Restricted Theses

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Evolutionary-based protein engineering of binding proteins and enzymes
(2026) Georgelin, Rosemary
The work in this thesis applies evolution-guided protein engineering to understand and design protein function. Ancestral sequence reconstruction, biophysical and enzymatic characterisation, and structural analysis are used to reveal mechanisms of molecular evolution that shape specificity and catalysis and how these mechanisms can be used to uncover new functionality in engineered proteins and enzymes, highlighting the broad applicability of these methods across diverse systems. Chapter 1 provides the conceptual framework for protein design and an overview of the key evolutionary methods used throughout the thesis. Chapter 2 examines the evolution of ligand binding from a thermodynamic perspective, using thermodynamics as a language to describe changes in affinity, specificity, and binding energetics over evolutionary time. This chapter also serves as an extended introduction to the included research articles. The first research article presents a comprehensive characterisation of ancestrally reconstructed LacI/GalR family transcription factors and shows that changes in binding specificity along the evolutionary trajectory of Escherichia coli LacI are driven by enthalpy-entropy trade-offs in response to environmental pressures, including temperature. In the most distant ancestor, binding is entropically driven via entropic redistribution and retained flexibility, highlighting the role of protein dynamics in the evolution of ligand specificity. These concepts are further developed in the published review article included in this chapter. Chapter 3 demonstrates how evolution-guided design can be used to engineer enzymes with novel catalytic functions, including biocatalysts for degradation and recycling of plastics, specifically polyethylene terephthalate (PET), nylon 6 and nylon 6,6. The first research article reconstructs evolutionary sequence space from PET-degrading cutinases to identify functional variants and reveal convergence among PET lineages. The second research article applies a similar strategy to evolve nylon 6,6 oligomer-degrading enzymes from serine-protease nylonases, discovering a novel class of nylon 6,6 hydrolases. Structural analysis shows this specificity shift arises from epistatic active-site mutations that enable favourable electrostatic interactions and improved complementarity of binding site size and shape. Chapter 4 synthesises these findings into a general discussion of key ideas and considers future directions in protein engineering, including the growing role of computational protein design in linking protein genotype and phenotype.
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Cellular and immunological consequences arising from impaired L-plastin function
(2026) Hernandez Gallardo, Raquel
Inborn errors of immunity (IEI) are genetic disorders affecting the immune system. Their disease burden is complex, with increased susceptibility to infections, autoimmunity, allergies, and malignancies. In this project, we studied a family presenting with an IEI resulting from a novel LCP1 variant (LCP1c.740-1G>A). Lymphopenia, neutropenia, and thrombocytopenia were reported in the affected individuals, spanning at least two generations. Whole-exome analysis revealed a mutation in the LCP1 gene affecting the splicing site upstream of exon eight. LCP1 encodes for L-plastin, a cytoskeleton protein predominantly expressed in leukocytes. Its actin-bundling activity is central to the immune response, particularly during integrin-mediated events, such as migration and the establishment of the immune synapse. The LCP1c.740-1G>A variant leads to two aberrant transcripts, both predicted to affect protein integrity: an in-frame deletion of 24 nucleotides; and a whole exon eight deletion resulting in a frameshift and the introduction of an early stop codon. We conducted further protein and cellular analysis using a mouse model expressing the orthologous variant. Expression of the small in-frame deletion transcript, and the reduction of protein synthesis were confirmed using mouse splenocytes. The mouse model exhibited a similar haematopoietic phenotype to patients. Circulating lymphocytes were proportionally decreased in Lcp1c.740-1G>A mice. T cells exhibited aberrant cytoskeleton organisation and impaired chemotaxis after CXCL12 stimulation. Similarly, the spreading capacity of platelets was reduced upon activation with collagen. By immunisation of the mouse model with sheep red blood cells, we confirmed impairments in the germinal centre reaction. We also generated a mouse model expressing the Lcp1c.694A>T variant, previously reported to cause human neutropenia, and observed a similar but more severe defect in response to immunisation. Significantly, we did not observe an immunisation defect in Lcp1-/- mice. In vitro T cell proliferation confirmed a decrease in cell proliferation for the three mouse models. However, the Lcp1c.740-1G>A and Lcp1c.694A>T variants selectively resulted in an accumulation of large cells with abnormally increased DNA content, as identified by flow cytometry analysis. We confirmed a gene-dose dependent accumulation of polyploid cells by microscopy, indicating a cytoskeleton defect in completing cytokinesis in the presence of abnormal forms of L-plastin, but not by the absence of it (Lcp1-/-). Finally, we performed transcriptome analysis of proliferating cells expressing Lcp1c.694A>T/c.694A>T and identified a signature of aberrant cell cycle progression and upregulation of inflammatory signals. In summary, LCP1 deficiency leads to a novel IEI arising from cytoskeleton defects, including a previously uncharacterized mechanism during cytokinesis.
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An Appetite for Aguaje: Harnessing Sustainability for Social, Economic, and Environmental Transformation in the Peruvian Amazon
(2026) Tung, Diana
The aguaje (Mauritia flexuosa) is one of the most significant palm species in the Amazon. Every part of the palm is utilised by Amazonian residents, and widespread commercialisation of the fruit in the Peruvian Amazon has rendered it an important part of economic life in this region. Unlike other areas in the Amazon where the aguaje grows, in the Peruvian Amazon, the aguaje reigns supreme as a foodstuff and as a key marker of Amazonian identity. The fruit is commercialised in a dizzying array of forms and consumed with voracity by local residents, as measured by the tonnage. The fruit is also at the centre of numerous mythologies, including that the fruit enhances women's curves and libido, tempers the effects of menopause, and can turn straight men gay if they consume too much of it. Based on 24 months of multi-sited ethnographic fieldwork in the Peruvian Amazon and other cities throughout Peru, this thesis examines how in recent years the aguaje has emerged as a contender for the global superfood market by tracing its transformations along the commodity chain. In particular, this thesis traces how multiple efforts to commercialise the aguaje for external markets, in Lima and internationally, are couched in the language of sustainability and environmental conservation, and which rely upon a narrow perspective of the Amazon as natural, wild, and fixed in time. In turn, these projects promulgate wide-ranging social, economic, and environmental transformations that radically reshape people, place, and palm. These processes of translation have only become even more accelerated in the post-Covid-19 context, especially in a nation which experienced some of the highest Covid-19 mortality rates in the world. As this thesis demonstrates, 'sustainability' in an age of planetary climate crisis may not only accentuate existing social and economic inequalities but create new forms of marginality. Amazonian residents overwhelmingly prefer their aguaje 'duro duro', a local expression literally translated as 'hard hard'. Throughout this thesis, instead of presupposing agency of the fruit, this idiomatic expression is utilised to capture the difficult, stubborn, and salacious sociomateriality of the aguaje, and which characterise the turbulent attempts to commercialise the aguaje thus far. The thesis this examines how, in interactions with different actors, such as harvesters, street vendors, government officials, entrepreneurs, multinational corporations, as well as conservationists, aguaje commercialisation undergoes different pathways as customary uses and meanings are stripped away and the fruit reshaped into an object of capitalist desire and planetary salvation. As an emerging commodity for the multi-billion-dollar global superfood market, tracing the aguaje's transformation is thus also an exercise in understanding how markets are made.
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Mobilising amidst Negotiated Repression: Islamist Opposition in Jokowi's Indonesia
(2026) Nuraniyah, Navhat
Islamist groups have posed a persistent challenge to the Indonesian state since independence, though for the most part, they remained politically sidelined. After democratisation in 1998, Islamist organisations grew in strength and sought to leverage their mobilising power to pressure successive governments to accommodate aspects of their aspirations. This pressure reached its peak in 2016 with the unprecedented Islamist mobilisation against Jakarta's non-Muslim governor, triggering a dramatic shift in state-Islamist relations, from toleration and accommodation to systematic repression. In the name of defending pluralism and democracy, President Joko Widodo (Jokowi) launched a crackdown on Islamist groups. The repression of Islamists has been one of the key dynamics driving Indonesia's democratic decline over the past few years. Islamists facilitated Jokowi's authoritarian learning by providing a testing ground for developing subtle coercive tools that preserved a democratic veneer, which I characterise as 'negotiated repression'. This thesis investigates the diverse strategies of Islamist opposition groups in response to state repression during Jokowi's presidency (2014-2024). Drawing on in-depth fieldwork with three major Islamist organisations, namely the Islamic Defenders Front (FPI), Hizbut Tahrir Indonesia (HTI), and Wahdah Islamiyah, I have categorised their strategies as 'open resistance', 'strategic engagement', and 'camouflaged resistance'. The strategic diversity is puzzling because, despite state crackdowns of varying intensity, all groups faced a general pattern of negotiated repression. Thus, the structural form of repression alone is inadequate to explain the variation. The thesis constructs an original analytical framework to explain how organisations navigate repressive environments in ways that reflect both structural constraints and internal priorities. It argues that Islamists' strategic choices hinge upon their organisational identity (encompassing ideological mission, method of change and practices) and institutional assets (e.g. schools, charity, businesses and social capital), while the execution of the strategies is constrained by ongoing interactions with the state. In this sense, identity and interests are mutually constitutive, and their interplay shapes Islamist strategy making. Once enacted, these strategic choices may evolve through a feedback loop, as Islamists adjust their tactics in tandem with state's responses. The study contributes to broader debates on sophisticated repression in semi-democracies, and on how dissenting civil society groups adapt to contexts of overpowering state control. Specifically, it advances Social Movement Theory (SMT) by introducing organisational identity as the variable that clarifies the interconnections among SMT's three components, namely movement's ideology, material resources, and political opportunity structure.
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The Kamapuk Fauna: A late Holocene vertebrate faunal sequence from the Western Highlands District, Papua New Guinea with implications for palaeoecology and archaeology
(1981) Aplin, Ken
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Deciphering the Musical Language of Nicolas Obouhow
(2017) Atri, Azadeh
Various styles and techniques of composition were experimented with and developed by avant-garde composers during the first decades of the 20th century. Nicolas Obouhow (1892-1954) plays a significant role as a composer who experimented, very early, with a 12-tone system and electronic sounds. His innovative ideas were not only a response to the Russian avant-garde movement, but were also part of the wider international quest for new means and techniques of composition. For Obouhow, art was a means to facilitate his mystical search, and his views on music place him in a broader international cultural context associated with the occult and a belief in the transcendental power of sound. Drawing from a wide range of primary sources, in particular the Obouhow Archive at the Bibliotheque Nationale de France, and contemporary newspapers and journals, I will firstly demonstrate how Obouhow's idiosyncratic ideas were formed and influenced by his spiritual beliefs and significant historical events such as the Russian Revolution and the First World War. Secondly, through examining his circle and important relationships, I will discuss how Obouhow's views were also in accord with the esoteric beliefs held by many others and how these views were part of a broader worldwide search for man's spiritual destiny. Finally, through detailed analysis of form, harmonic language, synthetic scale systems and orchestration, I will show how Obouhow contributed to the early decades of modernism and 12-tone writing.
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Nanostructured BaTiO3 Thin Films for Enhanced Photoresponse
(2026) Ji, Wenzhong
Light-driven devices are of great importance among emerging technologies such as artificial intelligence and quantum computing, owing to their remote-control ability, ultrafast response and low energy consumption. Ferroelectric materials have attracted considerable interest in this field. On the one hand, the bulk photovoltaic effect (BPV) allows spontaneous separation of photoexcited electron-hole pairs, simplifying device architectures. On the other hand, switchable polarization endows ferroelectric devices with memory and data processing functions. Despite these advantages, several challenges hinder practical implementation of traditional perovskite ferroelectrics, including the low photovoltage in thin films, slow response, limited absorption in the visible spectrum and substrate-dependent film growth. This thesis addresses these issues by exploring nanostructure engineering strategies using BaTiO3 (BTO) as a representative perovskite ferroelectric. The main achievements and outcomes are highlighted below. A record high photovoltage was achieved in a thin BTO film. Highly preferred-oriented BTO films were successfully grown on silicon substrates. The film exhibited a two-layer structure with different crystallographic orientations along the growth direction. This unique geometry enabled a high-power conversion efficiency (PCE) of 0.062% under ultraviolet light and a record open-circuit voltage of 1.07 V among pure ferroelectric films below 300 nm thickness. Systematic investigations attributed this enhancement to the BPV. This crystalline rearrangement strategy offers new insights into ferroelectric self-powered electronics demanding high driving voltage. A high-efficient, broadband, ultra-fast photodetector was demonstrated based on a three-dimensional BTO/SrRuO3 (SRO) heterostructure. The large mismatch strain at interfaces induced the formation of island-like SRO nanostructures. The crystalline and amorphous phases in the BTO layer were responsible for charge separation and transportation, respectively. In addition, the SRO with periodic nanostructured morphology effectively absorbed visible light. Consequently, the Au/BTO/SRO/Ag device had a responsivity of up to 0.166 A/W and fast rise/fall times of 3.7/4.7 microseconds. While SRO is widely used as a conductive electrode, this work demonstrated, for the first time, a synergetic photovoltaic process between BTO and SRO. Remarkably, the device performance surpasses that of reported self-powered photodetectors and is comparable to commercial photodetectors, highlighting the broad application potential of this stable and scalable metal oxide platform. Ferroelectric devices responsive to visible light were achieved by incorporating narrow-bandgap semiconductors into the ferroelectric matrix. BTO/CoFe2O4 (CFO) composite films with controllable composition were successfully synthesized. The transmission electron microscopy revealed a homogeneous structure, which has not been reported in perovskite/spinel material systems. Ferroelectricity was retained in a low-CFO-ratio composite, enabling polarization-dependent photocurrent under visible light. Utilizing visible-light-induced photocurrent as a readout signal offering a promising route toward energy-efficient ferroelectric memory and computing devices. Finally, the thickness-dependent charge separation mechanism in free-standing ferroelectric films was elucidated. Polycrystalline free-standing BTO films with lateral dimensions of hundreds of micrometers were fabricated. Kelvin probe force microscopy characterizations revealed a thickness-dependent surface charge behavior: in thinner films, near-surface band bending dominated charge separation, whereas in thicker films, ferroelectric polarization led to opposite carrier accumulation on the two surfaces. This newly identified mechanism provides guidance for exploring free-standing ferroelectrics in photocatalysis and advanced optoelectronic applications.
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Osseous Artefacts from later Prehistoric Southern Vietnam: A Technofunctional Analysis
(2026) Hull, Jennifer
Relatively large assemblages of osseous implements have been recovered from sites across Mainland and Island Southeast Asia. However, only a few detailed studies have been undertaken. The majority of studies thus far undertaken focussed on osseous implements from Late Pleistocene-Early Holocene contexts. These analyses have demonstrated that the technology can be traced back to at least 40,000 BP, and the abundance and diversity increases after the Terminal Pleistocene. These studies have also made a significant contribution to our understanding of human technological capabilities, as well as increased geographic distributions of bone tool manufacture, human mobility, and the evolving nature of their use across Southeast Asia. Much less well-understood is the continuing and expanding use of osseous raw materials for implement manufacture in the later Holocene, despite the availability of alternative technology. This project aims to begin addressing the deficiency in our understanding of the manufacture and use osseous technologies during the critical period in prehistory between c.4000-2500 BP with the arrival of agricultural communities and the emergence of metallurgy in Mainland Southeast Asia. What role did osseous implements have in varied toolkits during this period, how did osseous implements evolve through time, and what significance did these raw materials have for the manufacture of implements? To address these questions, technofunctional analyses were performed on osseous artefacts from five settlement sites in the Mekong Delta region of Southern Vietnam: the Neolithic sites of An Son (AS 4,000-3,200 BP), Loc Giang (LGi 3,900-3,200 BP), and Rach Nui (RN 3,430-3,050 BP), and the Metal Age sites of Go O Chua (GOC 3,000-1,250 BP) and Lo Gach (LG 2,800-2,700 BP). The main focus of the analysis to identify any preferences in raw material selection, manufacturing methods, and if these changed over time. The project also aimed to understand what, if any, social implications the development and use of this technology had. The study applied taxonomic comparisons to identify the osseous raw materials where possible. Following this, using reference materials, the manufacturing and use-wear traces were identified. As there are few standard practices for the analysis of osseous implements, this study also utilised several techniques originally designed for lithics analysis in an attempt to answer the research questions. During the Neolithic the assemblages analysed are comparably small to those of the Metal Age, and the variety of morphotypes are more limited. They consist primarily of pointed implements, with a high proportion of jabbing-style fish hooks (AS/LGi) and turtle shell adzes (RN). The variability between the assemblages at AS/LGi, and RN, suggests that there was preferential production for local requirements. An unexpected outcome of this research is that rather than osseous artefacts diminishing in significance with the introduction of metal implements, and metallurgy, they appear to proliferate. The functional use of the implements diversifies, and a variety of new and complex forms emerge. Furthermore, a nuanced relationship between the osseous and metal implements can be seen where forms crossover between the two technologies, indicating preferences in form and function for the equivalent implements. This research project demonstrates the significance of analytical study of osseous implements in understanding human behaviour and technological developments in the later Holocene. It illustrates that implement manufacture remained a significant part of technological strategies throughout the Neolithic and Metal Age. In fact, rather than observing a diminishment in the significance of osseous implement manufacture and diversity, with the introduction of metal, there is in fact a broad diversification, technological innovation, proliferation in the manufacture and notable increase in use contexts.
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Fused bis(bipyridine) ligand systems: coordination and electrochemistry with copper, rhenium and manganese
(2026) Hall, Peter
Bimetallic coordination complexes are of interest due to the unique properties which may arise from the positioning of two metal centres in proximity. In this thesis, research targeting redox-active bimetallic coordination complexes using ligands with fused bis(bipyridine) coordination motifs is presented in a series of studies with copper, rhenium and manganese. These studies comprise (i) self-assembly of bi- and multi-metallic coordination complexes with copper, and (ii) the use of bi- and mono-metallic rhenium and manganese complexes as catalysts for electrochemical CO2 reduction. Chapter 1 provides the background to the major concepts that underlie the content of this thesis: these being metal-metal cooperativity, and reduction of CO2 in electrochemical systems, and provides discussion of the methods that will be used to study electrochemical reactivity in this project. The design and synthesis of appropriate binucleating ligands is prerequisite for the study of redox-active bimetallic coordination complexes. In Chapter 2, the ligand designs enabling this project are discussed, with reference to (i) the redox activity of 2,2'-bipyridine; (ii) ligand designs containing multiple 2,2'-bipyridyl or other diimine donor motifs; and (iii) ligands containing fused oligopyridine cores such as the subjects of study: bis(6-R-2-pyridyl)-1,8-naphthyridine (R = H, L1; R = Me, L2), and bis(6-R-2-pyridyl)-1,8-diazaanthracene (R = H, L3; R = Me, L4). Bi- and multi-metallic copper complexes are of interest for study into mixed valence and (photo)redox systems. In Chapter 3 the synthesis of copper complexes of ligands L2-L4 is described. The complexes self-assemble into homoleptic helicate ([Cu2(L2)2](PF6)2, [3-1][PF6]2) or 2x2 grid ([Cu4(L3/L4)4][PF6]4, [3-2][PF6]4/[3-3][PF6]4) structures. These are studied using crystallographic, spectroscopic, and electrochemical methods, with attention given to metal- and ligand-centred redox activity. Rhenium bipyridine complexes of the form [Re(bpy)(CO)3X] (bpy = 2,2'-bipyridine, X = Cl, 4-A) are known catalysts for the electroreduction of CO2. In Chapter 4, an experimental description of rhenium complexes using L3 is given. Complexes [Re(L3)(CO)3Cl], (4-1), and the dirhenium complex [Re2(L3)(CO)6(Cl)2], (4-2), are studied via spectroscopic, crystallographic and electrochemical techniques. Evidence for catalytic rate enhancement was observed for 4-2 and data from our systems is compared to known monometallic and bimetallic rhenium systems to attempt to understand this cooperative behaviour. Extending from the previous chapter, Chapter 5 then discusses the effects of catalyst modifications on the structure and function of rhenium complexes within diazaanthracene ligand systems via the synthesis of rhenium complexes of L4. The complexes [Re(L4)(CO)3Cl] (5-1) and [Re2(L4)(CO)6(Cl)2] (5-2) are introduced and investigated, including comparisons to complexes 4-1 and 4-2 discussed in Chapter 4, and a description of isomerism at rhenium for 5-2. As was seen for 4-2, 5-2 was found to have high activity towards CO2 reduction compared to monometallic analogues. For the final study presented in this work, Chapter 6 considers the use of manganese as an earth-abundant alternative to rhenium for CO2 reduction catalysis. Here, complexes [Mn(L1)(CO)3Br] (6-1), [Mn(L2)(CO)3Br] (6-2), [Mn(L3)(CO)3Br] (6-3), [Mn2(L4)(CO)3Br] (6-4), [Mn(L3)(CO)6(Br)2] (6-5), [Mn(L4)(CO)6(Br)2] (6-6), [Mn(L3)(CO)6(NCMe)2][BF4]2 (6-7) and [Mn(L3)(CO)6(NCMe)2][BF4]2 (6-7)[Mn(L3)(CO)6(NCMe)2][BF4]2 (6-8) are described by various methods. It was found that the high activity of bimetallic rhenium systems described earlier did not translate directly to the manganese systems, and factors relating to this such as the stability of complexes under electrochemical conditions are discussed. Chapter 7 then concludes the thesis by providing a summary of the work as a whole, and discusses the prospectus for future work in this area.
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Picture Perfect Japan: Constructing Destination Image through Tourist-Generated Content
(2025) Tremayne, Lewis
This thesis investigates how tourist-generated content (TGC) – created by foreigners for foreigners – shapes destination image and visit intention through visual storytelling on social media. Focusing on the Chūbu and Tōhoku regions of Japan, the study analyses 180 content samples across three content types: micro-content (e.g. Instagram Reels), meso-content (YouTube videos under 30 minutes), and macro-content (videos over 30 minutes, including Twitch livestreams). Employing existing frameworks in tourism and social media research – such as destination image formation (Gartner 1994), tourist gaze (Urry 1990), authenticity (MacCannell 1973; Cohen 1988), and parasocial interaction (Horton & Wohl 1956) – seven criteria are assessed using visual content analysis: cognitive, affective, and conative image dimensions, trust, familiarity, authenticity focus, and parasocial interaction. Special Interest Tourism (SIT) forms are also measured to determine predictable narrative and structural patterns across these content types. Findings reveal that platform features and content structure – rather than geography alone – determine how destination image is constructed. Micro-content exhibits emotionally congruent and aesthetic, performative authenticity, often serving as an initial prompt for destination interest. Meso-content balances cognitive and affective dimensions, combining visual appeal with detailed narration and increased viewer-engagement. Macro-content exhibits the highest potential for authenticity and trust-building, often providing immersive and vicarious experiences with a resonant narrative. The study culminates in a typology of TGC-based destination branding, mapping how micro-meso-macro-content interacts with specific tourist gazes and image dimensions. This typology contributes to both tourism research and online destination branding, offering insights into how social media platforms mediate the emotional, cognitive, and behavioural components of visit intention – particularly in overlooked or post-disaster regions. The findings hold practical value for destination marketing organisations (DMOs), creators, and researchers interested in the nuanced construction of visual tourism media.
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Opening roads through kastom: vernacular diplomacies in Vanuatu
(2026) Naupa, Anna
This thesis explores the multiple modes of culturally-informed, everyday diplomacies practiced between different political communities and cultural groups in the Pacific island nation-state of Vanuatu. Melanesian diplomatic encounters are cultural, vernacular and scaled, occurring in deeply pluralistic contexts. However, there is a persistent lack of knowledge in Pacific scholarship about the cultural modes of engagement (kastom) in Melanesian statecraft and diplomacy. The failure to recognise the persistence of cultural and vernacular forms of diplomatic practice can be linked to their omission from international diplomatic and peace-making processes and lack of recognition as legitimate forms of contemporary diplomacy. This knowledge gap is addressed by adopting a broader research gaze that extends beyond state-centric conceptualisations of diplomacy to understand how cultural systems shape identities and relationships across boundaries, at local, national and international scales in the modern nation-state of Vanuatu. This more holistic approach to diplomacy invites closer examination of diplomatic cultures, the cultural and political communities and the spaces and boundaries between plural systems, as a zone of relational encounter. I refer to these multi-boundary, multi-identity and multi-scale practices as vernacular diplomacies. A core challenge for this thesis is to understand how pluralities coexist and how individuals and collectives embody plurality, introducing a series of research questions that engage the two transversal themes of scale and diplomacy. Exploring the transformation of Melanesian kastom-based systems of diplomacy, as they are embodied across varying scales of relationality, reveals an overarching research question: How does scale shape group identity and peaceful interactions or vernacular diplomacies across boundaries between communities, islands and states, and their respective cultural systems? The kastom road emerges as simultaneously the research method and the primary subject of this thesis. It unlocks understandings of Melanesian cosmology expressed through relational kastom roads but set against a backdrop of deeply traumatic cultural and political disruption and transformation across almost two centuries--from early European encounters through to postcolonial state-making. This thesis contributes new knowledge about the forms of vernacular diplomacies and the coexistence of multiple political communities and sovereignties that engage in encounters that can be described as diplomatic.
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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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