Restricted Theses

Permanent URI for this collectionhttps://hdl.handle.net/1885/9050

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Engineering improved plant Rubisco
Skinner, Tanya
Rubisco is the central CO2 fixing enzyme of photosynthesis and the primary gateway through which inorganic carbon enters the biosphere. Despite its essential role in sustaining life on Earth, the catalytic inefficiencies of Rubisco severely limit plant productivity. This has made improving plant Rubisco's catalytic efficiency one of the most important, yet technically challenging goals in crop engineering. Until recently, the inaccessibility of plant Rubisco to high-throughput engineering pipelines has limited experimental progress. However, solving its complex biogenesis requirements has allowed the development of SynBio tools to produce plant Rubisco in E. coli - offering transformative opportunities for rational and directed evolution approaches for catalytic optimisation. This thesis aimed to improve plant Rubisco by directed evolution. This was achieved by addressing four key aims: (1) developing a novel site-saturation variant library (SSVL) and nanopore sequencing based directed evolution pipeline to comprehensively map catalytically accessible sequence space for 15% of the tobacco Rubisco large subunit (RbcL), identifying new catalytic enhancing mutations, (2) developing an E. coli expression system for producing canola Rubisco, (3) testing the transferability of catalytic enhancing mutations identified in aim 1 from tobacco to canola Rubisco and (4) identifying new catalytic enhancing mutations in canola Rubisco via directed evolution. Chapter 3 introduced a new directed evolution framework that combined site-saturation variant libraries (SSVLs) targeted to key catalytic regions of tobacco RbcL with deep nanopore sequencing, establishing a high-resolution screening platform. Unlike conventional random mutagenesis, this approach enabled systematic testing of all non-wild type amino acid substitutions at each RbcL locus of interest. Functional screening in Rubisco-dependent E. coli (RDE) identified a range of mutations that enhanced catalytic activity, including up to 65% improvement in the rate of carboxylation (kcatc) and 20% improvement in carboxylation efficiency. Comprehensive biochemical characterisation of these in chapter 4 enabled predictive photosynthetic modelling that showed some mutants could support up to 21% improvements in Rubisco activity-limited photosynthesis under sub-saturating CO2 conditions. Together, chapters 3 and 4 demonstrated the utility of carefully designed directed evolution screens for optimising Rubisco beyond natural evolutionary limits. Given the inability of the tobacco Rubisco E. coli expression system to support production of canola Rubisco, chapter 5 describes the development of a canola-compatible expression system. This two-plasmid system comprised a plasmid encoding canola Rubisco (with Rubisco activase) and another encoding its cognate chloroplast folding and assembly proteins. Its capacity to produce canola Rubisco was validated along with confirmation that several catalytically beneficial mutations identified in tobacco RbcL (chapters 3 and 4) conveyed comparable improvements in canola. This motivated efforts to leverage the E. coli expression system for the directed evolution of canola Rubisco using a conventional error-prone PCR approach coupled with deep nanopore sequencing in chapter 6. An initial round of evolution primarily selected for Rubisco biogenesis (solubility) mutants, including an M309I catalytic switch, which improved kcatc but increased Kc. A second round of evolution on top of M309I identified mutations that restored Kc to improve carboxylation efficiency up to 31%. This work provides the most comprehensive directed evolution of crop Rubiscos to date and delivers a scalable, analytically rigorous framework for future Rubisco bioengineering, laying the foundation for realising the long-standing goal of engineering more efficient Rubiscos to enhance photosynthetic performance and crop yields.
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How To Build Conscious Machines
(2025) Bennett, Michael
How to build a conscious machine? For that matter, what is consciousness? Why is my world made of qualia like the colour red or the smell of coffee? Are these fundamental building blocks of reality, or can I break them down into something more basic? If so, that suggests qualia are like an abstraction layer in a computer. A simplification. Some say simplicity is the key to intelligence. Systems which prefer simpler models need fewer resources to adapt. They ``generalise'' better. Yet simplicity is a property of form. Generalisation is of function. Any correlation between them depends on interpretation. In theory there could be no correlation and yet in practice, there is. Why? Software depends on the hardware that interprets it. It is made of abstraction layers, each interpreted by the layer below. I argue hardware is just another layer. As software is interpreted by hardware, hardware is by physics. There is no way to know where the stack ends. Hence I formalise an infinite stack of layers to describe all possible worlds. Each layer embodies policies that constrain possible worlds. A task is the worlds in which it is completed. Adaptive systems are abstraction layers are polycomputers, and a policy simultaneously completes more than one task. When the environment changes state, a subset of tasks are completed. This is the cosmic ought from which goal-directed behaviour emerges (e.g. natural selection). ``Simp-maxing'' systems prefer simpler policies, and ``w-maxing'' systems choose weaker constraints on possible worlds. I show w-maxing maximises generalisation, proving an upper bound on intelligence. I show all policies can take equally simple forms. Simp-maxing shouldn't work. To explain why it does, I invoke the Bekenstein bound. It means layers can use only finite subsets of all possible forms. Processes that favour generalisation (e.g. natural selection) will then make weak constraints take simple forms. I perform experiments. W-maxing generalises at 110-500% the rate of simp-maxing. I formalise how systems delegate adaptation down their stacks. I show w-maxing will simp-max if control is infinitely delegated. Biological systems are more adaptable than artificial because they delegate adaptation further down. They are bioelectric polycomputers. As they scale from cells to organs, they go from simple attraction and repulsion to rich tapestries of valence. These tapestries classify objects and properties that cause valence, which I call causal-identities. I propose the psychophysical principle of causality arguing qualia are tapestries of valence. A vast orchestra of cells play a symphony of valence, classifying and judging. A system can learn 1ST, 2ND and higher order tapestries for itself. Phenomenal ``what it is like'' consciousness begins at 1ST-order-self. Conscious access for communication begins at 2ND-order-selves, making philosophical zombies impossible. This links intelligence and consciousness. So why do we have the qualia we do? A stable environment is a layer where systems can w-max without simp-maxing. Stacks can then grow tall and complex. This may shed light on the origins of life and the Fermi paradox. Diverse intelligences could be everywhere, but we cannot perceive them because they do not meet preconditions for a causal-identity afforded by our stack. I conclude by integrating all this to explain how to build a conscious machine, and a problem I call The Temporal Gap.
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Increasing the effectiveness of Lao bank regulation: can smart regulation make a difference?
(2025) Chanthasouk, Sithong
Thesis Title: Increasing the Effectiveness of Lao Bank Regulation: Can Smart Regulation Make a Difference? By Sithong Chanthasouk RegNet, ANU Abstract It is critical for the sustainable growth of the Lao economy that the banking system is both safe and sound. However, the Lao banking system remains fragile, and more effective regulation is needed. This study aims to identify a solution to enhance the effectiveness of Lao bank regulation, thereby promoting the safety and soundness of the country's banking system and effectively contributing to national socio-economic development. As a staff member of the Lao bank regulator, I inquire whether the concept of 'smart regulation', a form of regulatory pluralism, would increase the effectiveness of Lao bank regulation. To address this question, I identify the key features of Lao bank regulation that may have implications for the applicability of smart regulation. Using the viewpoints of key stakeholders, I examine the formulation of prudential requirements, enforcement, bank supervision, and resolution. Specifically, I examine how the Lao bank regulator utilizes various instruments and interacts with different stakeholders, as well as the dynamics of the regulatory powers generated within the public administration and bureaucracy of a socialist system. Applying a qualitative method using semi-structured interviews with key stakeholders and desk reviews, the study reveals that a 'power oriented' style is the defining feature of Lao bank regulation, and it has four key traits: selective responsiveness, lax enforcement, weak accountability, and difficult reforms. I argue that these traits limit the applicability of smart regulation and that the bank regulator needs to align the banking system with the public interest. The research findings not only highlight the significant challenges currently faced by Lao bank regulators but also provide practical recommendations to address these issues. The study contributes to regulatory discourse in a socialist, developing, and Southeast Asian context. It proposes further investigation into the typology of regulators and regulatory transparency, which may enhance the sustainability of the regulatory ecosystem.
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In silico design of novel thermostable and alkaline tolerant three-helical proteins for enhanced antibody purification in Industrial settings
(2025) Lorenzon, Mirco
Monoclonal antibodies (mAbs) have revolutionised therapeutic strategies across oncology, autoimmune diseases, and infectious diseases. Despite their success, large-scale production remains limited by purification bottlenecks, with Protein A affinity chromatography serving as the industry gold standard due to its high specificity and robust performance. However, Protein A-based purifications present key limitations, including high resin costs, sensitivity to alkaline cleaning, ligand degradation, and inefficiencies in purifying complex antibody formats. In response, this thesis applies advanced protein engineering methodologies to improve the stability and resilience of Protein A ligands under industrial conditions. A consensus design approach was employed to develop structurally robust Protein A variants. This led to the creation of a highly thermo- and chemically stable protein, a potential affibody-like scaffold named Thermobody, with a defined three-dimensional structure similar to the immunoglobulin (Ig)-binding domain of Protein A. Further rational engineering of this scaffold enabled the development of novel IgG binders with improved binding kinetics and enhanced thermal and chemical tolerance, offering a promising alternative to current Protein A-based ligands. Additionally, a supercharging protocol was applied to the Thermobody to modify its surface charge, improve solubility, and reduce aggregation, thereby extending the potential applications of this affibody-like scaffold and its variants beyond immunoglobulin purification. A positively supercharged version with membrane permeability was further explored for intracellular delivery applications. These supercharged Thermobody constructs were evaluated for their ability to traverse cell membranes, providing insight into their potential as intracellular targeting agents. The findings presented in this thesis support the development of more cost-effective and scalable purification strategies, addressing the evolving demands of the biopharmaceutical industry while broadening the application scope of engineered affinity ligands. To further optimise ligand performance, machine learning-guided design (Protein MPNN) was employed to predict scaffold binding potential to the Fc region of IgG. The combined effects of these strategies were assessed through biophysical characterisation techniques, including surface plasmon resonance (SPR), circular dichroism (CD), and stability assays under repeated high-pH exposure.
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Molecular approaches provide novel insights into the role of ABCA4 in bisretinoid clearance.
(2025) Skrzypek, Ruth
Many visual disorders including Stargardt's disease, an early onset macular dystrophy, are caused or contributed to by mutations in the gene encoding the human ATP-binding Cassette (ABC) transporter ABCA4. ABCA4 is expressed in the photoreceptor and retinal pigment epithelial cells of the eye and is thought to act as a lipid translocase of retinal-phospholipid conjugates involved in vision. Molecular investigations on ABCA4 will require its purification from a heterologous expression system capable of providing conditions for the expression of membrane proteins in a functional form. In this thesis I sought to validate a novel expression system for ABCA4 (Drosophila melanogaster eyes) and to expand on our understanding of the protein's function by investigating its interaction with a putative substrate (A2E). To validate the novel system, ABCA4 was compared to the established expression system in Spodoptera frugiperda insect cells. The protein from both systems was extracted, purified, and reconstituted into liposomes, and different biophysical characteristics were assessed. ABCA4 from both sources was structurally and functionally intact. However, there were marked differences in the ease of solubilisation, protein purity, product yield, oligomeric state, and the level of ATPase activity. This highlights the need to assess the products of different expression systems to ensure the fidelity of subsequent protein characterisation. Previous research has determined that ABCA4 can transport retinal, phosphotidylethanolamine, and the retinal-phospholipid conjugate N-retinylidene-PE (NRPE). In this thesis, I assessed whether the retinal-phospholipid conjugate A2E can also interact with ABCA4. Using a known substrate (retinal) as a control, I measured the binding of A2E to ABCA4 and its effect on the ATPase activity. Using molecular docking, I also defined the location for A2E binding to ABCA4. The binding and docking data both demonstrate that A2E can interact with ABCA4 and that it binds to the protein in the same substrate binding pocket as NRPE. This interaction hints at an expanded role for ABCA4 in the clearance of toxic products in the retinal pigment epithelial cells of the retina where A2E is formed.
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Neuronal signalling mechanisms between retinal ganglion cells and superior colliculus neurons during visual processing
(2025) Thomas, Felix
The superior colliculus (SC) is a conserved midbrain structure present in all vertebrates, crucial for integrating sensory signals to initiate motor commands. The mammalian SC has three layers: superficial, intermediate, and deep, aligned to the visual field. In mice, the superficial layer processes visual information from 85-90% of retinal ganglion cells (RGCs) originating from the retina. The functional connectivity between RGCs and superficial SC cell types in mice is unclear, and whether it exhibits synaptic plasticity remains unexplored. Additionally, the direct RGC input's role in binocular vision processing is unknown. This thesis investigates the biophysical and synaptic properties of the retinocollicular pathway through optogenetics and electrophysiology. To investigate monosynaptic RGC input to neurons in the superficial SC we virally expressed ChR2 in the retina and optogenetically stimulating RGC axons with light. We classified superficial SC neurons in vitro based on their electrophysiological and morphological properties, revealing four main cell types: wide-field (WF), horizontal, narrow-field (NF), and stellate. Light-evoked RGC monosynaptic responses were observed in all four cell types. We found RGC input to WF neurons evoked action potentials at more negative membrane potentials than during current injection, which was not observed in other cell types. In the presence of tetrodotoxin and 4-aminopyridine, RGC input evoked putative calcium spikes in horizontal, NF and stellate neurons, but not WF neurons. Our findings indicate that all four cell types of the superficial SC receive monosynaptic input from the retina. We investigated neurotransmitters in the retinocollicular pathway. Most light-induced monosynaptic RGC responses were mediated by glutamate, but some synaptic responses were not affected by glutamatergic antagonists. Different receptor antagonists revealed that stellate and horizontal cells receive GABAergic and cholinergic input via GABAA and nicotinic acetylcholine receptors. Thus, neurons in the superficial SC receive glutamatergic, GABAergic, and cholinergic RGC input in a cell-specific manner. We investigated synaptic plasticity at the RGC to WF neuron synapse using a spike-time-dependent plasticity (STDP) protocol during optogenetic RGC activation, inducing long-term potentiation (LTP) and long-term depression (LTD) in WF neurons. LTP depended on NMDA receptors and L-type Ca2+ channels, while LTD required only L-type Ca2+ channel activation. By investigating changes in the paired-pulse ratio and coefficient of variation, we determined that LTP was presynaptic and LTD postsynaptic. Similar findings in WF neurons identified via Ntsr1-tdTomato mice indicate that the RGC to WF synapse exhibits activity-dependent plasticity, suggesting its role in visual processing. We focused on direct retinal input's role in binocular processing in the SC. Binocular neurons exist in all three SC layers, but RGCs innervate only the superficial layer, primarily from the contralateral retina. Optogenetic RGC responses from the contralateral eye appeared throughout the superficial layer, while responses from the ipsilateral eye were seen only in the anteromedial region between the superficial and intermediate layers. This shows that RGC input convergence from both eyes occurs only in this limited SC area. Consequently, binocular visual information to other SC parts must use different pathways. Collectively, this thesis investigates visual processing in the SC with a focus on the biophysical and synaptic characteristics of the direct connection between the retina and specific cells types in the superficial SC. It provides a comprehensive examination of this critical visual pathway, which plays a key role in orientation movements as well as innate defensive behaviours.
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Drivers of electronic cigarette use among Australian adolescents
(2025) Yazidjoglou, Amelia
Adolescent electronic cigarette (e-cigarette) use is increasing and recognised as a global public health priority. E-cigarette use is associated with several health risks including addiction, poisonings, burns and injuries, and smoking initiation. While adolescents are particularly vulnerable to the known negative impacts of nicotine, important long-term health effects of e-cigarettes are unknown. Preventing adolescent e-cigarette exposure underpins most e-cigarette control polices and regulation, however there is a paucity of evidence investigating the factors underlying adolescent use. To address this evidence gap, my thesis uses mixed methods to explore drivers of e-cigarette use among Australian adolescents aged 14-17 years using data from the Generation Vape Project, along with relevant contextual factors. I consider and assess the efficacy of e-cigarettes for smoking and nicotine cessation, e-cigarette social norms, how health perceptions relate to non-use, and the relationship between sports and e-cigarette behaviour. My thesis finds limited and low certainty evidence that e-cigarettes are more efficacious than nicotine replacement therapy for smoking cessation, demonstrating that widespread and easy availability of e-cigarettes is unlikely to be an appropriate population tobacco control measure. Many adolescents hold positive e-cigarette social norms including misconceptions that e-cigarettes are normal, acceptable and used by most adolescents - likely influenced by social exposure, including observing use in public spaces, media and marketing. Perceiving e-cigarette harms is associated with never-use and is protective. However, among both users and non-users, most adolescents are aware of e-cigarette health risks, suggesting use may be driven by factors more compelling than knowledge. Sport performance and physical activity is greatly valued such that it can guide e-cigarette abstinence and cessation, highlighting a novel opportunity for intervention. Overall, my thesis finds that adolescents' e-cigarette use may not be informed by accurate health evidence but by an alternate, more persuasive narrative promoted by the e-cigarette industry. Claimed e-cigarette benefits have been distorted, including by industry, such that potential cessation benefits for smokers may have been misconstrued as positive health effects applicable to all users, including young people who have never smoked, and that e-cigarettes are also a smoking prevention tool. The e-cigarette industry has marketed e-cigarettes as essential to adolescent social capital and identity, been dismissive of harms, and implied an absence of evidence equates to an absence of risk. Furthermore, by actively shaping and highlighting the smoking cessation debate, the industry has distracted and diverted resources from other priority e-cigarette research and policy areas. Sustained and comprehensive e-cigarette control is necessary to curb drivers of e-cigarette use, promote non-use and protect health. This includes reducing industry influence by restricting exposure to pro-e-cigarette marketing and promotion, limiting access, reducing product appeal, enforcing policies and implementing quality health education. There is also a need for e-cigarette research and policy agendas to be determined by public health stakeholders, and not the e-cigarette industry and its allies, to ensure all priority areas are being addressed. Adolescents offer an invaluable and unique perspective on drivers impacting their e-cigarette use and it is crucial to include their voices to ensure health messages are believable and resonant.
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Institutional cooperation and rivalry in the Mekong sub-region
(2025) Dinh, Sach Nguyen
The Mekong sub-region is seeing the increased involvement of major powers, including the US, China, Japan, South Korea and India through cooperation mechanisms. Those platforms can be seen as institutions as they are created based on combined set of rules or norms that member states are committed to. This thesis examines the extent that institutions promote cooperation or restrain rivalry in the Mekong subregion and the impact upon the subregion. Cooperation and rivalry in the Mekong subregion can be seen at three levels: between China and lower Mekong countries, among lower Mekong countries, and between China on one side and the US and its allies on the other side. In that examination, the thesis adopts the frameworks which see that institutions set rules and norms for the behaviors of participating countries. Therefore, institutions will be able to promote cooperation among states. However, institutions can also be seen as the extension of state policy so institutions may have minimal impact on state behavior. In this understanding, institutions may be used in the competition between countries. The thesis uses empirical evidence to examine China behaviors and the responses by lower Mekong countries as well as how external powers are engaging in the subregion via institutions. Central in this examination is how institutions are used in their cooperation and rivalry. On that basis, the thesis argues that subregional institutions have been able to promote cooperation between lower Mekong countries, and to some extent between China and other Mekong riparian countries. However, institutions have promoted rivalry between China on one side and the US together with allies on the other side. This rivalry is seen at the diplomatic front and subregional economic programs.
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Experience-based Destination Competitiveness: Exploration through Big Data and AI Methods
(2025) Xia, Haiyang
Tourism is a major economic driver for many tourist destinations and a key contributor to sustainable development goals such as no poverty and zero hunger. As a result, destination competitiveness, which influences tourism development, has become a prominent focus in tourism research. However, despite extensive research, understanding of the destination competitiveness concept and its evaluation and improvement methods remains limited because of the complexity of the concept and the evolving nature of the tourism market. Furthermore, with the advent of the big data era, various forms of tourism big data (e.g. user-generated data), combined with advanced artificial intelligence (AI) methods, have proven valuable in advancing many fields of tourism research. However, little research has explored the integration of these new data sources and methods into destination competitiveness research. This thesis addresses these problems by advancing the definition, evaluation, and improvement methods of destination competitiveness and complementing related research methodologies through big data and AI-based methods. Three studies have been conducted to achieve this objective. Study 1 identifies theoretical lenses and research gaps for advancing the definition, evaluation and improvement of the destination competitiveness concept by comprehensively reviewing the literature through the topic modelling-based computational literature review. Study 2 addresses the research gap regarding experience-based destination competitiveness evaluation by applying touchpoint theory and aspect-based sentiment analysis. The study develops an analytical framework (i.e. method) to evaluate destination competitiveness based on tourists' satisfaction with key touchpoints (i.e. interactions at the destination) that are important to their travel experience. Study 3 addresses the research gap regarding the identification of optimal and targeted strategies to improve destination competitiveness. It develops an analytical framework that integrates the causal counterfactual AI algorithm, k-means clustering and the evaluation method from Study 2 to guide destinations in formulating competitiveness improvement strategies. Methodologically, this thesis extends destination competitiveness research with big data and AI-based methodology, which offers several advantages in data collection, analytical power, and insights generation. It also contributes to tourism and management research methods by introducing the computational literature review method for analysing large volumes of literature to identify future research directions. Additionally, it introduces prescriptive AI methods capable of capturing causality to support decision making, a capability not found in conventional descriptive and predictive AI methods. Theoretically, this thesis contributes to the literature by defining experience-based destination competitiveness, providing a complementary approach for destination competitiveness evaluation in today's experience-based tourism market. It also introduces a minimal change view of strategy development, which facilitates further exploration of destination competitiveness improvement through optimisation-based theories. Additionally, it extends destination competitiveness research from the country/regional level to the individual/business level, creating opportunities to theorise destination competitiveness from multiple levels. Practically, this thesis highlights the importance of monitoring tourist satisfaction at key touchpoints because it reveals competitive advantages and disadvantages. It also emphasises the need to consider necessary changes, potential outcomes, and differences among tourist groups when formulating competitiveness improvement strategies. This thesis demonstrates the value of user-generated data and provides prototype tools that can be adapted to evaluate destination competitiveness and develop data-driven improvement strategies.
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Decoding Thrombopoiesis: Insights from RNA Polymerase I Inhibition
(2025) Bhoopalan, Vijay
Platelets are the primary mediators of haemostasis, maintaining vascular integrity. Thrombocytopenia (a low platelet number in blood) is a common clinical observation. Current therapies for thrombocytopenia have limitations, highlighting a need for novel therapeutics. RNA polymerase I (Pol I) transcription is essential for ribosome biogenesis (Ribi), a process crucial for protein production. Pol I transcription positively regulates cellular proliferation pathways and is often upregulated in cancer. Inhibiting Pol I triggers p53-dependent and independent apoptosis. CX-5461, a first-in-class Pol I inhibitor, has demonstrated efficacy in Phase I/II trials. During preclinical testing, CX-5461 was shown to increase circulating mouse platelet numbers. This thesis aims to elucidate the mechanism(s) by which CX-5461 and other Ribi inhibitors elevate platelet numbers using experimental models in vitro and in vivo. In a first-in-human dose-escalation trial, a single dose of CX-5461 increased platelet counts (up to 34%) in 9/16 haematological malignancy patients. C57BL/6 mice were orally administered Ribi inhibitors, and blood cell numbers were measured, along with platelet receptors and activation markers and platelet production indices. Treatment with CX-5461, PMR-116 or BMH-21 led to a rapid, >1.5-fold increase in platelet counts by day 7, with sustained supraphysiological platelet levels reversible by treatment cessation. Flow cytometry and functional assays revealed normal platelet receptor levels and function. In a panel of 23 cytokines, serum from CX-5461-treated mice had only reduced C-C motif chemokine ligand (CCL) 5 and increased CCL11. Corresponding BM supernatants showed increased CCL11, interleukin (IL) 1-a, monocyte chemoattractant protein 1, CCL5, and keratinocyte chemoattractant. Haematopoietic cell subpopulations were immunophenotyped from murine bone marrow and cell cultures ex vivo. Inhibitor treatment showed normal megakaryocyte (MK) ploidy status and proplatelet formation. However, CX-5461 treatment induced a >2-fold increase in BM and splenic MK numbers and increased Sca1+MK, suggesting a non-canonical haematopoietic pathway activation. Non-canonical MK-biased haematopoiesis is characterised by directly differentiating haematopoietic stem/progenitor cells into MKs, bypassing oligopotent progenitors. MK colony-forming unit analysis revealed a significant increase in the total number of MK colonies. CX-5461 treatment increased BM MK-biased multipotent progenitor-2 cells (LSKCD135-CD48+CD150+). Plasma TPO (ELISA) and liver TPO mRNA levels (RT-qPCR) were unchanged. TPO receptor-deficient mice and carboplatin-induced thrombocytopenia models were employed to assess the therapeutic potential of CX-5461 in managing thrombocytopenia. Administration of CX-5461 in both models significantly increased platelet counts, indicating that CX-5461 promotes platelet production independently of the TPO receptor and accelerates platelet recovery following a nadir. To elucidate the mechanism of CX-5461-induced platelet production, single-cell RNA sequencing (scRNAseq) of 15,000 fluorescence-activated cell sorted LSK cells (50,000 reads/cell) from mice treated with either vehicle or CX-5461 for 2 weeks was performed. Gene expression analysis revealed that CX-5461 treatment increases p53 signalling and P-selectin gene expression features similar to MK-biased HSCs and myeloid-biased haematopoiesis. RNA velocity analysis showed a marked increase in the association of MK progenitor cells with mature MKs following treatment. CX-5461 treatment appears to increase circulating platelet levels by stimulating the MK-biased haematopoietic pathway independently of previously known triggers such as TPO. Ribi inhibitors offer a novel foundation for developing thrombopoietic drugs and provide a tool to further our understanding of both steady-state and stress thrombopoiesis.
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The Burden of Pollution: Trends in Life Expectancy and Health Disparities in the Asia-Pacific region
(2025) Somboonsin, Pattheera
The detrimental effects of environmental issues on human health have become a critical focus for the global public health community. At the heart of these challenges lies pollution-a consequence of human activity that disrupts natural ecosystems and profoundly affects populations. Pollution not only contributes to environmental degradation but also influences key demographic processes such as fertility, migration, and mortality. Despite the evident intersection of environmental factors and population health, the field of demography has traditionally focused less on the health outcomes and mortality caused by pollution compared to other scientific disciplines. Demographers, as experts in studying population dynamics and structural changes, have the potential to provide valuable insights into how environmental changes influence mortality and public health. By applying demographic methods and concepts, it is possible to uncover patterns and trends that inform more effective public policy planning to address these challenges. This thesis aims to enhance the understanding of mortality and morbidity burdens caused by pollution across the Asia-Pacific (APAC) region through the application of advanced demographic methodologies. It offers a novel and comprehensive analysis to quantify the life-years and healthy years lost due to pollution in the region, providing critical evidence to guide public health interventions and inform policy development aimed at mitigating the adverse effects of environmental degradation on human populations. The thesis is structured into seven chapters. The first chapter introduces the project and its significance. Chapters 2 investigate the effects of multiple pollutants (air, earth, and water) on mortality and morbidity in the Asia-Pacific region. Chapter 3 focuses on cause-specific mortality attributable to indoor and outdoor air pollution, exploring disparities in mortality by social and economic groups in both the APAC and European regions. Chapter 4 examines sex differences in life-years lost and unhealthy years attributable to air pollution in APAC region. Chapter 5 investigates the factors influencing global women's health due to household air pollution. Chapter 6 analyse subnational life-years lost due to fine particulate matter in Australia from 2001-2019. Finally, chapter 7 provides a concluding synthesis of findings. Supplementary materials include R programming code developed during the doctoral studies to facilitate the continuation of this research. The findings of this research emphasise the importance of applying demographic methodologies to address global environmental health challenges. By providing detailed insights into the impacts of pollution on human health, this work highlights the need for targeted, data-driven policies and interventions. Furthermore, it underscores the critical role of interdisciplinary research in advancing public health and mitigating the effects of environmental degradation on vulnerable populations.
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Three studies on the determinants and consequences of managerial incentives in global markets
(2025) Liu, Simeng
Abstract This thesis comprises three studies that examine the factors shaping managerial incentives and the impact of these incentives on corporate strategic decisions and outcomes in global markets. Study 1 examines the relation between female board representation and the adoption of corporate social responsibility (CSR) criteria in executive compensation contracts (hereafter, CSR contracting or CSR-based executive compensation) in an international setting. Using a comprehensive sample of 41,236 firm-year observations from 59 countries during the period 2002-2018, I find a positive and robust effect of female board representation on the likelihood of a firm adopting CSR-based compensation. Further, my cross-country moderating analyses indicate that the positive relation is more pronounced in countries with greater gender equity for senior positions and in countries with a lower degree of masculine culture. I also show that with greater female director representation, the use of CSR-based executive compensation is more conducive to enhancing CSR performance and firm value. Overall, this study sheds light on the effectiveness of introducing female directors in reinforcing the CSR orientation at the firm leadership level in a global context, which has implications for both business practitioners and researchers. Study 2 examines whether and how the use of CSR contracting affects a firm's stock price crash risk. Using a comprehensive sample of 42,049 firm-year observations from 53 countries from 2003 to 2019, I find that CSR contracting firms have greater stock price crash risk. This positive association can be attributed to exacerbated managerial bad news hoarding behavior and overinvestment. I further demonstrate that the positive relationship between CSR contracting and crash risk is more pronounced for firms with powerful CEOs, as well as in countries with inferior investor protection and disclosure transparency. Overall, my findings are consistent with the agency cost and managerial power perspective, suggesting that CSR contracting may be exploited by powerful and opportunistic managers as a means of diverting shareholders' attention and concealing bad financial news. My findings have implications for both researchers and business practitioners. Study 3 examines how managerial labor market considerations influence a firm's likelihood of cross-listing. Leveraging the staggered adoption of the Inevitable Disclosure Doctrine (IDD) - a legal doctrine enhancing trade secrets protection by restricting managerial mobility within the domestic labor market - by state courts in the United States, I provide robust evidence that firms are more likely to pursue cross-listing following IDD adoption. In analyzing cross-listing destination choices, I find that post-IDD adoption, firms tend to favor cross-listing in countries that are geographically and culturally closer to their home country, but that economic and legal proximity does not significantly influence their choice of destination. Further, the effect of IDD adoption on cross-listing is more pronounced for firms led by CEOs with a shorter tenure and higher general managerial ability, who are often more motivated and better equipped to pursue the international career opportunities. I also find that managers from IDD-adopting states whose firms have cross-listed abroad are more likely to transition to overseas jobs, secure CEO roles in foreign firms, and join larger foreign firms, providing evidence of the role of cross-listing in facilitating global job mobility for managers. This study identifies a previously unexplored motive for cross-listing, namely managers' labor market incentives, thereby offering new insights into the interplay between trade secrets protection, corporate strategic decisions, and managerial mobility in the global labor market.
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Advanced Synthesis and Scale-up of Earth-Abundant Catalysts for Electrochemical Water Splitting
(2025) Attar, Farid
The global energy crisis and pollution from fossil fuel have intensified the demand for sustainable solutions, with green hydrogen production by electrochemical water splitting emerging as a promising alternative. However, current electrolyser technologies face significant challenges particularly due to their reliance on expensive noble metal catalysts. To address these issues, multi-metallic, earth-abundant catalysts such as NiFe- and NiMo-based have emerged as viable alternatives. Despite their potential, these catalysts face barriers to widespread adoption due to complex fabrication and optimization processes. Moreover, scaling them from laboratory setting to industrial applications introduces additional complications, as the performance achieved in lab conditions often fails to translate directly to industrial electrolysers. This thesis aims to investigate scalable methods for synthesising efficient earth-abundant catalysts for water-splitting devices and to bridge the gap between lab-scale innovations and their industrial-scale applications. First, a one-step fabrication process for complex electrodes is investigated, focusing on optimising trimetallic NiFeMoN catalysts for the oxygen evolution reaction (OER). Using magnetron cosputtering, synthesis process is refined through statistical optimisation techniques, design of experiments (DOE) and response surface methodology (RSM). Analysis of variance (ANOVA) is employed to understand the interaction effects of synthesis parameters which are critical for achieving optimal performance. The optimised NiFeMoN exhibits high performance with a low overpotential of 216 mV at 10 mA/cm2 with stability over seven days. Furthermore, when integrated into a decoupled photoelectrode design, the sputtered NiFeMoN not only enhances OER performance but also effectively protects Si photoanodes from photo-corrosion. To develop an efficient transition metal-based multi-metallic carbide for the hydrogen evolution reaction (HER), thesis explores the utilisation of triple-target magnetron co-sputtering process. NiMoC is synthesised in a single step and at room temperature, exhibiting remarkable performance across a broad pH range. It demonstrates a superior overpotential of 26 mV with ten days' stability and 42 mV with 70 hours of stability in alkaline and acidic conditions, respectively. These enhancements are attributed to Mo2C and NiMo as active sites, with disordered and graphite-like carbon improving electrical conductivity and stability. When used as a cathode in an electrolyser, it achieves a cell voltage of 1.78 V at 0.5 A/cm2 and 1.87 V at 1 A/cm2, maintaining stability for nearly 70 hours. To facilitate the transition from lab-scale to industrial-scale catalysts, thesis explores the individual and interaction effects of operating parameters, electrolyte flow rate, KOH concentration, and temperature, along with a synthesis parameter, catalyst deposition time, in a zero-gap electrolyser. An artificial neural network combined with particle swarm optimisation (ANN-PSO) and the Box-Behnken design (BBD) are applied to model the system and uncover the interaction effects of parameters. The findings reveal an extended deposition time shifts the optimal KOH concentration and flow rate by 40.8% and 19%, respectively. Increasing flow rate reduces the optimal deposition time by 23%, while increasing the optimal KOH concentration by 30%. Furthermore, a genetic algorithm is employed to optimise zero-gap electrolyser, resulting in a 31.4% improvement in performance. Analysis using Garson's method shows that KOH concentration has the most substantial impact, while flow rate has the least. Deposition time exhibits an influence comparable to that of temperature. This work provides a systematic approach to catalyst synthesis and scaling, advancing the field of water splitting and paving the way for industrial deployment of cost-effective and efficient green hydrogen production technologies.
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Critical Polycentric Governance: Indigenous Peoples' Tenure Security in India's Forests
(2025) Adhikari, Dipika
Polycentric systems of governance, where diverse institutional actors including government, community and CSOs operate across multiple jurisdictional levels interdependently, are argued to offer unique opportunities to address complex collective action problems at scale. While an extensive literature focuses on polycentric governance for natural resource management, few studies examine how critical polycentric configuration may shape Indigenous tenure security in forest commons. Similarly, studies on Indigenous tenure reforms have rarely addressed whether and how polycentric governance systems are configured and performed to influence Indigenous tenure governance. To address these research gaps, this thesis examines how power operates within an (apparently) polycentric governance system to influence institutional arrangements and interactions for Indigenous Peoples' forest tenure security in India. Employing qualitative case study methods, the research focuses on one of India's minority Indigenous groups, the Rajwar peoples of the Kumaon Himalayas. The thesis adopts Carlisle and Gruby's (2019) polycentric governance framework as a conceptual foundation, coupled with Morrison et al.'s (2019) power typology as an analytical lens for a nuanced examination of power dimensions across polycentric configurations and interactions vis-a-vis Indigenous tenure governance. This thesis problematises contemporary notions of recentralisation and justice. It argues that while India's Forest Rights Act 2006 is designed to be polycentric, where multiple actors across scales and levels are empowered to exercise decision-making in cooperation with each other to foster Indigenous Peoples' tenure security, state actors reify their authority through policy design, pragmatic exercise and framing of power, not as an attempt to recentralise absolute control in one actor or institution (such as the centralised state government), but rather to reinforce the state's hegemonic and hierarchical governance instead of nested polycentric system. Through incongruities and ambiguities in the written rules, along with historically enjoyed pragmatic and framing power, state actors across multiple scales and levels attempt to sustain the pre-existing governance arrangement, that is, hierarchical and hegemonic in nature. They do so by deliberately misinterpreting and not complying with formal rules, dismissing traditional Indigenous institutions and Peoples (here, the Rajwar peoples), and framing the incapacity of self and other actors in implementation and decision-making processes, all while sustaining their discretionary powers in de-establishing Indigenous autonomy, cooperative linkages and conflict resolution mechanisms. Extending this logic further, the thesis argues that powerful actors create a superficial veneer of polycentric structure that symbolises 'just-washing' (analogous to greenwashing) in forest reforms. Indigenous tenure reforms, while in the first instance appearing a just and transformative model of polycentric governance, upon closer examination are revealed to be deeply flawed, ambiguous and incongruous, and entwined with powerful actors' hegemonic exercise of networked patronage and governmentality towards Indigenous Peoples. These findings are critical and novel to the advancement of polycentric governance scholarship and contribute significantly to the research and praxis of forest reforms and Indigenous justice.
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Becoming Inka: An Interpretative Narrative of the Metamorphosis, Taki and Landscape of Tanta Karwa
(2015) Dunbar Solas, Lisa Anne
Human sacrifice was a central institution in the Inka world. However, research into this subject is still in its infancy. To date, most studies have focused principally on reconstructing the final moments of Qhapaq Hucha, the Inka state ceremony, during which selected individuals were sacrificed at principal shrines, utilising both the archaeological record and the ethnohistorical documents. It is suggested that these studies have operated from a more etic view of sacrifice, which tends to cast the sacrificed individuals in a passive role, while it remains unclear how these events impacted communities and assisted to build relationships between them and Cusco, the Inka capital. A text-aided approach for both a study of the ethnohistorical documents and the archaeological record as well as a phenomenological one to build a more emic view of Inka religion, ceremony, sacrifice and landscape. A phenomenological perspective of sacrifice views it as a broader cultural process during which the landscape is transformed. This is explored through the case study of Tanta Karwa, an ethnohistorically reported example of Inka sacrifice in Ocros, Ancash, Peru. The 17th century document provides a window into understanding the nature of Inka sacrifice, ceremony and the role of landscape. It also raises a number of issues regarding the selection and redistribution process of individuals for sacrifice and also how communities were impacted by Inka presence. In order to establish an archaeological narrative of her sacrifice, it is critical to examine the processes of Inka ceremony in Cusco and its archaeology, as well as to explore the nature of Inka place-making. By re-situating Tanta Karwa into her cultural context, new insights into the transformation of individuals and groups through Inka domestication and the Qhapaq Hucha ceremony come to light. While the archaeological evidence of Inka presence in the Ocros valley is minimal, the documents state that the changes were profound. One is that Tanta Karwa, through this liminal period, is trained to become an aqlla, a noble Inka lady in order to serve the Sapa Inka, the ancestors and the Sun. Her role became that of an Inka intermediary with her sacrifice in Ocros and as a result a major regional oracle. By establishing new shrines and intermedaries, the Inka altered the ways in which communities gained access to sources of well-being and abundance and their ancestors. Through her transformation, Tanta Karwa becomes a reminder of the perpetual link between Ocros and the Inka.
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A Dialogue Between Nature and Culture: An Ethnography of the Talesh People's Calling Tradition
(2025) Jahandideh, Mitra
This thesis examines khele, a calling tradition of the Taleshi people in Iran, who primarily live in the county of Talesh in Gilan province, located on the southwestern coast of the Caspian Sea. Rooted in the region's diverse geography, which includes coastal areas, plains, foothills, and mountains, khele initially served as a practical communication tool for ranching, farming, and fishing activities. Over time, khele developed into a cultural practice performed at local concerts, representing the Taleshi nomadic and agricultural lifestyle and evoking memories of rural life. This research explores how khele reflects the social, occupational, and emotional aspects of the Taleshi rural life, highlighting the people's relationship with their environment. It also investigates how khele contributes to the formation of cultural identity, memory, and a sense of belonging and well-being among the Taleshi communities. To examine these dynamics, I employed an ethnographic approach that included observational ethnography, netnography, soundscape recordings, and interviews (individual, feedback, and walking) conducted in the living and working places of the Taleshi people over a period of 12 months. The findings demonstrate that khele acts in different ways: practically for communication, emotionally for self-expression, and symbolically in cultural performances. Khele is an important cultural marker that connects the community to the past through memory, sound and place. This thesis also demonstrates how khele has changed in response to urbanization and technological changes, shifting from a daily tool to a cultural symbol in performances and gatherings. This shift highlights the resilience of the Taleshi people, who have preserved their cultural heritage while adapting to modern life. This thesis contributes to ethnomusicology, anthropology and sound studies by providing a conceptual framework for understanding traditional and transformed calls, and demonstrating how calling traditions shape cultural and ecological understandings. It highlights the role of soundscape and landscape in constructing cultural meaning and memory, while also providing insights into the broader impact of sound in human-environment interactions. This work shows how khele represents the sonic world of the Taleshi people and contributes to the ongoing transformation of their cultural heritage.
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An investigation of rumination constructs at different levels of cognitive load
(2025) Vella, Justin
Four studies investigated the relationships between executive functioning performance under different types of cognitive load (intrinsic and extraneous), and operationalisations of rumination (brooding, reflection and content-independent), while also exploring whether self-regulatory depletion and working memory training can play a role in influencing these relationships. To first determine whether different types of cognitive load correspond to different kinds of rumination, Study 1 experimentally manipulated load using negative priming and modified continuous performance tasks while examining mood, self-reported rumination, and task-related thoughts over a three-week period. Findings for the continuous performance tasks suggested specific forms of rumination may predict performance under specific forms of load, but this was qualified by the very strong impact of the extraneous load manipulation, limited temporal resolution of the content-independent rumination questionnaires, and the extent of element interactivity in the intrinsic load manipulation. This posed three further questions, addressed by the ensuing studies. Study 2 assessed whether a weaker extraneous load manipulation would yield different results by administering a revised form of the continuous performance task manipulation. Results suggested that while rumination continued to correlate with and predict constructs in ways similar to before, to some extent it positively correlated with better performance at this reduced level of extraneous load. Study 3 investigated whether a task with higher element interactivity than the modified continuous performance task would yield different results for intrinsic load relative to Study 1, and also explored the possibility that self-regulatory depletion may be an overlooked process in the relationship between rumination and executive performance. We administered a Stroop task that manipulated intrinsic load by adding conflictual response rules, creating more interactivity between task elements, and manipulated self-regulatory depletion using the classic e-crossing task. Again, results suggested that rumination positively correlated with some indicators of better executive function performance, but also some other indices of reduced performance on the task, as well as expected variables such as low mood. Results did not support a significant effect of self-regulatory depletion on the other variables of interest. Study 4 explored if working memory training tasks may be used to bolster performance under extraneous load from a rumination induction. Participants completed a very brief working memory training paradigm based on reading span tasks. Operation span tasks were administered before and after to measure executive function performance. The latter operation span was preceded by a rumination induction. While there was evidence that the training paradigm was somewhat effective in improving operation span performance, the rumination inductions resulted in limited effects, which may have been due to the impact of the cognitive tasks upon mood. Broadly, thesis results suggested a nuanced relationship between rumination and level of cognitive load, and bore out the position that information processing theories of rumination may benefit from distinguishing intrinsic and extraneous loads when manipulating them. They also indicated that rumination measures should continue to include content-dependent and independent forms, but efforts to explore timecourse of self-reported rumination and self-regulatory depletion contributed little to our results. Findings were limited by the use of generally unemotive stimuli on behavioural tasks, sampling constraints, multiple comparisons and paradigm limitations. Overall, this thesis supports greater consideration of cognitive load type in future information processing studies of rumination.
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Low Impedance Moisture Electric Generator for Wearable Devices
(2025) Zhao, Mingjie
As global warming intensifies and energy crises become more urgent, the significance of renewable energy technologies that transform sustainable and eco-friendly sources into electricity is becoming increasingly clear. Concurrently, the swift advancement of the Internet of Things (IoT) and wearable devices poses an ongoing challenge in discovering efficient methods to power these portable electronics. Given the context, one of the energy conversion method has come under light, and that is: Moisture Electric Generation (MEG), of which is capable of generating power by moisture, and can be designed in various shapes or forms to be wearable, thereby fulfilling the power needs of IoT devices. In this thesis, we have analysed some of the state-of-the-art MEG devices, focusing on its key performance factors: distinct mechanism, choice of structure, and selection of material. In the meanwhile, we have also developed a planar MEG device by integrating MXene with anionic and cationic polyelectrolytes, and examined its structural, morphological, water absorption and conductivity properties via varies characterization method. With our selection of additives, MEG showed excellent water absorption, retention, and ionic conductivity, resulting in significant improvements in power density, reaching 3.47 mW/cm3 at 90% relative humidity. We successfully integrated MEGs arrays into fabrics, enabling wearable devices to be powered even at environments with low humidity. Our work provides an innovative strategy for fabricating high-performance MEGs. This approach has great potential for resilient and eco-friendly power generation in wearable devices, capable of meeting challenging operating conditions and battery-free scenarios.
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Mechanics Fleeing Communism: Russian Refugees in Iran and their Emigration to Australia, 1920-1960
(2025) James, Marcus
My thesis is a study of the Russian refugees who fled to Iran after the Bolshevik Revolution and lived there for decades including through the Second World War, before being displaced again and emigrating to Australia among other countries in the 1950s. While the first wave of these refugee after the Revolution fitted the accepted Russian emigre profile of former military officers, professionals and businessmen, most Russian refugees in Iran in this period were distinctly different. They had fled the Soviet Union in the early 1930s due to the Soviet dekulakisation and collectivisation campaigns. They comprised a hitherto unstudied wave of Russian emigration between the first wave after the Revolution and the second wave of Displaced Persons after the Second World War. They were overwhelmingly better-off peasants and tradesmen, especially carpenters and mechanics, so quite distinct from most of those who emigrated to the cities in Europe and China. They were mostly Russian Orthodox, but including a significant minority of religious dissenters, and ethnically about 70 per cent Russian with the remainder Ukrainian. The Russian refugee community in Iran was small, numbering some 2-3,000 people at its peak at the end of the Second World War, but nevertheless still comprised the largest group of Russian refugees in the Middle East. They contributed to the Allied victory through their work on the Lend-Lease Persian Corridor supply line operated by the Soviet, American and British forces in Iran during the War. After the war they faced an increasingly unstable situation, with the Soviet attempt to carve off the province of Azerbaijan in 1946 and the battle with the British and eventually America too over the nationalisation of Iran's oil resources. Due to heightened Iranian nationalism and nascent Cold War tensions, these European refugees were told that they had to leave Iran unless they could obtain citizenship, face repatriation to the Soviet Union or exile to islands in the Persian Gulf. However, they were fortunate that at this time, Australia and some other countries had initiated mass immigration programs. With the help of Russian emigre monarchist, church, and military networks, the United Nations High Commissioner for Refugees and refugee relief agencies such as the Tolstoy Foundation, a group of these refugees was able to settle in Australia. Their initial settlement experience in Australia is also considered.
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Making Repression Pay: The Political Economy of Organ Trafficking in China
(2025) Robertson, Matthew
States kill for many reasons: to punish criminals, suppress dissent, or as part of warfare. Sometimes, they kill for profit. This thesis explores how the People's Republic of China transformed repression into a lucrative industry by trafficking the organs of both death penalty and political prisoners, whom they killed in the process. Drawing on extensive empirical evidence and innovative computational methods, I show how China's organ transplantation system grew rapidly by exploiting vulnerable prison populations. This process -- which I term extractive repression -- not only generated substantial economic rents for state and medical actors but also advanced China's standing in global transplant medicine. The case of state-sponsored organ trafficking in the PRC challenges conventional wisdom about the relationship between repression and development. It demonstrates how, under certain conditions, violence can fuel economic growth and technological advancement rather than impede them. By framing human organs as 'lootable assets' akin to natural resources, this research contributes to literature on the political economy of authoritarianism, predatory states, and the commodification of human life. The thesis is a mixed-methods project. It leverages large language models, computational text analysis, and forensic statistics to uncover evidence of unethical medical practices in an authoritarian context. At the same time, it contains extensive qualitative analysis of Chinese-language primary source documents. It relies on both statistical and qualitative evidence to advance its claims. The format of the thesis is a compilation of published works. There are four papers, three of which have been published, one of which is presented here in manuscript form. The structure is as follows: 1. Introduction 2. [Draft manuscript] Extractive repression: Human organ markets in the People's Republic of China 3. [Published in the American Journal of Transplantation, 2022] Execution by organ procurement: Breaching the dead donor rule in China 4. [Published in the edited volume The Xinjiang Emergency, 2022] Predatory biopolitics: Organ harvesting and other means of monetising Uyghur 'surplus' 5. [Published in BMC Medical Ethics, 2020] Analysis of official deceased organ donation data casts doubt on the credibility of China's organ transplant reform

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