Open Access Theses

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Access status: Open Access ,
Molecular characterisation of niches for hematopoiesis in murine spleen
(2015-01) Tran, Vinson
Recent evidence for in vitro hematopoiesis driven by a splenic stromal cell line raises questions about possible niches in spleen. These studies have led to the identification of stromal lines which differ as supporters (5G3) and non-supporters (3B5) of in vitro hematopoiesis. When 5G3 stroma was overlaid with lineage negative (Lin) bone marrow progenitors, hematopoiesis ensued and a dendritic-like cell-type 'L-DC' was produced. Transcriptome analysis identified genes specifically expressed by 5G3, which regulated hematopoiesis from overlaid hematopoietic stem/progenitor cells. Initially, the role of these genes in hematopoiesis was investigated using antibodies and synthetic peptides as potential inhibitors in in vitro co-cultures of Lin bone marrow over 5G3 stroma. Additionally, soluble factors encoded by 5G3 but not 3B5 were added to 3B5 co-cultures in order to determine whether they could restore hematopoiesis. These studies support a role for several genes described previously in hematopoiesis. Aldh1 drives the development of conventional (c)-DC like cells through retinoic acid production. Csf1 and Igf2 encode growth factors that drive cDC-like cell development and the proliferation of progenitors. Cxcl12 encodes a chemokine and Spp1, a growth factor; both are important for cell production in co-cultures by maintaining progenitors in a quiescent state. Svep1 and Vcam1 encode adhesion molecules important for the development of L-DC and all subsets. In order to determine a functional role for candidate genes in hematopoiesis, shRNA was used to reduce target gene expression in 5G3 stroma. Knockdown of Svep1 and Csf1 had minimal effect on cell production. However, knockdown of Igf2 led to progenitor cell, DC and myeloid cell reduction. 5G3 was shown previously to support L-DC development directly from hematopoietic stem cells (HSC). shRNA was therefore used to identify signalling molecules, which regulate early events in hematopoiesis. Longterm HSC (LT-HSC), multi-potent progenitors (MPP) and macrophage dendritic progenitors (MDP) were tested in co-cultures involving Svep1, Csf1 and Igf2 knockdown 5G3 stroma. L-DC are known to develop directly from LT-HSC and MPP. Csf1 was found to be an important factor for self-renewal of progenitors within the MPP subset. Igf2 acted as a growth factor for both dendritic and myeloid cells developing from LT-HSC and MDP. Since Svep1 is a cell surface protein expressed by 5G3 that contributes specifically to L-DC development; it was thought to be a marker of a 5G3 equivalent cell-type in vivo. Due to a lack of available antibodies specific to murine SVEP1, SmartFlare probes were used to identify Svep1-expressing stromal cells amongst dissociated tissues ex vivo. Svep1-expressing stromal cells could not be specifically identified using SmartFlare probes, because of limitations in the target specificity of SmartFlare probes, as well as variations in the ability of different cell types to take up probes. The results presented here identify several molecules that make up the splenic stromal cell niche, supporting in vitro hematopoiesis. Overall, these studies highlight the importance of the 5G3 stromal cell line in supporting differentiation amongst overlaid bone marrow progenitors, identifying it as a model system for analysing signalling events that drive early hematopoiesis
Access status: Open Access ,
Confidence estimation via tail functions
(2015-01) Yang, Mo,
This thesis advances the theory of tail functions for confidence estimation, as originally formulated by Puza and O'Neill (2006a, 2006b). The theory is extended to the case where nuisance parameters are present and to where a joint confidence set is required for two or more parameters. The use of tail functions for the confidence estimation of partially defined parameters is also explored. In the thesis, confidence sets obtained via the tail functions approach are mainly evaluated by the conditional expected volume, or the prior expected volume, when prior information is available. The optimisation procedure of confidence sets in terms of minimising the expected volume under various constraints is illustrated with normally distributed samples under the framework of non-decreasing tail functions. Comparisons are made with the approach to confidence estimation in Brown, Casella and Hwang (1995). The thesis also further develops the tail functions approach to confidence estimation for parameters of discrete distributions, in particular, the geometric and negative binomial. A review of the theory of Pratt (1961) on confidence estimation via the likelihood function precedes an examination of various weight functions in relation to minimisation of expected volume. A new weight function is proposed and the associated confidence intervals studied. Early in the thesis, the class of piecewise-constant tail functions is introduced and subsequently used to help solve the difficult equations that arise in later chapters.
Access status: Open Access ,
The archaeology of Rossel Island, Massim, Papua New Guinea : towards a prehistory of the Louisiade Archipelago
(2014-12) Shaw, Benjamin Jon
The research presented in this thesis is focused on the archaeology of Rossel Island, the easternmost island in the Milne Bay Province, otherwise known culturally as the Massim. Rossel Island is one of the larger islands in the Louisiade Archipelago, and situated 400km from the mainland it is also one of the most isolated islands in the region. The people on the island today speak a Non-Austronesian language that is unrelated to the Austronesian languages spoken elsewhere in the Massim. The complexities of their cultural traditions are also regionally unparalleled and the people themselves are genetically distinct. Rossel Island is therefore seen as a unique outlier in the Massim region. The major aims of the archaeological project were twofold. First, to develop a chronology for human occupation on Rossel Island; and secondly, to identify spatial and temporal changes in the archaeological record that relate to the cultural development of this unique island population in prehistory. To place Rossel Island in a comparative regional framework, excavation was also undertaken on Nimowa Island in the Louisiade Archipelago, 80km to the west of Rossel. Nimowa and its people are physically and culturally different to Rossel. Eight of the sites excavated on Rossel, and one excavated on Nimowa are presented in this thesis. Excavation and radiocarbon dating indicates that people have been on Rossel Island since at least 2500-2350 BP. However, waisted stone blades found on the surface suggest that the island was colonised considerably earlier than this, probably during the Late Pleistocene when sea levels were lower and the island was much larger. Lapita people are likely to have re-settled the Massim Islands after 3000 BP, but they either did not reach Rossel or did not settle on the island. Pottery and people had been on Nimowa since at least 1350-1300 BP. However, pottery was not introduced to Rossel until 550 BP. Rossel Island had an aceramic culture prior to this time. A southern Massim or Louisiade Archipelago pottery tradition had developed by 1350 BP, which consisted of a suite of relatively standardised vessel forms and decorative motifs. Pottery in the Louisiade Archipelago has then remained relatively consistent throughout the last millennia until colonial contact. The subsequent introduction of pottery to Rossel Island is argued to have coincided with the development of the Kula regional exchange network, which connected many of the islands in the Massim region. Rossel was never directly involved in Kula exchange; however one of the main Kula trade items, the bagi shell necklace, is made on Rossel Island and is recognised as a high quality and highly valued product. Archaeological evidence confirms that bagi style necklaces were being made on Rossel Island when pottery was first introduced. It appears that when the southern Massim islands became integrated into the Kula network, trade links between Rossel and the neighbouring islands in the Louisiade Archipelago were strengthened. Pottery was probably exchanged for bagi necklaces, which subsequently entered the Kula exchange.
Access status: Open Access ,
Iran's China Pivot: A Neoclassical Realist Vision from 2005-2024
(2026) Baghernia, Niloufar
For more than 20 years, Iran's eastward shift persisted despite significant political and ideological differences among Iranian leaders. Why did Iran's foreign policy pivot toward China from 2005 to 2024? What explains this continuity among administrations that are otherwise diverse? During this period, Iran operated within an international environment characterised by the gradual decline of U.S. unipolar dominance and the expanding influence of China across Asia and the Middle East. These structural changes altered Iran's strategic direction in foreign policy by increasing the viability of eastward engagement. Rather than responding passively to these structural changes, Iranian policymakers viewed the shifting distribution of power as an opportunity to integrate the country into alternative economic and diplomatic networks centred on Asia. Although intensifying U.S. sanctions and coercive measures increased the urgency and strategic cost of delaying this reorientation, they did not dictate its direction. This thesis contends that Iran's eastward pivot demonstrates how a sanctioned middle power can actively adapt to and reinforce broader processes of systemic transformation. Yet, while structure explains the rationale behind Iran's foreign policy shift towards China, it does not fully explain how the pivot unfolded. Despite similar structural forces, the timing, depth, and form of the shift varied across periods. Hence, this study, through a neoclassical realist lens, argues that structure was the principal catalyst of the shift, while domestic agency influenced its timing, presentation, and intensity. President Ahmadinejad shifted toward China for ideological resistance; President Rouhani preferred a formal strategic partnership; and President Raisi pursued a strategic alliance, which remained only partially realised. The thesis also employs Type III neoclassical realism and shows Iran's broader contributions to the Asianisation of Asia. Empirically, it demonstrates that Iran's sustained focus on foreign policy, trade, and diplomatic engagement with Asia, particularly China, reinforced patterns of exchange in Asia from 2005 to 2024, despite the restricted and asymmetrical nature of Iranian interactions. While Iran was not the principal driver of Asianisation or a catalyst for the transformation of regional order, its actions contributed to the persistence and normalisation of Asia-focused ties over time. Theoretically, the thesis illustrates how the cumulative actions of a sanctioned middle power can reinforce broader structural processes, such as Asianisation, over the medium to long term. This perspective challenges neoclassical realist scholars, including Ripsman, Taliaferro, and Lobell, who attribute systemic change primarily to great-power interactions. This study employs a qualitative research method and discourse analysis to interpret themes, patterns, and meanings within the materials.
Access status: Open Access ,
Structural Analysis and Exhalite Studies in the Peelwood - Cordillera Area, NSW
Slater, Raymond M.
Field mapping in the Peelwood-Cordillera area reveals the complex spatial relationships exhibited by widely variable lithofacies, which reflect cyclical periods of deposition associated with an unstable, submarine volcanic environment. Rapid lateral and vertical facies changes, and the lack of useful marker horizons preclude the definition of major structural features, although it is probable that the area responded to deformation in a similar fashion to adjoining areas. Widely developed kink folding is interpreted as the result of a later phase of deformation, and is developed on all scal.es. The waning stages of active volcanic cycles are marked locally by the formation of sub-economic deposits of stratabound, pyritic base metal mineralization. Massive sulphides are general.ly enclosed by, and partial.ly laterally equivalent to, high silica cherty rocks believed also to be the result of volcanic exhalations. Geochemical analyses of the cherts show low and irregular abundances of all elements except silica, and the correlations they displayed indicate that most elements were probably supplied to these rocks from a detrital fraction. Petrographic evidence suggests at least partial derivation by silicification of pre-existing volcanic or volcaniclastic rocks, and the occurrence of radiolarian remains further supports a composite origin for these rocks, involving volcanic and elastic components in addition to chemical preci pitation.
Access status: Open Access ,
Beyond sequence similarity: Computational classification of plant enzymes through electrostatic similarity
(2026) Mortimer, Matt
Here's the cleaned version: Thesis significance statements * Methodological Approach: This thesis applies a progression of computational classification methods to plant enzymes (phytoene synthase, DXO1, eIF4E, and the stress-sensing nucleotide phosphatases). Beginning with SSNs and Evolocity network analysis for large-scale classification, progressing through molecular phylogenetics for evolutionary inference, then structural similarity comparison, and culminating in a novel Fourier-decomposed electrostatic field comparison approach. Each method revealed limitations that motivated the next, with the electrostatic approach detecting functional relationships invisible to sequence and structural methods. * Key Evolutionary Discovery: Functional relationships can diverge from phylogenetic relationships. I show phylogenetically distinct proteins can share catalytic properties (Algal AHL and Ancient CNP clustering electrostatically with SAL), while phylogenetically similar proteins can be functionally divergent (TaSAL1/TaSAL2 with opposing yield effects; AHL-alpha/AHL-beta with differential pH sensitivity). * Biological Significance: Neo-functionalisation following whole-genome duplication is pervasive across plant protein families, with novel regulatory functions arising in DXO1, eIF(ISO)4E, and AHL sub-clades. The electrostatic clustering of Algal AHL and Ancient CNP with SAL suggests continuous PAP catabolic capacity across Viridiplantae, resolving an apparent functional gap spanning hundreds of millions of years where lineages lacking SAL appeared to have no enzyme for this essential function. This approach demonstrated that evolutionary classification can significantly inform decision making in breeding and genetic manipulation in crop species as demonstrated in SAL mutant wheat field trials. Abstract High-throughput sequencing has generated over 246 million protein sequences, yet fewer than 0.3% have experimental validation. This gap is acute in plants, where frequent whole-genome duplication creates paralogues that sequence-based methods cannot reliably classify as functionally equivalent or divergent. This thesis applies a progression of computational classification methods to plant enzymes. Structural modelling of phytoene synthase variants elucidated mechanisms of enzyme dysfunction. Evolocity network analysis of DXO1 and eIF4E identified angiosperm-specific neo-functionalisation events. Sequence similarity networks combined with molecular phylogenetics classified the nucleotide phosphatase family into three distinct groups (SAL, AHL, CNP) and predicted functional divergence between wheat SAL paralogues, subsequently validated by field trials showing opposing yield effects. Each method revealed limitations motivating the next, culminating in a novel approach comparing Fourier-decomposed active site electrostatic fields across 506 enzymes. Since catalysis depends on the electrostatic environment governing substrate binding, this captures functional information that sequence and structure cannot provide. Electrostatic analysis detected functional relationships invisible to other methods where Algal AHL and Ancient CNP clustered with SAL despite phylogenetic divergence, while AHL sub-clades showed regulatory divergence despite sequence conservation.
Access status: Open Access ,
Harnessing Synthetic Biology for Retrograde Signalling in Plants.
(2026) Tsang, Natalie
Plants rely on precise communication between organelles and the nucleus to regulate gene expression-based stress responses, enabling acclimation to changing environments that impact photosynthesis and respiration. A major pathway in this communication is retrograde signaling, where signals from organelles such as chloroplasts inform the nucleus of cellular status. Among these signals, reactive oxygen species (ROS) play a central role. However, their reactive and overlapping nature complicates the study of individual ROS effects. Hydrogen peroxide (H2O2) is a key retrograde signal, functioning both as a damaging molecule under oxidative stress and as a trigger for protective gene expression. Yet, studying H2O2 directly remains difficult due to its overlap with other signals. This thesis aims to develop a synthetic toolkit for investigating the direct role of H2O2 and eventually enable construction of customizable signaling circuits to enhance plant stress response specificity and sensitivity. By engineering modular components that mimic or respond to H2O2 signaling, this work lays the foundation for precise probing of redox biology and future improvements in crop resilience. The first stage focuses on establishing chloroplast outer envelope targeting for synthetic sensing. Given the chloroplast's role in environmental sensing, I hypothesized that positioning synthetic modules at its surface would enable fast, spatially relevant responses. I screened ten targeting domains fused to mCherry in Arabidopsis protoplasts, identifying domains capable of specific outer envelope localization for use in later toolkit development. Building on this, I investigated aquaporins as H2O2 transporters in modulating chloroplast-derived H2O2 flux. I used AtTIP1;1, previously shown to transport H2O2, to explore how altering aquaporin-mediated flux affects retrograde signaling. Fusing AtTIP1;1 to the selected targeting domains, I confirmed that these modifications did not impair H2O2 transport. AlphaFold2 modeling showed intact pore structures, and yeast assays confirmed comparable transport efficiency between native and engineered AtTIP1;1. GFP-tagged constructs confirmed membrane localization in yeast. Additionally, I generated AtTIP1;1 overexpression lines in both wild-type and knockout Arabidopsis backgrounds to provide resources for studying increased H2O2 sensitivity in planta. The final part of this work developed a synthetic H2O2-responsive cleavage system based on the transcription factor ANAC017. Under oxidative stress, ANAC017 is cleaved from the endoplasmic reticulum membrane, releasing it to activate gene expression. I adapted this natural cleavage event into a synthetic tool by fusing ANAC017's cleavage site to mCherry, tethered to the chloroplast outer envelope. Protoplast expression and exogenous H2O2 treatment revealed possible cleavage and reporter release, indicating preserved functionality in this synthetic context. In parallel, I evaluated two orthogonal proteases (TVMVP and TEVP) for conditional cleavage of synthetic constructs. Co-expression in protoplasts showed efficient cleavage with minimal cross-reactivity, supporting their use in logic-based synthetic circuits. Together, this work establishes a modular toolkit combining chloroplast targeting, engineered H2O2 transporters, and cleavage-based response modules. These tools enable new strategies for dissecting and rewiring retrograde signaling, advancing both the understanding of H2O2's role in plant stress signaling and the development of synthetic biology applications in crops.
Access status: Open Access ,
On the Nature and Normativity of Imagination
(2018) Barner, Alma Karin
As a child, I often imagined that I was a space astronaut. Today I imagined what I could have for lunch and what I could wear for a concert. Pilots imagine performing water landings in an emergency. We might imagine full grown trees, while planting tree seeds. We use imagination to plan daily activities, prepare for important events, evaluate past choices and actions, predict other people’s mental states, and many more cognitive tasks. We imagine trees, while planting tree seeds, because we want to plant in a way that will leave enough space between the trees. We imagine what we could wear for a concert on our way home from work so that we know whether to do laundry first. The topic of this dissertation is the nature and normativity of imagination. While imagination plays a plethora of cognitive roles in reasoning, its nature and function is not very well understood. Moreover, it has received far less systematic attention from philosophers of mind than other mental states, such as beliefs, desires or perceptions. The dissertation aims to diminish this research gap. It has two parts, each of which contain two chapters. Part I focuses on the normativity of imagination, while Part II concerns the contents and phenomenology of imagination. It is a popular assumption in philosophy that imagination puts us in touch with the possible. The epistemic thesis that imagination is a guide to possibility has received a fair amount of attention in recent years. The normative thesis that imagination aims at the possible, like belief aims at truth, has only been discussed in passing. In Chapter 1 I give in-depth arguments against the normative thesis. Yet imaginings can only play cognitive roles, if they are normatively constrained in some way. In chapter 2 I present my own account of the normativity of imagination. On this view, imagination is not subject to intrinsic attitude-specific norms, but hypothetical norms, such as norms on intentions, and norms of instrumental rationality. I further argue that imagination shares semantic and normative properties with scientific models. Various prominent definitions of the nature of imagination appeal to perception. In Chapter 3 I critically evaluate the appeal to perception in defining the nature of imagination. I argue that common definitions of imagination cannot do justice to the nature of the contents and phenomenology of imagination, as the analogy to perception is taken too far. In the final chapter 4 I bring together the findings of the previous chapters and apply them to the case of imagining perceptual experiences. Here I argue that imagining perceptual experiences requires conceptual stipulations. This is designed to further illustrate and corroborate the views advanced. This dissertation highlights the uniqueness of imagination in many ways: Unlike beliefs, desires and perceptions, imagination is not subject to attitude-specific normativity (chapters 1 and 2). Imagination is akin to scientific model construction (chapter 2). Imagination is not always phenomenally similar to sense perception in important ways (chapter 3). Moreover, imagination contents involve conceptual stipulations, which further distinguishes them from perceptual states (chapters 3 and 4).
Access status: Open Access ,
Characterisation and Engineering of New Biocatalysts
(2026) Breeze, Callum
Biocatalysis - using natures catalysts to catalyse chemical reactions - is an interesting and expanding field in protein biochemistry. Biocatalysis typically makes use of enzymes, the proteinogenic catalysts present throughout nature. Enzymes have numerous advantages over traditional small molecule catalysts in synthesis, namely their environmentally friendly conditions and waste, and their high selectivity, comprising of stereo-, regio-, and enantio-selectivity. However, enzymes have two major disadvantages: their instability under industrial synthesis conditions, especially elevated temperatures and organic solvents, and their slow speed, especially when utilising non-natural substrates. The limitations of enzymes can be overcome using enzyme engineering. Enzyme engineering approaches can range from rationally designed mutations, relying on a comprehensive understanding of the enzyme, to completely random, resulting in thousands of enzyme variants. Furthermore, computationally driven techniques can be phylogeny, physics, or machine learning based. These engineered variants, along with wildtype enzymes, can be used for the stereoselective synthesis of small molecule drugs, the degradation of waste materials, and the treatment of textiles in manufacturing. For these applications, both wildtype and engineered enzymes need to be characterised to understand their biochemistry, mechanism, and kinetics. In this thesis I characterised wildtype and engineered enzymes structurally using X-ray crystallography, biochemically using liquid chromatography-mass spectrometry based assays, and kinetically using colorimetric kinetic assays. Across each chapter, I integrated protein biochemistry knowledge with experimental approaches to characterise these enzymes. The engineered enzyme variants in this thesis were made using two approaches: a rational approach involving the swapping of natural metal ion cofactors for non-natural metal ion cofactors; and a phylogenetics based approach involving the statistical inference of ancestral enzyme sequences at nodes of a phylogenetic tree. Chapter 1 outlines the foundational concepts and ideas that underpin this thesis. Chapter 2 investigates the rational design of a model metalloenzyme by swapping the natural bimetallic centre with a non-natural monometallic centre. Chapter 3 investigates the dye degrading properties of a newly isolated bacterial strain, using a combined microbiology, genetics, and biochemistry approach. An enzyme capable of turning over malachite green was characterised. Chapter 4 investigates the ancestral protein reconstruction of a family of epoxyketone synthases to generate an enzyme variant library, which catalyse the synthesis of a,b-epoxyketones. These enzymes were screened against a range of substrates, including two therapeutically relevant substrates. Chapter 5 investigates the same enzyme variant library generated in Chapter 4, but investigates their ability to synthesise a precursor to another a,b-epoxyketone. Chapter 5 also investigates the suitability of using a photocleavable protecting group during a,b-epoxyketone synthesis, and attempted to generate X-ray crystallography standard protein crystals of active epoxyketone synthases. Overall, this work advances our understanding of biocatalysis and biodegradation, and also generated an enzyme capable of producing a therapeutically relevant a,b-epoxyketone.
Access status: Open Access ,
Evolution of dosage compensation and x chromosome inactivation in therian mammals
(2015-03) Rodriguez Delgado, Claudia,
The sex chromosomes in therian mammals (eutherian mammals and marsupials) evolved from an identical autosomal pair. One of the two chromosomes in the original pair degraded in males due to suppression of recombination, resulting in monosomy of the X chromosome in males. It has been accepted for years that the differences in gene dosage that resulted from monosomy of the X chromosome in males were restored in a two-step way, firstly by upregulating the single X chromosome in males, then by transcriptionally silencing one X chromosome in females, in a process known as X chromosome inactivation (XCI). Though XCI has been extensively studied at the mechanistic and evolutionary level, upregulation of the X chromosome (which presumably preceded XCI) was assumed as a fact for decades, and has only been recently investigated and questioned. To gain insights into how the dosage compensation system evolved upon emergence of the sex chromosomes in therians, I tested upregulation of the X in marsupials and eutherian mammals distantly related to human and mouse. I observed that global upregulation of the X occurred in the marsupial lineage but not in the eutherian lineage. The eutherian X chromosome was augmented by the addition of an autosomal region (XAR), and I show that, similar to the marsupial X, this region has been upregulated in eutherians. Underlying differences in the XCI system between marsupials and eutherians have been previously described. I confirmed that paternally imprinted XCI is common to somatic tissues in the marsupial clade, in contrast to the conserved random XCI observed in eutherian embryonic tissues. I observed that as opposed to eutherians, escapee genes are not confined to the recent evolutionary strata on the X. A similarity with the eutherian clade is that the proportion of genes that escape XCI differs between species of the same clade; I observed that a greater proportion of genes (̃30%) escape XCI in tammar wallaby, in contrast to the 14% escape reported for opossum. I proposed a model for evolution of dosage compensation, where upregulation of the X chromosome started for a few dosage sensitive genes in the therian ancestor, and evolved into a global system in marsupials but not in eutherians. In addition, I discuss the relationship between upregulation of the X chromosome and evolution of XCI.
Access status: Open Access ,
Gamma-ray bursts : cosmological probes and their connection to supernovae
(2014-08) Rapoport, Sharon
Observed from the nearest galaxies to the beginning of times, Gamma-ray bursts (GRBs) remain the most energetic event in the Universe known to date. As their cone of light travels through the cosmos, the imprint of everything in its path is embedded in the spectra and light curves we observe, providing us with the three dimensional map of matter. This thesis studies the statistical properties of strong MgII absorbers found along the line of sight to GRBs. Firstly, the possibility that the over abundance of these systems could be due to strong gravitational lensing bias is tested. While it is probable that the detection of GRBs and their counterparts in two independent bands ($\gamma$-rays and optical) leads to some lensing bias, it is found that it can not fully resolve the discrepancy in the statistics for these over-common absorbers. After ruling lensing as a potential explanation, a test for the statement that strong MgII are over abundant towards GRBs is conducted, finding that this observation is likely to suffer from low number statistics and can be made insignificant when considering dust obscuration towards the test sample of quasars. Beyond their capability to serve as cosmological probes, GRBs are a fascinating physical phenomenon. Focusing on long GRBs, which are believed to be associated with core-collapse supernovae (CC SNe), the following simulations are developed: evolving a pre- main sequence star using artificial mass loss recipe until before its core collapses --> parameterising the central engine with a piston driven explosion and following the hydrodynamics until the ejecta reaches homologous expansion --> solving for the post-explosion abundances using a post processing nuclear network --> using a radiative transfer (RT) code to calculate the observable properties of the SNe. Since the RT has never been previously used for CC SNe, a comparison of this code to what has been previously used for these SNe is made. The superiority of the code used in this thesis is proven by its ability to not only reproduce the main spectral features found in previous results, but to change the expectation of luminosity from the different viewing angles which could be done due to this coherent time dependent code. An observer located off the GRB axis is actually found to observe a brighter SN than the observe who detected the GRB itself. Once the proficiency of the RT code was proven, a grid of model spanning different explosion parameters and progenitor properties is created. An array of degeneracies between the model parameters is found, proving that using the Arnett relation for estimating the explosion energy and ejected progenitor mass suffers from large uncertainties."
Access status: Open Access ,
Chemoenzymatic syntheses of allocedrane and prezizaane-type sesquiterpenes
(2015-01) Sharma, Mukesh Kant
Various genetically modified microorganisms that over-express dioxygenase-type enzymes can be used for the whole-cell biotransformation of a wide range of arenes into the corresponding cis-1,2-dihydrocatechol (c-DHC). These metabolites, which are obtained in essentially enantiopure form, can serve as valuable starting materials in chemical synthesis. This thesis describes the application of certain c-DHCs to the synthesis of biologically active and or synthetically challenging natural products. In particular, it details the use of Type 1 intramolecular Diels-Alder (IMDA) adducts derived from c-DHCs in the synthesis of the tashironins and related compounds belonging to the allocedrane class of natural product. The tashironins possesses complex structures and display interesting biological properties including neurotropic activity. As such they are considered to be useful leads in developing new therapies for treating neurodegenerative afflictions such as Alzheimer's and Parkinson's diseases. In the process of the campaign towards tashironins, several highly oxygenated tri- and tetra-cyclic compounds were prepared. These are described in Chapter Two and Three and are expected to possess similar biological properties to the natural products. Chapter Four of the thesis describes the synthesis of members of prezizaane group of compounds that are biogenetically related to allocedranes, sesquiterpenoids that are highly prized in the flavour and fragrance industry. During the course of preparing the prezizaanes, a novel Wagner-Meerwein rearrangement of the allocedrane system was discovered that afforded a pleasantly smelling compound that is enantiomerically related to the natural product isopipitzol.
Access status: Open Access ,
Proposed Topic: Revealing the therapeutic potential of the epitranscriptome and translational regulation at the onset of Leukemia drug resistance
(2026) Ravindran, Agin
B-cell acute lymphoblastic Leukemia (B-ALL) is characterised by prevalent chromosomal translocations leading to the expression of gene fusions. Distinct B-ALL fusions can lead to different proliferative and survival capacities of malignant cells. Consequently, subtype-specific B-ALL fusions exhibit diverse responses to chemotherapy, which can result in therapy resistance through yet unknown mechanisms. Deep investigation of gene expression control can be an entry point to highlight the subtype-specific drug resistance responses in B-ALL. A preliminary analysis of B-ALL patient samples revealed that B-ALL shows gene expression alterations potentially linked to RNA processing mechanisms, including translation and RNA modifications. Across a panel of 11 common B-ALL subtypes, these alterations occurred as specific to the two most common B-ALL fusion types, ETV6-RUNX1 and KMT2A-MLLT1. Importantly, these subtypes are also associated with highly divergent prognoses, with ETV6-RUNX1 having a more favourable prognoses and KMT2A-MLLT1 known to relapse. Recent published studies also point to the dynamic involvement of translational control and the epitranscriptome in cancer drug resistance across cancers, but the role of these mechanisms in B-ALL remains unknown. Here, we set out to directly investigate RNA-level signatures of resistance to common chemotherapy in B-ALL. For the first time, we revealed accurate compositional information about the native transcriptome including RNA modification profiles, and the linking functional effects recorded at the level of RNA translatability and stability. To establish cell models recapitulating the two B-ALL fusion subtypes and subtype-specific resistance development, we used REH (ETV6-RUNX1) and KOPN-8 (KMT2A-MLLT1) cell lines, alongside a non-malignant B-cell line, GM12878. We employed multiple successive rounds of treatment with vincristine (VCR), a prototypical chemotherapy drug used in many haematological malignancy treatment regimens, to progress both B-ALL cell lines to acquired resistance. We then used the advantages of direct RNA long read sequencing to accurately compare the native transcriptomes, RNA modification patterns, stability profiles and per-isoform translatability of the original vs. VCR-resistant cells using innovative in-house developed methods. At the epitranscriptome level, we showed that METTL3-dependent m6A was upregulated in malignant cells for both B-ALL tumour backgrounds. However, there was no change in METTL3-dependent m6A upon developing VCR resistance for both subtypes. However, for PUS7-dependent pseudouridine, while there was no alteration in malignant B-ALL cells, unexpectedly, we observed a significant increase upon acquiring vincristine resistance in both subtypes. From a translational standpoint, while global translation rates increased in B-ALL malignancy for both subtypes, we observed an overall reduction in translation linked to acquired resistance that may potentially be attributed to epitranscriptomic alterations in PUS7- and DKC1-dependent pseudouridine. In the polysome bound fractions, we observed a shift in PUS7 and DKC1 transcripts from the light polysomal fraction into the heavy polysomal fraction. Our work is first to provide a deep transcriptomic insight into the RNA-level mechanisms governing drug resistance onset in a prevalent blood cancer. We also highlight a potential mechanism linking the increased gene-level expression and epitranscriptomic signatures of PUS7-dependent pseudouridine on downstream effectors of mammalian targeting of rapamycin (mTOR) signaling pathway as a way of decelerating translation rates in VCR-resistant B-ALL cells. These results not only reveal that RNA modifying proteins potentially serve as novel biomarkers of early VCR resistance, but they also open avenues into using PUS7 and potentially DKC1 as novel therapeutic targets for overcoming VCR resistance in leukemia chemotherapy.
Access status: Open Access ,
Accelerating Computational Chemistry Algorithms: towards Accurate Binding Free Energies
(2026) Yu, Fiona
Advances in high performance computing (HPC) are pivotal for accelerating drug discovery by offering the capacity for large scale high accuracy virtual screening. There has been considerable interest in the large scale application of the Quantum Mechanical / Poisson-Boltzmann Surface Area (QM/PBSA) end point method towards predicting binding affinities of protein-ligand systems. However, its application is severely limited by the high computational costs of traditional QM methods as well as the slow performance of existing PBE solvers for PBSA calculations. This thesis presents methods and algorithms to overcome such bottlenecks. The first half of this thesis is dedicated to accelerating QM calculations. An automated accurate molecular fragmentation scheme is presented that divides large systems into smaller, computationally feasible partitions, whilst enhancing algorithmic parallelisability. Its applicability on protein and lipoglycans/glycolipids is demonstrated. On the other hand, improved initial guess methods for self-consistent field (SCF) calculations are presented (basis set projection and fragmentation) and their performance is systematically analysed against the traditional superposition of atomic density (SAD) scheme. Results consistently indicate the improved performance of SCF calculations with non-SAD schemes. To address the lack of fast PBE solvers to model solvation, a high-performance GPU-accelerated solver is presented. The algorithm exploits the sparsity pattern exposed in its application on molecular systems to accelerate matrix-vector contractions prevalent in conjugate gradient solvers, outperforming existing multi-core CPU and GPU-based PBE solvers. These tools are integrated into a QM/PBSA workflow and applied to large biologically relevant protein-ligand complexes to predict binding affinities. The influence of various factors---fragmentation level, protonation states, and solvation methods---on the performance of the proposed QM/PBSA workflow is systematically analysed and compared to other computational approaches including alchemical free energy and scoring function methods. This thesis seeks to improve upon the accuracy, computational efficiency and feasibility of large scale QM/PBSA workflows by leveraging chemical concepts and HPC optimisations. Beyond drug discovery, the methodologies presented have broad applicability to molecular molecular systems beyond proteins, supporting research in materials science, chemistry and energy applications. Such advancements become increasingly important as HPC systems continue to evolve, offering the potential to study molecular systems at even larger scales and and higher accuracy.
Access status: Open Access ,
Enhancing surveillance of notifiable diseases in South Australia, 2023 - 2024
(2026) Freeman, Tom
From February 2023 to December 2024, I undertook a 22-month field placement within the Disease Surveillance and Investigation Section (DSIS) of the Communicable Disease Control Branch (CDCB), SA Health. During the placement, I undertook multiple projects to demonstrate the core competencies of the Master of Philosophy (Applied Epidemiology) (MAE) program including conducting an analysis of a public health dataset, investigating an acute public health problem or threat, designing and conducting an epidemiological study, and establishing and evaluating a surveillance system. The first chapter introduces my field placement, summarises my projects and outlines my primary role within DSIS. The second chapter describes establishing and evaluating an automated enhanced surveillance system piloted for varicella and Salmonella cases notified in South Australia. The established surveillance system utilised Short Message Service and online surveys to collect enhanced surveillance data directly from varicella and Salmonella cases which were then automatically integrated into the existing notifiable disease surveillance system in South Australia. The new system was evaluated against specific attributes as per the United States Centers for Disease Control and Prevention Guidelines. The evaluation recommended continued use of the automated enhanced surveillance system for varicella and Salmonella notifications, as well as expansion for use with other notifiable diseases. The establishment of this system was presented at the Communicable Diseases & Immunisation Conference 2024 in Brisbane, Australia. The third chapter describes the epidemiological study conducted as part of the broader evaluation of the automated enhanced surveillance system established in Chapter 2. The nested before-and-after intervention study evaluated the data completeness and representativeness attributes of the piloted system. The study finds significant improvements to data completeness and validates the pilot populations are representative of expected disease populations for both Salmonella and varicella. The fourth chapter describes the investigation of an acute public health problem or threat competency through the investigation of a Salmonella Virchow outbreak in a childcare centre. I was the lead investigator for the outbreak which involved epidemiological, environmental and laboratory investigations. Person-to-person transmission was the most likely mode identified in the outbreak. A literature review was conducted as part of the project to further understand non-foodborne Salmonella transmission in childcare centres. The outbreak investigation has also been drafted as a manuscript for submission to the Communicable Diseases Intelligence journal. The fifth chapter presents the analysis of a public health data set competency through the production of the COVID-19 Annual Surveillance Report 2021 for South Australia. This project was a descriptive analysis of COVID-19 notifications between 1 January 2021 to 31 December 2021 in South Australia. During 2021, South Australia experienced almost no community transmission of COVID-19 until 23 November 2021 when the state borders were opened, and community cases increased. A lay summary was produced as part of the project and published on the SA Health website. It was the first comprehensive description of COVID-19 notifications in 2021 produced by CDCB. The sixth chapter provides learnings from multiple teaching activities conducted during the MAE program and describes other experiences and public health activities during my placement. This includes a six-week fellowship with the World Health Organization Western Pacific Regional Office in Manila, Philippines. The teaching activities include peer-to-peer teaching to first-year MAE scholars and lessons from the field activities with fellow MAE scholars.
Access status: Open Access ,
Nonstandard estimation for the von Mises Fisher distribution
(2017-07) Ghodsi, Maryam
The main focus of this thesis is to provide a theoretical analysis of certain statistical models incorporating constraints of various kinds. The models are motivated with data examples using spherical distributions fitted to asset allocation data related to financial portfolios. We fit models consisting of several von Mises Fisher distributions of di↵erent dimensions to a sample of such financial data. Our analysis of the properties of the corresponding hypothesis test statistics under this model combines Silvey’s approach towards constraints on the parameter space with Cherno↵’s innovations to find the asymptotic distributions of the likelihood ratio (deviance) statistics. Silvapulle and Sen detail situations when some constraints are imposed on either the parameter space or on the underlying distribution, where the information matrix is positive definite. But, in some examples, the expectation of the second derivative need not be a positive definite matrix. In such cases, methodology developed by Maller and others can be applied as it does not require the information matrix to be positive definite. Consequently, we apply this methodology to hypothesis tests for the equality of concentration parameters in the spherical subcomponent model. Properties of the tests are examined by simulations and a real data application is given.
Access status: Open Access ,
Walking at Weereewa
(2015-11) Flemons, Lynne Maree
In Australia, over the past thirty years or so, there has been a change in the way non-Indigenous visual artists have interpreted the nation’s landscape. During this period a cultural shift has occurred, from one where the term ‘landscape’ refers to a view from a fixed point in time, as in the European landscape tradition, to a broader awareness where the landscape is interpreted in terms of its memory, history, mythology, as well as its physical features. This change in perception has its origins in a deeper understanding of the Australian landscape; one that has been promoted both through the works of Indigenous artists and by a broader desire amongst their non-Indigenous colleagues to experience this unique environment as a composite of all its elements rather than just a visual scene to be captured by the artist’s brush. To help me understand and articulate these changes I have drawn upon both phenomenology and cross-cultural mapping. Phenomenology is a philosophical concept describing our interactions with, and our reactions to, the phenomena that comprise everyday life. In my research I walked extensively on the lake bed of Weereewa (Lake George) at different times of the year, experiencing the whole environment, from the sky above to the tiniest crack in the mud, using all my physical senses while being constantly aware of the Aboriginal history on this lake bed that preceded me, and any other European presence, by thousands of years. I became embedded within the whole landscape; truly able to experience its many facets through my senses. This is the essence of phenomenology. Cross-cultural mapping, on the other hand, describes the way people of different cultures record their memories of a place. It asks the question, how have they mapped the land around them and for what purposes? In my research I looked at how both Indigenous and non-Indigenous artists have gone about the process of mapping the land, and it is from these findings, in combination with my own experiences on the lake that much of my studio work has developed. My studio work consists of cut-outs and drawings that reflect the physical and temporal phenomena of the Weeweera landscape: its clouds, shadows, changing colours, remnant water, cultural relics, land-use practices and the impacts of both weather and time on its human and geological histories. My experiences of the lake are represented as a series of ‘fragments’ that engage with its different histories: the Aboriginal, the settler and the geological. In developing these fragments into wall installations and watercolour works on paper, using a process I called an ecology of drawing, I have been able to bring together all the influences on my work, enabling me to express my experiences of the lake in a new visual language.
Access status: Open Access ,
Microbiome dynamics during rust fungal infections
(2026) Graetz, Abigail
Plants don't exist naturally in isolation. They are surrounded by, colonised by, and interact with, microorganisms. Plant microbiomes have many reported benefits to their hosts, from directly suppressing pathogen infection to improving nutrient availability. While leveraging these benefits for agricultural benefit is of great research interest, we lack fundamental understanding of the composition and diversity of plant microbiomes in non-model systems. Environmental DNA (eDNA) sequencing has opened new doors for profiling microbial communities, enabling molecular delineation of species with morphological similarities, or for which pure in vitro culture is not possible. Metabarcoding, using the 16S region for bacteria, or the internal transcribed spacer (ITS) region for fungi, can increase sample throughput, and identify many organisms simultaneously from a single sample. Using long-read sequencing to encompass entire metabarcode sequences can give insight at the species level, but this technology has not been thoroughly benchmarked for applications in microbial metabarcoding. In this thesis, I benchmark and optimise a wet lab and bioinformatics workflow for using Oxford Nanopore Technologies long-read sequencing to profile microbial communities with metabarcodes. I present a novel multiplexing strategy to improve cost-effectiveness, and use an in silico mock community to demonstrate robust, species-level identification of fungi using long-read ITS sequences. I have then applied my knowledge from this benchmarking work to two leaf microbiome datasets: a sample set of rust fungus-infected wild grasses, and a sample set encompassing three spore stages of the wheat stripe rust fungus (Puccinia striiformis f. sp. tritici) across the sexual and asexual phases of its life cycle. I compare fungal and bacterial community composition and abundance across levels of infection status and host plant, to better understand how rust fungal infection influences microbiome community dynamics in the phyllosphere.
Access status: Open Access ,
Exploring cortical information processing using optogenetics
(2014-12) Rudinski, Stephen Alexander
Optogenetics provides a powerful new tool for studying the way neurons integrate the inputs they receive, and how this shapes information processing in the brain. In this thesis we apply this new tool to investigate the mechanisms governing information processing in the somatosensory cortex of the mouse. The first aspect of this study characterised the expression and activation of channelrhodopsin-2 (ChR2) in somatosensory barrel cortex of a widely used transgenic mouse line where ChR2 expression is driven by the Thy-1 promoter. Within somatosensory barrel cortex ChR2 expression was found in 96% of layer V and 72% of layer II/III pyramidal neurons. Expression of ChR2 was also found in the majority of fast-spiking interneurons in both layer II/III and V (78% and 86% respectively). This study shows that ChR2 expression is not limited to layer V pyramidal neurons in this mouse model as is commonly assumed. The second aspect of this study developed a spatiotemporally precise method for optogenetic stimulation based on a projector-based optical interface. As proof-of-principle, three studies were conducted to assess the application of this method. Firstly, subcellular dendritic photo-stimulation was used to investigate the somatic impact of distal dendritic inputs in cortical pyramidal neurons. Secondly, this method was applied to mapping the spatial distribution of synaptic inputs to neurons in layer II/III and IV within somatosensory barrel cortex. We demonstrate that layer II/III pyramidal cells receive the majority of their excitatory synaptic input from layer IV and II/III, with fewer and weaker inputs arising from layer V within the same barrel. Interneurons in layer II/III also received extensive excitatory synaptic input from layer IV in addition to surrounding layer II/III cells. The vertical profile of excitatory input to layer IV neurons indicated stronger input from layer IV and layer V than from layer II/III within the same barrel. Similar intra-columnar input profiles were also seen in interneurons residing in layer IV, where inputs were more numerous and stronger from layer IV than from layer II/III or layer V. Thirdly, using a thalamocortical slice we show that thalamocortical inputs arising from the thalamus have significantly higher connection probability and input strength in layer IV compared layer II/III and V. The final aspect of this study investigated how inhibition targeted to somatic versus dendritic compartments shapes the firing output of layer V pyramidal neurons, and how the location of excitatory input influences this process. The findings presented illustrate that when excitatory drive is close to the soma both somatic and dendritic GABAA-mediated inhibition has a purely subtractive effect on input-output relationships, whereas subtractive and divisive effects are observed during dendritic excitatory input. Somatic inhibition produces significantly more subtractive effects when excitation is driven somatically, whereas more divisive effects are observed during dendritic excitatory input. Together these findings suggest that both somatic and dendritic inhibition can generate divisive gain control provided excitatory drive is concentrated in dendritic compartments.
Access status: Open Access ,
The scope of global gene expression in peripheral blood for anti-doping testing
(2016-09) Hausner, Sarah Claudia
This study aimed to determine, whether measures of gene expression can detect the effects of autologous blood transfusion, which is used illicitly by athletes to enhance performance. Gene expression data from blood samples collected longitudinally from subjects participating in two autologous blood transfusion Trials were analysed. Four participants in both Trials were transfused with 3U blood. Four additional subjects were transfused with 1U blood in the second Trial. In the first Trial samples were collected at baseline, 21 days post phlebotomy, and at 7, 14 and 28 days post re-infusion. During the second Trial samples were collected at baseline and 14-days post re-infusion. Chapter 2 describes transfusion-induced signatures of differentially expressed genes. Generalized linear modelling with subsequent Bayes moderation and FDR adjustment for multiple testing was used to identify characteristic transfusion-induced signatures of differentially expressed genes for follow-up testing at 7, 14, 21 and 28 days post re-infusion. We detected transfusion effects with 100% accuracy in samples collected 14 days post-transfusion in Trial 1 and reproduced these findings in Trial 2. The transfusion-response signatures were enriched for genes linked to the physiological response to autologous transfusion, including inhibition of erythropoiesis, impairment of cortical cytoskeleton and cell cortex formation and suppression of heme biosynthesis. These responses to transfusion remained detectable for at least 28 days after transfusion. Chapter 3 describes the results of the Weighted Gene Co-Expression Network Analysis, which results in a range of quantitative network descriptors with diagnostic potential (i.e., eigengene score, intra-modular connectivity score, extra-modular connectivity score). We identified conserved patterns of gene-expression network organisation through assignment of genes to distinct modules based on their co-expression similarity across all available sample data. We assessed the impact of transfusion on gene-expression networks by comparing intra- vs. extra- modular connectivities at different stages of the interventions. We also compared the characteristics of the modules with blood markers obtained from the participants. We investigated the functional enrichment of modules and of the most interconnected genes within each module (hubgenes). Finally, we quantified module-module interconnectedness and rated connection strength to assess the effect of transfusion on the transcriptome’s organisational structure. We were able to detect transfusion at 14 days post blood re-infusion with 100% accuracy in Trial 1 and reproduce these findings in Trial 2. The peripheral blood transcriptome is organised into distinct modules with characteristic transfusion-induced changes that reflect relevant physiological processes, such as suppression of erythropoiesis and metabolic response to alterations in blood composition. Peripheral blood transcriptome has great potential as a diagnostic tool for autologous blood transfusion, which remains hard to detect by other methods. It can also potentially detect physiologicaL responses to a wide range interventions. ‘Hubgene’ analysis, in particular, which allows assessment of intrinsic network properties through both quantitative (hubgene connectivities) and qualitative (hubgene function) measures, may be of great value in testing for responses to a wide range of substances and procedures, and in testing for yet unknown doping agents.

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