Restricted Theses

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Characterisation of wide field neurons in the superior colliculus using the Ntsr1-Cre GN209 mouse line
(2026) Feng, Xiaolong
Since Cajal established the neuron doctrine in the late nineteenth century, neuroscience has sought to classify the diversity of neurons and understand how they communicate. Advances in genetics, imaging, and electrophysiology have refined our ability to define neuronal types by integrating molecular identity, morphology, and physiological properties. In this thesis, we characterised genetically identified neuron types in the Ntsr1-Cre GN209 line and focused on wide-field neurons (WFNs) in the superior colliculus to examine their intrinsic features and communication mechanisms. First, we mapped Cre-dependent expression throughout the brain and identified regions with strong labelling using Ntsr1-Cre GN 209 line. Whole-cell recordings and biocytin reconstructions showed that this line labels distinct neuronal classes, including Purkinje cells in the cerebellum, GABAergic interneurons in the inferior colliculus, WFNs in the superior colliculus, medium spiny neurons in the striatum, and pyramidal-like cells in the anterior olfactory nucleus, piriform cortex, and subiculum. Statistical analysis confirmed consistent within-region profiles and clear separation between classes, defining the cellular targets of the Ntsr1-Cre GN209 line and providing a validated reference for cell-specific research. We next examined WFNs in detail. Most intrinsic properties, including resting membrane potential (RMP), input resistance, and action potential (AP) threshold, showed no developmental change after two weeks, while AP width, after-hyperpolarisation, and sag kinetics stabilised by six weeks, indicating early functional maturity. WFNs exhibited large voltage sags, depolarised RMP, and gradual RMP drift after depolarisation. Blocking hyperpolarization-activated cyclic nucleotide-gated (HCN) channels with ZD7288 reduced sag amplitude, hyperpolarised RMP, and suppressed RMP drift, showing that HCN activity dominates subthreshold dynamics. Morphological experiments using sparse viral labelling provided quantitative references for imaging precision and tissue swelling during clearing, laying groundwork for further structural analysis. Finally, we investigated how WFNs communicate. Paired recordings showed that about 12% of pairs were electrically connected, including combinations of Cre positive and negative WFNs. Both depolarising and hyperpolarising responses were transmitted bidirectionally, indicating gap junctions between WFNs. Mefloquine reduced coupling without affecting intrinsic excitability, confirming a specific effect on gap junctions. Pharmacological and optogenetic tests showed that cadmium chloride blocked synaptic responses but not optogenetically evoked coupling, whereas mefloquine abolished electrical responses. Neurobiotin tracing revealed coupled cells beyond the Cre positive population, including neuronal and non-neuronal elements, suggesting that WFNs form a heterogeneous electrically connected network within the superficial colliculus. Translational profiling of Cre positive WFNs detected connexin 36 and connexin 43, indicating these connexins underlie the coupling. Functionally, coupled pairs fired synchronously with short delays, showing that gap junctions enable fast and coordinated activity among WFNs. This work systematically maps and classifies Cre-labelled neurons across the brain using the Ntsr1-Cre GN209 line, providing a reference for future cell-type-specific studies and a quantitative framework for neuronal classification. It further defines the physiological and structural properties of WFNs and reveals that they form an electrically coupled network in the superficial superior colliculus. This discovery establishes a cellular basis for understanding how WFNs coordinate activity and offers a foundation for future studies exploring how such networks influence visually guided behaviours.
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[The title is withdrawn]
(2026) Ji, Dawei
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Design and development of Non-Noble metal catalysts in N-ethylcarbazole hydrogenation for Liquid Organic Hydrogen Carrier (LOHC) systems
(2026) Permude, Preetham
Hydrogen can play a significant role as a clean energy vector due to its abundance, high gravimetric energy density, and environmental friendliness. However, efficient hydrogen storage remains a bottleneck that poses economic and technological challenges to the current system. Liquid organic hydrogen storage (LOHSs) have drawn intensive attention for their excellent compatibility with the existing fuel infrastructure. Among the Liquid Organic Hydrogen Carrier's (LOHC) under development, N-ethylcarbazole (NEC) is an attractive option mainly due to its ability to undergo hydrogenation cycle below 473K. Recent research have investigated noble metal catalysts for hydrogenation of N-ethylcarbazole and very limited efforts have been conducted for noble metal free catalysts. It is noted that comprehensive analysis involving both catalyst and carrier (N-ethylcarbazole) change during hydrogenation process is lacking in literature hindering the development of this technology. In our first work, we have comprehensively investigated noble-metal-free catalyst, Cu-doped NiO as well as the carrier (N-ethylcarbazole) during the hydrogenation process. Insights into the role of Cu doping during hydrogenation of N-ethylcarbazole was obtained through in-depth experimental and theoretical analysis of carrier and catalyst. Our findings indicate that optimal Cu doping enhances the hydrogenation performance of NiO, with a hydrogen storage capacity of up to 5.43 wt% in the first cycle and achieving hydrogenation efficiency greater than 90% during three cycles. Our study explored the structural formation of 12H-NEC diastereomers using advanced spectral techniques, revealing the complex nature of the hydrogenation process. The structural evolution as well as recyclability of Cu4-NiO catalyst during the hydrogenation process was investigated and it was found that reducing environment of hydrogen converted the Cu4-NiO catalyst into an alloy during the first cycle. Our results revealed that the catalysts acts as a reservoir during the hydrogenation process confirmed by the growth of nickel hydroxide during the hydrogenation process. In the following work, Cu-doped NiFe2O4 catalyst for NEC hydrogenation and the effect of Cu-doping on the catalytic performance was investigated. Our results show that optimum doping improved the hydrogenation performance of NiFe2O4, and 4 mol% Cu doped catalyst showed the best performance among all the doped catalysts with hydrogen storage capacity of 5.41 wt% and 93.4% hydrogenation efficiency. Enhanced surface charge density was identified as key contributor to the catalytic performance. The catalyst was stable in reducing hydrogen environment confirmed through comprehensive analytical techniques. To understand the structure of the fully hydrogenated 12H-NEC, investigation of the hydrogenated product was carried out using Nuclear Magnetic Resonance (NMR, including Heteronuclear Single Quantum Coherence (HSQC) and Heteronuclear Multiple Bond Correlation (HMBC)). Also, Diffusion Resolved Encoded Acquisition Method for Transverse Relaxation and Mixing Time Evaluation (DREAMTIME) Nuclear Magnetic Resonance (NMR) spectroscopy was employed for the first-time in the field of hydrogen storage to understand the composition of the hydrogenated product. Through our analysis, we confirmed that the structure obtained from 12H-NEC was (4aR, 4bS, 8aS, 9aS) -9-ethyl-4a, 4b, 8a, 9a-tetramethyldodecahydro-1H-carbazole and our analysis paves way for understanding the relationship between catalyst design and hydrogenation process. To the best of my knowledge, this is among the first PhD thesis in Australia dedicated to the investigation of catalysts for hydrogenation of liquid organic hydrogen carriers (N-ethylcarbazole). Our work makes a pioneering contribution to the national research landscape in the field of hydrogen storage specifically in relation to liquid organic hydrogen carriers.
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Harvesting the half: the persistence of sharecropping in Samcholing, Bhutan
(2016-12) Penjore, Dorji
This dissertation is an anthropological inquiry into why sharecropping of paddy persists in Samcholing village, Bhutan, when it has largely disappeared from other villages in the country. It presents a detailed ethnographic discussion of the phenomenon of sharecropping as an agricultural technology, as a type of social organization and as a central focus of social and cultural life of Samcholing. It is an observation and analysis of sharecropping as it has developed historically over the centuries and how it has persisted to the present in Samcholing. The study is placed within the general criticism of sharecropping as an inefficient agricultural organization that is incongruous with capitalism. The general consensus until recently has thus been that sharecropping is bound to disappear once the transition to capitalism is completed. Similarly destined for the disappearance is the peasant or family farm as a result of capitalist transformations of agriculture. Based on one-year of fieldwork and a household survey, the study shows that landlessness, a common reason for sharecropping, partly explains the persistence of sharecropping in Samcholing, which is confined to cultivating wetland paddy, as an important subsistence strategy in the household economy, since absentee landowners own more than half of the village’s paddy fields. However, the bigger and the more complex reasons are embedded, far beneath the topsoil that the sharecroppers till every agricultural season, in the subsoil of Samcholing’s history, social structure, and geography. While the study locates the immediate causes for institutionalizing sharecropping in the social reform of the 1960s during which an underclass of people - the ancestors of people in Samcholing - was abolished and sharecropping introduced as a progressive tenancy, the complex history of land tenure in the village and the emergence of a locally distinctive system provides the essential context for understanding agrarian relation in the village.
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Development of Novel Therapeutics: From Small Molecules to Biologics
(2026) Davies, Lani
The dynamic global health landscape demands innovative therapeutics to address multiple challenges. Broady, therapeutics fall into three main categories: small molecules, peptides and biologics. Small molecules continue to dominate the pharmaceutical landscape due to their ease of synthesis and use, while biologics are emerging as the next-generation tool for high precision therapy and diagnostics, and personalised medicine. Peptides lie at the interface of these two classes and combine the high specificity of biologics with the simplicity of small-molecule drugs, presenting a unique class of therapeutic diagnostics (theranostics). As the demand for targeted, efficient and adaptable medicine grows, the advancement of each class of therapeutics is essential in shaping the future of healthcare (Chapter One). Heparanase is the only known mammalian enzyme to catalyse the hydrolysis of heparan sulfate, a major component of the extracellular matrix. Also, it is upregulated in every human cancer studied to date where it contributes to larger tumour size and metastasis, and is implicated in several other chronic human diseases, such as Crohn's disease and diabetes. However, despite extensive research, no specific heparanase inhibitors have progressed through clinical trials. As such, it is clear that heparanase is an important drug target where traditional drug design methods have failed to produce effective inhibitors. Chapter two explores an emerging method of small molecule drug discovery, known as fragment-based drug discovery (FBDD) and its application to this prominent drug target, where several novel binders and inhibitors of heparanase were discovered and FBDD principles were used to decrease the IC50 of a selected fragment by more than seven-fold. Peptide-based drugs are rapidly emerging as next-generation therapeutics (e.g. Ozempic) due to their favourable characteristics compared to small molecules and biologics. However, many canonical peptides are restricted in their therapeutic applications due to inherent limitations caused by their flexible structures and susceptibility to proteolysis. Macrocyclisation is a commonly employed method to mitigate these limitations. Chapter three introduces oxime ligation, a biocompatible, selective, one-pot macrocyclisation technique that can be applied to a variety of amino acid sequences and is fully amenable to automation. Similarly, multicyclic peptides offer the opportunity to further stabilise peptide structures. Bismuth serves as a simple, single atom cyclisation scaffold that has therapeutic applications in chemotherapy, while also conferring superior structural stability to multicyclic peptides (Chapter Four). Biologics are the largest class of drugs and are becoming increasingly popular for use in personalised and targeted therapies, such as radiotherapy where they are conjugated to a therapeutic isotope. Nanobodies, the smallest naturally occurring antigen-binding fragments, have superior pharmacokinetic properties when compared to their larger counterpart, antibodies. Chapter Five describes the introduction of a single cysteine mutation adjacent to the canonical disulfide bond present in nanobodies, generating a metal binding site. Similarly, affibodies are incredibly small, engineered antigen-binding proteins derived from the antigen-binding domain of staphylococcal surface protein A that have excellent therapeutic properties. In Chapter Six, three cysteine residues are engineered into affibodies to generate a metal-binding site within the protein. These engineered metal-binding proteins form highly stable metal complexes and represent a new class of theranostics with promise for applications in imaging and radiotherapy.
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The Contribution of Pathogenic Genetic Variants to the Development of Autoimmunity and Kidney Disease
(2026) Lea-Henry, Tom
Irreversible damage or reduction in kidney function is termed chronic kidney disease (CKD). CKD is highly prevalent and is increasing in incidence, with projections for this to become one of the top five leading causes of death worldwide. This is particularly true for Indigenous Australians who experience a disproportionate burden of kidney disease with onset 30 years younger than other Australians. An important cause of CKD is autoimmune glomerulonephritis (GN) which is the second most common cause of end-stage kidney disease (ESKD) worldwide. Despite this, the development of new therapeutic treatment strategies has been limited, and current therapy relies on aggressive, broad-spectrum immunosuppression. In contrast, personalised medicine approaches target therapy to the specific dysregulated immune pathway in individual patients and promises improved efficacy with reduced risk of excessive immunosuppression. We use an established pipeline that incorporates analysis of genetic variants, immunophenotyping, and transcriptomics to identify therapeutic targets in autoimmunity. Single nucleotide variants (SNV) in humans are associated with the development of autoimmunity, GN, and CKD. The genetic risk in these disorders generally does not obey Mendelian inheritance patterns but rather more complex patterns of genetic inheritance. To investigate the role of rare SNVs in human autoimmune disease, we compared the burden of rare SNVs in the endosomal Toll-like receptor (eTLR) pathway. The eTLR pathway is important for identification of RNA and DNA viruses and is implicated in the development of systemic lupus erythematosus (SLE). We find that rare SNVs in the eTLR pathway are enriched among individuals with SLE, an autoimmune disease that causes GN in half of affected individuals. These results support a role for rare single nucleotide polymorphisms in complex diseases. We found 5 rare missense SNVs in the TNFAIP3 gene among the Indigenous Australian inhabitants of the Tiwi Islands. TNFAIP3 is an important negative regulator of inflammation including that arising from the eTLR pathway and has been associated with the development of autoimmunity and kidney disease. The Indigenous Australian inhabitants of the Tiwi Islands are a genetically distinct Indigenous Australian group and experience the highest rate of CKD in the world. We find that several of these TNFAIP3 variants fail to suppress inflammatory NFKB signalling. A mouse model of the most damaging of these SNVs worsens GN when crossed to an important mouse model of autoimmunity. This suggests that this TNFAIP3/Tnfaip3 variant is less able to regulate kidney inflammation following an inciting immune response. The dysregulation of inflammatory signalling arising from this variant is therefore a putative molecular target for novel therapy development. Previously this group has identified several rare SNVs in the Src-B family kinase gene BLK that were enriched among individuals with SLE. BLK was previously thought to be a redundant gene, yet SNVs in BLK are associated with the development of many autoimmune diseases; suggesting that it has important unrecognised roles in the immune system. Using a mouse model carrying a Blk SNV orthologous to that from a patient with SLE, we identify an unexpected role for Blk in licensing the development of GN in several mouse models. This is the target on ongoing drug development efforts aiming to reproduce the impact on protein function seen with this SNV. In summary, we identify two novel molecular targets in kidney disease through the analysis of rare genetic variants. By targeting inflammatory TLR signalling pathways mediated by TNFAIP3, we have identified the first potential novel therapeutic strategy targeting kidney disease in Indigenous Australians. Furthermore, the development of a specific inhibitor of BLK has the potential to improve treatment options for a range of autoimmune kidney diseases.
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Coupled Eco-hydrological Modelling for Assessing Environmental Flow Releases
(2026) Liu, Moyang
Environmental flow management is a key measure for vegetation restoration and maintenance, and has yielded a variety of positive ecological outcomes. Remote sensing can be used to monitor and improve our understanding of vegetation condition in response to hydro-climatic factors by providing high spatial and temporal resolution data over long periods. This is particularly useful in data-scarce or remote regions. However, using remote sensing data to predict vegetation response to flooding and drought and to inform environmental water management remains challenging in semi-arid floodplain wetlands, where vegetation condition exhibits high heterogeneity during inundation. This research focuses on a semi-arid floodplain-lakes system in the northern Murray-Darling Basin, Australia - the Narran Lakes floodplain. Through four interrelated chapters, this thesis analyses vegetation response to hydro-climatic factors and leverages this understanding for the development and application of an eco-hydrological model to support environmental flow delivery in this region. Chapter 2 analyses the effect of hydro-climatic factors on vegetation condition during 2000-2021 using correlation analysis and generalised additive models. The analysis considers five key variables: precipitation, inflow, soil moisture, temperature, and solar exposure. Results show that soil moisture is the primary factor influencing NDVI (Normalized Difference Vegetation Index). Water availability factors including soil moisture, inflow, and precipitation interact in a complex manner to affect NDVI. Chapter 3 develops a coupled eco-hydrological model that simulates vegetation condition from soil moisture deficit in response to hydro-climatic inputs. The model integrates three components: an inundation module to simulate inundation extent, a soil moisture accounting module adapted from IHACRES-CMD, and an ecological response module that estimates vegetation condition using Leaf Area Index (LAI). Results show that the simulation of inundation extent achieves high accuracy, and the model captures general trends for LAI values in the Narran Lakes. Chapter 4 assesses vegetation condition in response to different environmental flow scenarios, incorporating predictive uncertainty using Bayesian inference. Results show no clear long-term decline in vegetation condition across annual and 5-year scales, though periods of drought stress and greater variability have increased since the 2000s; During the growth period, an LAI below 0.4-0.6, accounting for predictive uncertainty in threshold estimates, indicates that the vegetation is in a critical state; Environmental water delivered during the growth period can improve vegetation condition, with improvements plateauing around 50,000 ML. Chapter 5 proposes a framework for reflecting on modelling decisions through a fitness-for-purpose lens and pathway perspective consisting of four steps: a) Modelling decision boundaries; b) Modelling pathway and reasoning; c) Evaluation of modelling decisions; and d) Iterative refinement. Applied to the eco-hydrological model, this framework comprehensively investigates and rates modelling decisions made in the modelling cycle. The application of this framework provides practical guidance for improving model reliability and usability. In summary, this thesis investigates vegetation dynamics in response to hydro-climatic drivers in the Narran Lakes and develops a coupled modelling approach to inform environmental flow management. It demonstrates the dominant role of soil moisture in influencing vegetation condition in the Narran Lakes, introduces a novel coupled eco-hydrological model to predict vegetation response, incorporates predictive uncertainty in scenario analysis, and provides a framework to reflect on modelling decisions. These contributions offer technical support for vegetation monitoring and conservation in the context of environmental flow management in semi-arid wetlands.
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Haemostatic defects in B-cell malignancies
(2026) Brysland, Simone
Optimal platelet, coagulation and vascular bed functions are crucial for haemostasis, with impairments resulting in bleeding and thrombosis. Waldenstrom Macroglobulinaemia (WM) is a rare lymphoma, characterised by the myeloid differentiation primary response (MYD)88L265P mutation in 92% of patients. Clinical features include bone marrow (BM) infiltration and immunoglobulin (Ig)M paraprotein hypersecretion by malignant lymphoplasmacytoid B cells, and hyperviscosity and bleeding symptoms. WM is treated with Bruton's tyrosine kinase inhibitors (BTKis), which can exacerbate bleeding. Haemostatic functions are understudied in WM. This thesis aimed to evaluate platelet and coagulation functions in untreated (n=13) and BTKi-treated (n=5) WM patients, compared to healthy donors (HDs, n=15). Distinct phenotypes were identified using multivariate analyses. The effects of IgM paraprotein on haemostasis and the presence of MYD88L265P in the platelet-producing megakaryocytes (MKs) were also assessed. Untreated WM patients displayed mildly reduced platelet counts (151+/-79x109/L), which correlated with 3.8-fold increased thrombopoietin (TPO) levels. Platelets from untreated but not BTKi-treated WM patients displayed reduced reticulation and desialylation, possibly indicating deranged age and lifespan. These platelets displayed normal levels of adheso-signalling surface receptors and responses to physiological agonists, however contributions to the acceleration of thrombin generation were decreased by 74% relative to HD platelets. Despite untreated WM patients being stable and not displaying bleeding symptoms, multivariate analyses distinguished their platelet phenotypes from HDs with relative accuracy, based on reduced platelet counts, reticulation and fibrinogen binding to unstimulated platelets, and elevated TPO levels. These analyses also accurately distinguished BTKi-treated from untreated WM patient platelets based on reduced glycoprotein (GP)VI-mediated platelet activation response and GPVI, CD9 and soluble GPVI levels. WM patient plasma samples displayed delayed and reduced thrombin generation compared to HDs. Coagulation factor contributions to thrombus amplitude were increased in WM patient whole blood samples, possibly indicating increased fibrinogen contribution. Multivariate analyses accurately distinguished coagulation phenotypes in WM patients with cardiovascular comorbidities from those without, based on accelerated and increased thrombin generation measurements. IgM paraprotein was enriched from WM plasma to a purity of 83%. When included in platelet assays, 50-60 mg/mL IgM (equivalent to levels observed in hyperviscosity patients) reduced HD platelet adhesion, spreading and aggregatory responses to physiological agonists. IgM bound to activated platelets, possibly electrostatically. IgM reduced plasma thrombin generation potential by 6%. Haematopoietic cells were sorted from WM patient BM aspirates. MYD88L265P was identified in isolated B cells in 67% (6/9) patients, and intriguingly, also in 50% (3/6) lymphoid progenitors, 33% (2/6) stem cells and 20% (2/10) MKs. Platelets from a WM patient with MYD88L265P in the BM displayed 38% increased Toll-like receptor-mediated platelet activation, upstream of Myd88, compared to a WM patient without the mutation. This novel finding suggests that constitutively active Myd88L265P may be present in WM platelets and may alter inflammatory signalling responses to relevant pathogens. This is the first study to investigate haemostasis in a WM cohort of this size, using modern, sensitive, research techniques. This work identified platelet and coagulation defects in stable, well-managed WM patients, which were exacerbated by BTKi therapy or inclusion of IgM paraprotein. These defects may underpin bleeding in symptomatic WM patients. Monitoring of platelet and coagulation properties using multivariate analyses may help stratify patients for bleeding risk and personalise treatments accordingly.
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Towards understanding and targeting the Plasmodium falciparum CoA biosynthesis pathway
(2026) Liu, Xiangning
Pantothenate, a precursor of the fundamental enzyme cofactor coenzyme A (CoA), is an essential nutrient for the intraerythrocytic stage of the human malaria parasite Plasmodium falciparum. P. falciparum has been shown to be capable of de novo synthesis of CoA from pantothenate via a five-step universal pathway. Pantothenate kinase (PanK) catalyses the first step of the CoA biosynthesis, which has been suggested to determine the rate of CoA biosynthesis in many organisms. In contrast, the phosphopantothenoylcysteine synthetase (PPCS)-mediated step has been proposed as the flux control step of the parasite CoA biosynthesis. P. falciparum expresses two PanKs, PfPanK1 and PfPanK2, which assemble into a unique heteromeric complex with a potential regulatory protein, Pf14-3-3I. Similarly, the parasite expresses two putative PfPPCSs, PfPPCS1 and PfPPCS2, neither of which have been characterised. Site-directed mutagenesis of key residues in PfPanK1 and PfPanK2 predicted to be involved in active site stabilisation was performed. Bioinformatic and mutagenesis studies revealed that the heteromeric PfPanK complex only possesses one functional active site. A parasite line that allows inducible knockdown of PfPanK2 was generated and PfPanK2 was found to be essential for normal intraerythrocytic proliferation of P. falciparum. Mass spectrometry analyses of phospho-peptide enriched, immunoprecipitated PfPanK samples revealed phosphorylation sites in PfPanK1 and PfPanK2 that were additional to the previously reported sites. Mutagenesis of four predicted Pf14-3-3I binding sites in PfPanK1 significantly reduced the amount of Pf14-3-3I bound to the PfPanK complex, with S334 being the most likely binding site. Heterologous expression of the PfPanK complex was attempted using the insect cell protein expression system. Although some of the expressed components aggregated, enough remained soluble, naturally formed the complex in situ and, crucially, when purified, the complex was functional. Further, results from both the heterologous expression and P. falciparum mutagenesis studies suggest that Pf14-3-3I may be non-essential for PfPanK activity. To investigate the two putative PfPPCSs, transgenic parasites overexpressing a green fluorescent protein tagged PfPPCS1 or PfPPCS2 were generated. Results from western blots, fluorescence-coupled size exclusion chromatography and mass spectrometry revealed that the two PfPPCSs associate into a single, functional PPCS heteromer that, unlike any other eukaryotic PPCS reported to date, is unable to use ATP for activity. Bioinformatic analyses uncovered a prokaryote-like helical component of PfPPCS as important for the nucleotide specificity and potentially holding the key for its stringency for CTP. Moreover, it was found that the complex is the target of multiple antiplasmodial pantothenate analogues and may interact with other pantothenate analogues that target different steps in CoA biosynthesis/utilisation. Isoxazole or thiazole substitution of the labile amide bond in pantothenamides (PanAms) led to identification of several novel PanAm-mimics with sub-micromolar potency against intraerythrocytic stage P. falciparum and were non-cytotoxic to mammalian cells. Kinetic studies identified the selected compounds as substrates of the human PanK3 enzyme, but with much lower affinity compared to that of pantothenate. Computational modelling showed that minor modifications can significantly influence the optimal side chain-configurations and the biological activity. This study has advanced our knowledge of the heteromeric PfPanK complex, marked the identification of the first heteromeric PPCS complex and contributed to a better understanding of the parasite CoA biosynthesis. This study offers new opportunities for designing inhibitors that exploit the unique features of the PfPPCS complex, and hopefully, may expedite the identification of new drugs targeting P. falciparum pantothenate utilisation.
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"too notorious to be denied": The Murdering Gully Massacre(s)
(2026) Nevalainen, Alycia
On 1 November 1839, Charles Sievwright reported that an Aboriginal named "Tainneague" had told him up to thirty Aboriginal people had been killed in a "massacre" that involved "Hamilton, Taylor and Broomfield". Seven other Aboriginal people would provide similar accounts. Eight weeks later, Sievwright arrived at the massacre site to find Taylor had fled, and local colonists provided depositions that were "more of an exculpatory than inculpatory character". Despite Taylor being involved in numerous other violent incidents against Aboriginal people, he was seemingly lauded by colonial society rather than shunned for his crimes. He was twice appointed a Magistrate and nominated into the Melbourne Club by the former Chief Commissioner of Police and President of the Legislative Council. Arriving in Australia from what appears to have been a relatively poor family, he died a "gentleman" ensconced in the wealth he amassed from pastoral pursuits. While the Australian historical narrative now explicitly acknowledges frontier conflict, as this study only located detailed and contextualised accounts for two per cent of the massacres reputed to have occurred, it remains an under-researched component of our nation's history. Accounts of massacres are also mostly presented as contextless vignettes in which victims (and perpetrators) lack any humanising details and which, consequently, provide minimal insight into the colonial process and the lived experiences of those directly involved in them. While such an approach has been successful in demonstrating the extent of frontier conflict, it has facilitated a narrative where massacres appear as isolated events, anomalies in an otherwise peaceful colonisation. Further, as with most histories of colonising nations, colonist-authors of massacres have mostly spoken over Aboriginal people rather than carefully listening to their words. Indeed, in the instance of the Murdering Gully massacre, disregarding what the victims told about the incident has resulted in the truth of what happened essentially remaining hidden in plain sight for almost two hundred years. As Australia heads into an age of "truth-telling" about our complicated past, what accounts will be used to tell this "truth"? Will it be those that are essentially "a story twice written on the same manuscript"? Rather than "talking over" the victims of the massacre, which has often characterised colonist-created histories of colonising nations, this study sought to privilege the Aboriginal voice. While this was complicated by being unable to locate anyone who identified as belonging to the Jarcoort nation who were recorded as those involved in the massacre, postcolonial methods were employed, such as privileging the Aboriginal accounts of the incident and stripping the colonial ideologies embedded in colonist accounts of the victims. Using such postcolonial methodologies provided access to the Jarcoort voice, which revealed previously unrecognised details about the massacre which enabled the creation of an in-depth and contextualised microhistory of the incident. Further, the resultant narrative expands what is known of the everyday realities of Aboriginal people and the colonists, as well as the colonisation of south-east Australia. For instance, contrasting the belief that massacres were anomalies in an otherwise peaceful colonisation, the Murdering Gully massacre was one of a series of escalating incidents between the Jarcoort and the colonists. Consequently, this thesis argues that taking a postcolonial microhistorical approach enables the development of an in-depth contextualised account of the Murdering Gully massacre, which provides significant insight into the everyday lived experiences of Aboriginal people and colonists during the colonisation of Australia.
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The nutritional ecology of the Zanzibar red colobus (Piliocolobus kirkii) within modified habitats
(2026) Semmler, Sofie
As primate habitats are being continually altered by human activity, animals need to adapt in various ways in order to survive. This is particularly true for folivorous primates as modified landscapes usually results in directly affecting their food resources. With disturbed habitats comes an increased number of introduced plant species. These exotic plants most often contain unfamiliar secondary compounds that can be potentially harmful when ingested. There is currently little work that investigates how living in a modified environment impacts the dietary ecology of folivores, which is vital when implementing conservation strategies to ensure their survival. This study focuses on four groups of endangered Zanzibar red colobus monkeys (Piliocolobus kirkii) that live in a variety of anthropogenically modified habitats in the Jozani Chwaka-Bay National Park & Biosphere Reserve, Zanzibar. One group resided in the southern part of the National Park, utilising heavily disturbed regenerated edge forest and the surround shambas (farmlands). Three other groups deeper in the forest were also followed, whose habitat disturbance levels ranged from low to moderate. Within these environments, some groups have adopted the unusual behaviour of consuming charcoal, which is thought to serve as a detoxification agent by adsorbing harmful phenolic compounds found in many of these introduced plant species. By comparing data on different habitats, behaviours, diets and the chemical constituents of food plants, a better understanding of how these folivores have adapted to cope with modified environments, will be gained. Results indicate that habitats, behaviours, diets and feeding strategies have changed since research was conducted in the area by Mturi (1991) and Siex (2003). Overall, the shamba group had a larger home range, a broader dietary diversity containing more exotic plant species and consumed charcoal most frequently, compared to the forest groups. Nutritional analysis of samples from each groups diet, indicated that the ZRC food items differed greatly in levels of important constituents; with the overall nutritional profile of samples from one group being higher in protein, while that of the other groups excelled in energy, minerals or was relatively balanced. Habitat disturbance levels did not coincide with the nutritional fingerprints of the samples analysed. This study elucidates how the ZRC are using their habitats when exposed to modified habitats along with how better conservation strategies can be implemented to benefit this endemic species.
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Feeding your guests: The role of putative amino acid transporters UMAMIT in symbiotic root nodulation in the model legume Medicago truncatula
Winning, Courtney
This thesis investigates the role of UMAMIT Nodulins (UTNs) in the symbiotic relationship between legumes and rhizobia, which are necessary for symbiotic nitrogen fixation. This symbiotic relationship involves the plant providing nutrients to the bacteria, with amino acids being a potential source of nitrogen. However, the specific genes responsible for transporting these amino acids were not known. I identified eight UTN genes specifically expressed during nodulation of Medicago truncatula. Phylogenetic analysis grouped UTNs into two clades within the UMAMIT family, with UTN1 and UTN2 falling in clade I and UTNs3-8 clustering in a legume-sequence rich clade III with additional nodulin like expression, suggesting their function is conserved across different legume species. To investigate the role of these UTNs, I generated triple mutant knockout lines, targeting UTNs 1, 2, and 6. These mutant plants did not show significant differences in nodule number compared to wild-type plants, suggesting that these UTNs are not essential for the initial formation of nodules. However, the mutants displayed a reduced amount of pink leghemoglobin containing nodules at 14 days post inoculation, and showed changes in starch accumulation patterns, indicating impaired nitrogen fixation in the mature nodules. Promoter:GUS fusion analysis revealed distinct and overlapping expression patterns for different UTNs, suggesting a potential role in supporting rhizobia in the infection zones, and, later, the nitrogen fixation zone. Specifically, UTN1 expression was localized to nodulation zone II and the interzone. UTN2 was expressed in multiple tissues, including zone II, the interzone, zone III and the nodule vascular traces. UTN6 was primarily expressed in infected cells in zone III and the nodule endoderm. Antibodies were raised against a 13 amino acid epitope from the C-terminal region of UTN2. Western blotting studies verified that UTN2 was a nodulin. Immunofluorescence studies on nodule tissue sections revealed that the UTN2 protein localised to multiple membranes within the mature nodule, specifically the symbiosome membrane of infected cells, the cell periphery of non-infected cells, and the periphery of multiple cell types in root vascular bundles of nodules, including those immediately adjacent to the xylem vessels. The localization pattern of UTN2 to the symbiosome membrane suggests a direct role for this protein in facilitating nutrient exchange between the plant and rhizobia at the symbiotic interface. The presence of UTN2 in nodule vascular bundles supported a role for this protein in amino acid transport from, and, potentially, to the nodule. This is the first investigation of a symbiosome localised UTN. The stains and materials generated in this thesis represent new tools to investigate host-symbiont dependencies. The results also indicate that the substrates transported by UTNs1 2 and 6 are likely to be necessary for rhizobia to establish a normal metabolism in root nodules.
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Explaining China's Financial Policy Interests: Discursive Contestation, Economic Crisis, and Policy Change (1988-2020)
(2025) He, WENTING
From the late 1980s to 2020, China's financial reform has followed a slow and fragmented path. Plans for financial liberalisation were varyingly constrained, postponed, or reversed, especially during times of economic crises. What explains China's financial policy interests from the late 1980s, and how have economic crises influenced those interests? Conventional analyses typically point to the structural effect of the distribution of state capabilities, domestic coalitional struggles, or prevailing ideas on state interests, where crises are exogenous shocks that disrupt and reconfigure structures. While these analyses offer useful insights into structural constraints, they nevertheless underrate actors' agency to think, speak, and act beyond those constraints, enabled by the intersubjective nature of international politics. They overlook how actors can strategically contest and reconstruct the meanings of ongoing events, including economic crises, through ongoing discursive interaction. Addressing the oversight, this thesis develops a theoretical framework for the discursive construction of state interests across periods of stability and crisis, one that takes both structural constraints and agency seriously. Through this theoretical lens, this thesis examines how China's financial policy interests have been discursively constructed from the late 1980s, with a focus on four major economic crises: the late-1980s inflation crisis, the 1997 Asian Financial Crisis, the 2008 Global Financial Crisis, and the 2015 stock market crash. It argues that China's financial policy interests are shaped by ongoing discursive contestations, particularly during crises, over how the financial market should serve the party-state's goals. First, China's financial policy interests are subject to discursive contestations among domestic stakeholders over how the financial market operates, particularly in relation to the lessons learned from economic crises. Second, these interests have been influenced by China's distinct and enduring conception of state-market relations, which views the market as a tool to advance the state's political objectives. To offer deeper insights into this conception, this thesis further traces China's historical understanding of state-market relations from the Warring States period to the late Qing dynasty over a span of more than 2,000 years, suggesting that this conception was historically developed, deeply rooted in China's economic thought, and has provided a structural context in which contemporary China's financial policy debates occur. Taken as a whole, China's financial policy interests are contingent on the dynamic interplay between structural contexts and actors' strategic efforts to interpret, navigate, and reshape them through discursive interactions.
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Materiality, Re-Enchantment, and the Spiritual Imagination in Shakespearean Romance
(2025) Taylor, Barbara
In the final years of his professional life, William Shakespeare's drama entered the period we now refer to as his "late romances," plays in which the supernatural world hovers at the edges of all action, and the lines between tragedy and comedy blur. These plays, written and first performed between 1608-1613, pushed the limits of what was considered stageable and believable in the early modern playhouse. In doing so, this collection of plays responded to a post-Reformation crisis of the spiritual imagination--what to believe, and how to conceive of it--through creative experiments in "enchantment". This thesis argues that these plays amount to a seventeenth-century project of "re-enchantment," and seeks to amend teleological accounts of "the disenchantment of the world" by suggesting that creative resistance to disenchantment was already in progress in the early seventeenth century. Far from being immaterial fantasy, the plays under consideration in this thesis--Pericles, Cymbeline, The Winter's Tale, The Tempest, Henry VIII (All Is True), and The Two Noble Kinsmen--each materialise post-Reformation spiritual dilemmas in performance, bringing to the forefront drama's potential to make visible the otherwise invisible facets of spiritual crisis: contested spaces like Purgatory, the vitality of objects such as relics, and the embodied experience of prophecy. By combining theoretical approaches from areas of ecocriticism, materialism, and affect theory, I explore how the material spaces, objects, and bodies in these texts engage with early modern spiritual dilemmas. Across three case studies, I undertake close readings of theatrical texts in pairs, paying attention to their original performance conditions, and placing them in conversation with each other as well as contemporaneous theological, political, and imaginative writing of the period. In the first case study, I position the oceanic spaces of Pericles and The Tempest as experimental navigations of an alternative Purgatory. In the second, I trace the stage lives of theatrical props in Cymbeline and All Is True as desacralized relics. In the third and final case study, I consider the implications of embodying and producing prophecy in The Winter's Tale and The Two Noble Kinsmen. Together, these case studies test my theory of "the dramaturgy of enchantment," to suggest that re-enchantment is an integral part of these plays' literary construction and reception, with the capacity to induce wonder, awe, terror, and pleasure in the audience. Enchantment is thus positioned as an ambivalent cultural mood; one that can accelerate the decay of damaged sites of spiritual fulfilment, or work to repair them.
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Prototyping Proactive Responsible AI Practices
(2025) Ruster, Lorenn
As Artificial Intelligence (AI) rapidly expands across industries, bringing potential and actual harms, the need for responsible AI practices grows increasingly urgent. Yet beyond legal and regulatory compliance, what responsible AI practices are and how to enact them remains elusive. This thesis asks: How can entrepreneurial organisations, committed to responsible AI, enact proactive responsibility? And what might this mean for the future of responsible AI as a field of study and practice? I explored these questions through design intervention research with five entrepreneurial organisations committed to responsible practice. Grounded in pragmatism, the research engaged with three sub-questions of interest: how to get started with responsible AI in practice, how to embed a commitment to human-centred values, and how to sustain responsible AI efforts over time. Three prototypes emerged: a responsible AI pledge-making process, a Dignity Lens for AI development and integrated reflective practices. Using five theoretical lenses - cybernetic awareness, systems thinking, affordances, dignity, and responsibility - the prototypes produced and reflected upon advance the field of responsible AI in several ways. First, the thesis asserts that protective responsibility orientations are necessary but insufficient in responsible AI, and demonstrates a complementary approach: proactive responsible AI practices. Second, the thesis establishes systems-informed pledge-making as an alternative pathway to principles-only frameworks. Third, it extends the set of values operationalised in AI development beyond usual principles - fairness, accuracy, transparency, privacy - to include human-centred values, like dignity. Fourth, it critiques the gap-bridge metaphor that is commonly used to describe the relationship between responsible AI principles and practices through evidence of integrated, non-linear, values-dynamic relations; different metaphors such as a hive or jazz duet are offered as starting point alternatives. Finally, the thesis exemplifies how entrepreneurial organisations can actively engage in responsible AI through small-scale projects and decisions. Together, these contributions expand and challenge prevailing perspectives on responsible AI, offering practical guidance for AI developers, managers and leaders, as well as new insights for scholars studying technological transformation. Overall, this transdisciplinary, engaged scholarship delivers theoretical, methodological, and practical contributions that extend beyond academia. Theoretically, the thesis reconfigures how we understand and practice responsible AI. Methodologically, the work shows how to conduct design intervention research in responsible AI contexts. Practically, the prototypes deliver tangible value for practitioners and the broader field. For example, the Dignity Lens represents a first-in-kind implementable framework that assists practitioners to operationalise dignity throughout the AI development process, and is currently embedded into the operations of a seven-person data science team, demonstrating impact beyond the life of the thesis. How to do responsible AI in practice is far from settled. While current approaches offer partial solutions, this thesis "researches into being" new practices, broadening what is possible in responsible AI.
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Beyond Borders: A Craniometric Exploration of Population Affinities and Individual Ancestries in the Nile Valley during the Early to Mid-Second Millennium BCE.
(2025) Clark, Bonnie
Using craniometric analysis against a contextualised backdrop, this thesis examines interpopulation affinity and intrapopulation diversity of the Nubian and Egyptian Nile Valley during the first half of the second millennium BCE (c.2000-1500 BCE). This time is characterised by intense interactions between Egyptians and Nubians, and provides artistic, textual, and archaeological evidence of heightened relationships with people from outlying regions. Previous quantitative and qualitative cranial and dental studies of Egyptian and Nubian groups have found anomalies or variation during this time, but often lack contextualised explanations or are confined by their biocultural, temporal, or spatial scope. Few consider the individuals within the populations. This thesis not only establishes the origins and relatedness of Nilotic groups within a discrete but dynamic period, but also draws upon regional and global samples to investigate relationships between populations, as well as the individual outliers concealed within. By layering a combination of statistical tests over multiple scenarios, biological relationships which mirror cultural and geographical borders are revealed. However, the populations of the Nile Valley are also closely intertwined. Inconsistencies that arise within the samples used both challenge and support previous findings, yet correlate with historically documented events. Despite general homogeneity of the Nilotic groups, both admixed and foreign (non-Nilotic) individuals are detected and their ancestral origins investigated. Through this approach, this thesis contributes to current understandings of population dynamics within Egypt, Nubia, and neighbouring regions, and reveals implications for broadening discourse on mobility, migration, and estimation of ancestry during the first half of the second millennium BCE.
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Summary jurisprudence in unsettled Places: culture, 'miscognition' and sentencing law.
(2025) Spiers Williams, Mary
Summary courts of jurisdiction in central Australia 'miscognise' culture by not recognising that the everyday practices of settler Australians are cultural practices. This has implications for sentencing law: settler Australian cultural practices are transformed into norms, against which those who have 'distinctive' (different from settler) cultural practices are judged. The racialised logics of this process affect the interpretation of the material presented in the sentencing hearing. A typical approach of sentencing courts is to associate the cause of criminality with a defendant's departure from western social practices that have become normalised in Australia. This becomes problematic for desert peoples, where their everyday practices are distinctive from that of the settler Australian norm. This can result in distinctive cultural practices being mistaken as the underlying cause of criminality, leading to the stigmatisation of desert peoples' cultural and legal practices - which occurred in several of the case studies presented in this dissertation. One consequence of this stigmatisation, which I witnessed in my research, was that defence lawyers tended not to make submissions that suggested that their clients engaged in distinctive cultural practices, and legal actors conducted their cases as if they had little insight into their client's distinctive ways of being. One effect of this was that valued cultural practices, legal philosophies and associated practices had no influence on sentencing court jurisprudence. This undermined a purported value of the common law (including sentencing law) - its responsiveness to its cultural and normative context. This dissertation explores the implications of this misrepresentation - or 'miscognition' - for the jurisprudence that these courts produce. Exploring the everyday practices of the courts, which harden problematic 'common sense' into legal concepts, reveals not only the privileging of western cultural practices in some cases. In their everyday production of jurisprudence, the observed summary courts were affected by the underlying settler perspective of entitlement to dominate this place. Legal representatives typically avoided critiquing the contribution colonialism may have made to criminality. Case studies include; one instance of a magistrate (and appeal court justice) in effect decriminalising coloniser-settler practices that the Northern Territory Parliament had impugned; other instances of magistrates asserting a settler monopoly over the legal field and denouncing Aboriginal law and the desert people who asserted its legitimacy, effectiveness and ongoing relevance; other instances in which the court appeared uninterested in identifying and addressing the more complex underlying causes of crime; and in a series of interrelated cases, magistrates exhorted desistance of Aboriginal legal and cultural practices that are socially constructive for desert people. In its pursuit of this colonialist objective, the court risked abrogating its responsibility for its own traditions - that is, to uphold the rule of law - and risked transgressing the civil rights that justify the existence of the criminal court in the Anglophone system of governance.
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Abortion against State and Church: Refusing Reproduction in a Legally Restricted Context
(2025) Koralewska, Inga
In the last decade, Poland has witnessed the rapid rise of an abortion liberation movement formed in response to the Catholic nationalist far right and its efforts to restrict reproductive rights. The movement began with mass street protests against Catholic nationalism and evolved into an ecology of organisations centred around Abortion Support Groups (ASGs) that help Polish women to obtain abortions through extra-legal means. Advancing critical feminist scholarship and inspired by Gramscian theories of power, this thesis investigates the possibilities of social change in a context where formal political channels of reform are blocked. It argues that the emergent abortion liberation movement has brought about profound change in the area of informal politics, even though it has so far failed to affect restrictive abortion laws or prevent their further tightening. The movement's counterhegemonic project challenges the longstanding alliance between the Polish state and the Catholic Church and has successfully shifted the stigmatising views of abortion that had permeated the Polish public sphere since the 1990s. This, it is argued, has led to the effective social decriminalisation of abortion even while anti-abortion laws remain in place. In advancing this argument, the thesis engages in critical discussion with Marxist and Left Accelerationist thinkers who claim that contemporary social movements against capitalism have largely failed in their attempts to effect lasting change. The thesis questions why these theorists routinely omit discussion of abortion liberation movements and argues that the omission reflects a serious oversight in their understanding of both capitalism and the possibilities of anti-capitalist resistance. By insisting on the inclusion of the sphere of reproduction in the understanding of what constitutes capitalism, this thesis approaches struggles over reproductive rights as profoundly connected to anti-capitalist resistance. This thesis employs qualitative research methods, drawing upon three sources, i) in-depth interviews with ASG activists and women who have used their services, ii) ASG websites and social media profiles, and iii) media and non-governmental reports on anti-Church protests. By investigating the possibilities of informal political power, the thesis contributes to recent debates about resistance on the left and to critical feminist work on abortion, social movements and reproductive justice.
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Bimetallic complexes of an unsymmetrical, dinucleating pyrazole-derived pincer ligand
(2025) Ngwenya, Vuyelwa
In this work, we describe the systematic synthesis and characterisation of homo- and heterobimetallic complexes of an unsymmetrical, dinucleating ligand. The pyrazole moiety of the ligand has a proton responsive NH that can be deprotonated by base therefore allowing for the stepwise synthesis of bimetallic complexes. The unsymmetrical nature of the ligand also allowed for a novel study into the pocket switching of metals in the different pockets. These complexes were all investigated as potential catalysts in transfer hydrogenation. Chapter 2: Synthesis and characterisation of homometallic nickel complexes of PNNNNH ligand are reported and their reactivity explored. The redox properties of the mononickel complex in acetonitrile indicated two quasi-reversible reduction events, while the electrochemical profile of the dinickel complex in DMF indicated multiple redox events in its CV. The insolubility of these complexes particularly the dinickel complex prompted a co-ligand study in which the chloride ligands were substituted for nitrates and sulphates, but these led to the formation of trinickel bis-chelated complexes. These complexes were also investigated for their potential as electrocatalysts for proton reduction. Chapter 3: The first examples of Ni-based heterobimetallic complexes are reported using the PNNNNH ligand. The proton-responsive nature of the pyrazole ligand core allows for the stepwise synthesis of heterobimetallic complexes via the monometallic nickel and ruthenium complexes. Although selectivity for the PNN pincer pocket is observed with Ni, the complexation to the bidentate NN-pocket is favoured with more sterically encumbered Ru complexes. The identification of the first dinuclear NiFe complex of the PNNNN systems was characterised by X-ray crystallography, but unfortunately a bulk product was never isolated. When the Ru analogues were used, soluble diamagnetic complexes were obtained. Although the two Ru precursors used in this study are closely related, they both gave different NiRu structures with the former leading to a NiRu complex with a bridging Cl ligand while the later gave a NiRu complex with no bridging ligand. Chapter 4: A novel study of pocket switching is explored in this chapter. In Chapter 3, it was illustrated that Ru preferentially binds to the NN pocket rather than the PNN pocket, a process that could be led by steric and kinetic control. Coordination of Ru to the PNN site could be achieved thermally using high temperatures. Two mono RuPNN complexes were synthesised and served as precursors to pocket-switched heterobimetallic RuPNN,NiNN complexes. The pocket switched RuNi complexes were found to be more air- and moisture-stable compared to the NiRu complexes. Chapter 5: In this chapter, we explored the reactivity of the homometallic and heterobimetallic complexes in transfer hydrogenation. The homometallic nickel complexes were ineffective in catalysis even in the presence of a diboron activator. The mono RuNN complex only showed 44% conversion of benzophenone after 24 hrs. However, the mono RuPNN complexes showed over 95% conversion within 2 hrs. Notably, when Ni was added, more than 2-fold reduction in conversion was observed for the heterobimetallic complexes. This suggests Ru is the catalytically active site and is most effective when it is coordinated in the pincer pocket.
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A Multicentre Study of Staging and Prognosis in Head & Neck Cutaneous Squamous Cell Carcinoma with Lymph Node Metastases
(2025) Ebrahimi, Ardalan
An accurate staging system is essential for all cancers with risk stratification guiding treatment decisions and allowing clinicians to counsel patients. The standard staging system used worldwide is the Tumour, Node, Metastasis (TNM) staging system developed by the American Joint Committee on Cancer (AJCC). The TNM stage for HNcSCC with nodal metastases is based on the pathological lymph node (pN) classification used for mucosal head and neck cancers. In the 8th edition Staging Manual published in 2017, the AJCC introduced extranodal extension (ENE) to the pN classification, upstaging patients with ENE to either pN2a or pN3b categories and therefore TNM Stage IV. Despite the intuitive appeal of introducing ENE into the staging system given it is a well-accepted prognostic factor in head and neck cancer, several Australian studies comparing the prognostic performance of the 7th and 8th edition TNM systems in patients with HNcSCC with lymph node metastases found the 8th edition system had very low predictive power. These findings highlighted the need to develop a nodal staging system specific to HNcSCC and prompted the current PhD thesis. We aimed to: 1) critically assess the prognostic performance of the 8th edition AJCC staging system using objective statistical measures of model performance; 2) to compare the performance of the 8th edition TNM staging system with several previously published alternative staging systems (N1S3 and ITEM) designed specifically to predict disease-specific survival in patients with HNcSCC with nodal metastases; 3) to define important prognostic factors in HNcSCC with nodal metastases, with a focus on analysing issues relevant to staging and prognosis to inform future revisions of the HNcSCC staging. The thesis was based on a retrospective cohort of 1309 patients with HNcSCC with metastases to parotid and/or cervical nodes, treated between 1980-2017 with curative intent surgery +/- adjuvant radiotherapy, with a median follow-up of 3.2 years. We showed based on objective statistical measures that the TNM staging performs poorly and violates all the characteristics of an ideal staging system with poor balance between groups, low predictive power and lack of monotonicity, hazard discrimination and hazard consistency. Perhaps the most important findings relate to ENE which was present far more frequently in HNcSCC than mucosal cancers. We demonstrated that the AJCC system ascribes excessive weight to ENE and results in the vast majority of patients being inappropriately classified as TNM Stage IV despite many having an excellent prognosis. Importantly, we demonstrated that additional information on the number of nodal metastases as a categorical variable with 1-2, 3-4 and >=5 nodes should be included in the staging system. Another key finding was that immunosuppression is an independent strong adverse prognostic factor irrespective of the cause and merits incorporation into the prognostic stage groups of the TNM. Finally, perineural invasion was consistently associated with reduced survival and we recommend consideration of adding clinical perineural invasion into the staging system. Our analysis of the influence of the primary tumour (T stage) in the presence of nodal metastases cast doubt on its prognostic value in this context and suggests a re-evaluation is required. Finally, we were the first group to examine determinants of distant metastatic failure in HNcSCC and developed a simple intuitive distant metastasis risk score that stratified risk of distant metastatic failure well and may prove useful in clinical decision making. This thesis has established the need for major changes to the nodal staging system for HNcSCC and provides insights on important prognostic factors to help guide this process. We hope that a system specific to HNcSCC can be developed and validated that reflects its distinct tumour biology and provides clinicians with a more accurate tool to risk stratify patients.

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