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Integrating Nature's Covalent Strategies with Proteomics to Interrogate the Function of Protein Modifications
No full textPost-translational modifications (PTMs) expand biological functions beyond genetic coding. This thesis
harnesses nature-inspired covalent chemistries to study electrophilic protein modifications and their
crosstalk with enzymatic PTMs. Mass spectrometry (MS)-based proteomics uncovers PTM functions
and effects on protein-protein interactions (Chapter 1).
Chapter 2 presents a chemically induced proximity approach using HaloTag technology—HaloTAC—
to induce targeted protein modifications. First-generation HaloTACs recruited AMPK, ULK1, and
p300/CBP to phosphorylate and acetylate model proteins Akt and PTEN. Triplex SILAC-MS revealed
modification sites.
Chapter 3 introduces thrombosis, a major cause of stroke and heart attack, exploring antithrombotic
therapies and the link between PTM dysregulation and thrombosis. It introduces thrombosis and
hemostasis pathways foundational to drug discovery.
Chapter 4 identifies safer antiplatelet candidates and platelet protein targets for stroke treatment.
Sulforaphane (SFN), an electrophilic natural product, showed antiplatelet activity. Activity-based
protein profiling (ABPP) and label-free quantification (LFQ) proteomics identified PDIA6 as SFN’s
main target, with covalent cysteine modification linked to SFN’s favorable safety profile. SFN’s stroke
efficacy was confirmed in a murine model.
Chapter 5 examines five electrophilic natural products (SFN, 6-shogaol, xanthohumol, 9-nitrooleic
acid, and oleocanthal) and their interactions with the platelet ubiquitin-proteasome system (UPS).
Competitive ABPP approaches revealed UPS-related targets, including deubiquitinases (DUBs), E1,
E2, and E3 ligases, whose activities were affected by natural product binding. Two DUB-targeting
chimeras (DUBTACs) were synthesized to modulate HDAC6 expression.
In summary, this thesis leverages natural covalent chemistries and MS-based proteomics to study
PTMs, uncover new druggable targets, and inform cardiovascular therapeutics
Recovery and secondary prevention challenges in people with acute coronary syndrome: digital and peer solution
No full textSelf-management of coronary heart disease (CHD) is an important aspect of acute coronary syndrome (ACS) recovery, however, may be hindered by cognitive impairment, psychosocial impacts, and a lack of available support after discharge. The impact of cognitive challenges after ACS, especially in spontaneous coronary artery dissection (SCAD), is not well understood. Peer support and health information websites may offer valuable solutions to these issues. The aim of this thesis was to explore the nature and experiences of cognitive challenges, the online information available for SCAD survivors, and the potential effectiveness of peer support, during and after ACS admission. Cognitive challenges were evaluated using: 1) an observational descriptive study of ACS inpatients screened for mild cognitive impairment, 2) seven thematically analysed focus groups of SCAD survivors exploring experiences of brain fog. Potential solutions for recovery and secondary prevention challenges were evaluated using: 1) appraisal of the websites publicly available for SCAD survivors, 2) systematic review and meta-analysis of coronary heart disease peer support interventions, 3) semi-structured focus groups and interviews with consumers and clinicians, identifying peer support benefits and priorities for future interventions. Mild cognitive impairment was identified in 53% of ACS inpatients, with single and older patients at highest risk. Patients with SCAD experienced brain fog, including memory, concentration and judgement issues. Websites for SCAD survivors (n=50) varied from average to poor in content, quality, suitability, readability and interactivity. Meta-analysis (n=16) indicated peer support interventions improved self-efficacy, self-management behaviour, and reduced readmissions. Priorities for peer support included awareness, flexibility, resources, autonomy, safeguarding, and simple interfaces
Strategic Airline Decarbonisation from a Door-to-Door Perspective
No full textThis thesis examines practical, near-term ways for airlines to cut emissions as climate pressures intensify. Aviation produces ~2.5% of global CO₂ (close to 5% of non-CO2 effects are included). With passenger demand continuing to grow, unchecked growth could expose airlines to significant risks.
Rather than waiting for future technologies, the research focuses on “low-hanging fruit”: ready-now, cost-effective measures that can be implemented quickly, complementing longer-term solutions such as sustainable aviation fuel (SAF) and hydrogen.
Two pillars anchor the thesis. First, airline carbon calculators are gate-to-gate, ignoring ground connections. In car-dependent markets, these ground segments can add up to 22% to total trip emissions. A novel door-to-door (D2D) model shows that simple shifts to airport ground trips can save more CO₂ on busy domestic routes than SAF blends at lower cost. The thesis tests how travellers respond when D2D CO₂ communication during flight booking. Choice experiments with 1,000+ respondents in Australia and New Zealand show meaningful shifts toward greener ground options, especially on shorter routes.
Second, choice experiments assess willingness-to-pay (WTP) for SAF via book-and-claim carbon offsets. It reveals most passengers offer premiums far below SAF’s current cost, highlighting financial risk if SAF mandates expand without policy support. A latent-class analysis identifies three segments: enthusiastic supporters (25%), indifferent avoiders (13%), and a cautious majority (62%). Stronger, verifiable traceability (e.g., blockchain-enabled tracking) boosts carbon offset’s uptake especially amongst the last cohort.
The thesis recommends embedding D2D calculators in booking flows, using targeted policy to narrow the SAF cost-WTP gap, and redesigning offsets around radical transparency. It extends carbon accounting beyond the airport fence and provides tools airlines and regulators can deploy within quarters, not decades
Targeted foundational supports for people with psychosocial disability outside of the NDIS: model background and rationale
No full textThis paper provides further background and rationale for a proposed model for delivering targeted foundational supports for people with psychosocial disability who are outside the National Disability Insurance Scheme (NDIS). This paper supplements the summary paper by outlining key elements of available research and data that informed the development of this model
Precision Medicine Approaches for the Modulation of Target Proteins
No full textPrecision medicine has emerged as a transformative approach in healthcare, enabling tailored treatments based on genetic, lifestyle, and environmental factors. To advance this field, new drug modalities are needed that precisely target molecular drivers of disease while minimising off-target effects. Traditional discovery approaches, however, are often slow and costly.
Following the Human Genome Project, innovative design strategies have expanded the scope of precision medicine. Among these, bifunctional molecules such as PROTACs, PHICS, and AceTACs have gained prominence for modulating protein function via post-translational modifications, moving beyond the binary activation–inhibition paradigm. In parallel, covalent chemistry targeting non-conserved cysteine residues offers isoform-selective precision medicines, exemplified by ritlecitinib (Litfulo), a first-in-class covalent JAK3 inhibitor.
This thesis explores new therapeutic scaffolds based on bifunctional molecules and covalent inhibitors. A novel series of degraders was designed, synthesised, and evaluated in vitro against breast cancer-relevant proteins including Akt, CDK2, and sirtuins. From this work, the sirtuin-targeting degrader led to the conceptualisation of DeAceTAC, a modality designed to selectively induce deacetylation of proteins such as PTEN and Akt, which are critical in breast cancer pathophysiology.
In parallel, potent covalent inhibitors of Pyk2 were developed as antiplatelet agents. The lead candidate showed selective inhibition of Pyk2, sparing its paralogue FAK, essential for normal haemostasis. In preclinical models, these inhibitors enhanced the clot-busting efficacy of tissue plasminogen activator (tPA) without increasing bleeding risk.
Collectively, this work demonstrates the potential of bifunctional and covalent strategies to advance next-generation precision medicines for complex diseases, from breast cancer to thrombotic stroke
Degradation of M-N-C Catalysts and Their Mitigation Strategies for Oxygen Reduction Reaction
No full textFossil fuels come with significant disadvantages, primarily due to their contribution to greenhouse gas emissions, which drive climate change and environmental damage. This has led to an urgent need for cleaner, more sustainable energy sources. Electrochemical energy systems, such as fuel cells, metal-air batteries, and electrolyzes, offer promising alternatives for energy generation and storage. In these systems, the oxygen reduction reaction is a key process occurring at the cathode. ORR can follow two main pathways: the four-electron pathway, which directly reduces oxygen to water and is more efficient, and the two-electron pathway, which produces hydrogen peroxide as an intermediate and is less efficient. Traditionally, platinum group metals have been used as the primary catalysts for ORR due to their high activity and good stability. However, PGMs have significant drawbacks, including high cost and limited availability. These issues create challenges for the widespread adoption of sustainable energy technologies. As a result, there has been a growing interest in developing non-precious metal catalysts as alternatives. Among these, single-atom catalysts have gained attention due to their promising performance, lower cost, and greater abundance compared to PGMs. Despite these advantages, M-N-C catalysts face limitations, including low intrinsic activity and fast degradation, especially in acidic media. These weaknesses hinder their practical use and long-term stability in real-world applications. Understanding these challenges is crucial for improving the performance and durability of M-N-C catalysts for ORR. This thesis focuses on developing multiscale engineering strategies aimed at enhancing the intrinsic activity of MNCs and gaining deeper insights into their degradation mechanisms
A Transdiagnostic Approach to Fears of Recurrence and Progression in People with Mental Health Conditions
No full textFears of recurrence and progression (FORP) are a common response to chronic illness, but they can
become distressing and disabling. In cancer, FORP is well understood, yet little is known about
FORP in mental health conditions, particularly as existing research is mostly limited to fear of
psychosis relapse in schizophrenia. This thesis examines whether mental health-related FORP
extends to non-psychotic conditions and whether it constitutes a distinct transdiagnostic construct.
Chapter 2 reports a mixed-method systematic review and meta-synthesis. Qualitative synthesis
produced a preliminary model of mental health-related FORP, relevant to those with and without
psychosis, while narrative review of quantitative studies showed links between FORP, poorer
psychological outcomes, reduced quality of life, and altered health behaviours, including increased
medication adherence, across diagnoses. Chapter 3 extends this model using qualitative interviews
of people with people with psychotic and non-psychotic conditions (n=18), further supporting
transdiagnostic relevance, and a survey (n=269) offering preliminary quantitative support. To enable
further research, Chapter 4 describes development and validation of a novel FORP questionnaire
(n=905). This measure showed strong psychometrics, discriminant validity from mental health
anxiety, and invariance across groups with and without histories of psychosis or mania, supporting its
transdiagnostic use. Chapter 5 describes a 14-day ecological momentary assessment study (n=68),
identifying intrusive memories, shame, and negative appraisals of mental state fluctuations as
predictors of subsequent FORP, whereas attentional focus was not predictive. Together, these
studies provide robust evidence that mental health-related FORP is a distinct, measurable,
transdiagnostic construct. Chapter 6 considers clinical and theoretical implications and highlights the
need for further research, given indications that FORP may predict relapse
Mindful Defense Against Mobile Security Threats: Conceptualization and Operationalization of Mobile Security Mindfulness
No full textMobile technologies have become integral to daily life, and security threats that target personal mobile devices are emerging as a result. Because the information security (InfoSec) literature has focused largely on the workplace, it has yet to fully take into account the unique security issues that arise from users’ daily mobile-use settings and the contextual characteristics of those settings. To advance InfoSec research, this paper theorizes an individual’s dynamic, mobile security mindset for recognizing and responding to mobile security threats (MSTs) as mobile security mindfulness (MSM). Using a two-phase mixed-methods approach, we develop this novel construct with four core dimensions identified through qualitative interviews. We then develop and validate a multidimensional scale for measuring MSM using quantitative methods. Our study on MSM construct and instrument development provides a novel theoretical lens for understanding mobile-device users’ situational decision-making in MSTs responses, enhances the theoretical precision of mindfulness theory in mobile-security contexts, and offers a tool for predicting users’ security behaviors specific to mobile device use
Utilising field-based technology to explore the relationship between high-speed running biomechanics and hamstring strain injury
No full textThis PhD thesis investigated the relationship between high-speed running biomechanics and hamstring strain injury (HSI). Exploration and utilisation of portable technology became critical constituents of this research, ensuring the running biomechanical variables investigated reflected that of real-world, field-based settings. First, a systematic review was conducted to summarise the existing evidence on the relationship between running biomechanics and HSI and, direct any spatiotemporal, kinematic and kinetic aspects requiring further investigation. Next, the methodological considerations for quantifying running biomechanical variables of interest in a field-based environment was explored, which led to validation of an inertial measurement unit system against the gold standard 3D Motion Analysis Laboratory. Validated kinematic and spatiotemporal outcome measures were then utilised in a field-based observational study (combined cross-sectional and prospective cohort study), investigating variances in running biomechanics as a risk factor for HSI. Force-velocity profiling (FVP), a previously validated novel portable method for quantifying kinetic outcome variables, was also incorporated in the study. Inopportunely, restrictions imposed with COVID-19 adversely impacted recruitment in the study, resulting in a limited sample size. Nevertheless, the study facilitated a good feasibility trial of novel technology, and the biomechanical findings present a case for further investigation. Key findings included preliminary evidence that reduced anterior pelvic tilt at point of contact and a velocity-oriented FVP was associated with HSI. This research culminates with a detailed discussion of research findings, as well as practical insights for future adoption of portable technologies for high-speed running biomechanical analysis and recommendations for further research in the HSI prevention realm
Understanding the lived experience of people who have had or continue to have ECT as they participate in daily life.
No full textBackground
There is limited knowledge about long term impacts of ECT on individuals, especially from a lived experience perspective. The aim of this thesis was to explore the long-term impacts of ECT on people’s daily lives and the strategies they employ to minimise or manage them.
Methods
Study 1: A qualitative meta-synthesis was conducted. Results sections of eligible papers were analysed thematically.
Study 2: A constructivist grounded theory was conducted involving two phases; interviews followed by focus groups. In both phases, an iterative process of data collection and analysis occurred. Data were analysed using constant comparative analysis.
Findings
Study 1 - Meta synthesis
The results sections of all 16 included publications were analysed thematically, resulting in identification of 11 long-term impacts, four social influences, and five strategies employed to navigate these long-term impacts.
Study 2 - Constructivist grounded theory
Twenty-three people participated in semi-structured interviews and 26 people participated in focus groups. Data were coded into four overarching categories: (1) My ECT experience; (2) Long-term impacts; (3) My strategies and (4) barriers to developing strategies.
Conclusions
This thesis has highlighted the need for people with a lived experience of ECT to be given support and resources to live well post ECT. The ECT experience is much more than the “ZAP” in the clinic. People DO experience direct long-term impacts both positive and negative, including cognitive/memory AND emotional/psychological impacts. These direct long-term impacts have a flow on impact on people’s lives. People’s journey of developing strategies is typically a lonely and unsupported one, and there is an untapped potential for peer support roles within the ECT context