acquired through categorically different types of mutations, and that minor genotypic differences significantly influence evolutionary routes to resistance. By quantifying mutation frequency with single base pair resolution, QMS-seq informs about the underlying mechanisms of resistance and identifies mutational hotspots within genes. Our method provides a way to rapidly screen for resistance mutations while assessing the impact of multiple confounding factors
Effectiveness of electronic quality improvement activities to reduce cardiovascular disease risk in people with chronic kidney disease in general practice: A cluster randomised trial with active control (Preprint)
No full textBACKGROUND: Future Health Today (FHT) is a program integrated with electronic medical record (EMR) systems in general practice and comprises (1) a practice dashboard to identify people at risk of, or with, chronic disease who may benefit from intervention; (2) active clinical decision support (CDS) at the point of care; and (3) quality improvement activities. One module within FHT aims to facilitate cardiovascular disease (CVD) risk reduction in people with chronic kidney disease (CKD) through the recommendation of angiotensin-converting enzyme inhibitor inhibitors (ACEI), angiotensin receptor blockers (ARB), or statins according to Australian guidelines (defined as appropriate pharmacological therapy).
OBJECTIVE: This study aimed to determine if the FHT program increases the proportion of general practice patients with CKD receiving appropriate pharmacological therapy (statins alone, ACEI or ARB alone, or both) to reduce CVD risk at 12 months postrandomization compared with active control (primary outcome). METHODS: General practices recruited through practice-based research networks in Victoria and Tasmania were randomly allocated 1:1 to the FHT CKD module or active control. The intervention was delivered to practices between October 4, 2021, and September 30, 2022. Data extracted from EMRs for eligible patients identified at baseline were used to evaluate the trial outcomes at the completion of the intervention period. The primary analysis used an intention-to-treat approach. The intervention effect for the primary outcome was estimated with a marginal logistic model using generalized estimating equations with robust SE.
RESULTS: Overall, of the 734 eligible patients from 19 intervention practices and 715 from 21 control practices, 82 (11.2%) and 70 (9.8%), respectively, had received appropriate pharmacological therapy (statins alone, ACEI or ARB alone, or both) at 12 months postintervention to reduce CVD risk, with an estimated between-trial group difference (Diff) of 2.0% (95% CI -1.6% to 5.7%) and odds ratio of 1.24 (95% CI 0.85 to 1.81; P=.26). Of the 470 intervention patients and 425 control patients that received a recommendation for statins, 61 (13%) and 38 (9%) were prescribed statins at follow-up (Diff 4.3%, 95% CI 0 to 8.6%; odds ratio 1.55, 95% CI 1.02 to 2.35; P=.04). There was no statistical evidence to support between-group differences in other secondary outcomes and general practice health care use.
CONCLUSIONS: FHT harnesses the data stored within EMRs to translate guidelines into practice through quality improvement activities and active clinical decision support. In this instance, it did not result in a difference in prescribing or clinical outcomes except for small changes in statin prescribing. This may relate to COVID-19-related disruptions, technical implementation challenges, and recruiting higher performing practices to the trial. A separate process evaluation will further explore factors impacting implementation and engagement with FHT.
TRIAL REGISTRATION: ACTRN12620000993998; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380119