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The Development of Novel Lung-Tropic AAVs to Support a Gene Therapy for Cystic Fibrosis
No full textCystic fibrosis (CF) is a life-shortening disease that affects all mucosal surfaces of the body, with the more severe symptoms manifesting in the respiratory system. This monogenic disease is caused by a variety of mutations in the CFTR gene. This project aimed to identify/develop multiple lung targeted AAV capsids in support of a gene therapy for CF. Novel capsids were specifically evaluated for their ability to target human airway basal (AB) cells, which are the progenitors of the CFTR producing airway epithelial cells and ionocytes. To bypass the airway's innate defences, including the thick mucus layer, which is especially prominent in people with CF, whilst also addressing peripheral symptoms, capsids were engineered for effective transduction following systemic administration.
This thesis employed three approaches to develop novel lung targeted AAV capsids. Firstly, a high-throughput approach to identify currently available capsids with previously unrealised lung tropism. Secondly, directed evolution to develop novel, bioengineered capsids with improved lung transduction efficiency. Finally, the isolation of novel, natural AAV capsid variants from human lung tissue sample.
To address challenges relating to clinical translation of AAV transduction efficiency, a ‘multi-model’ approach was employed for capsid evaluation. A mouse model was used to evaluate capsids based on their ability to travel to the lungs following systemic administration, a precision cut human lung slice model was used to assess the capsids’ ability to transduce human lung tissue, and finally primary human airway basal cells were used to evaluate the capsids’ ability to transduce the target cells.
This study identified multiple AAV capsids with improved transduction efficiency in pre-clinical lung models over current benchmarks such as AAV2 and AAV6. Whilst these capsids require further evaluation, they could be prime candidates for use in pre-clinical studies or even clinical translation
Podcasting and Play: Gaming Podcasts and the Changing Face of Gaming Media
No full textGaming podcasts, despite being an important aspect of the gaming media landscape, have not yet been the subject of any significant analysis in either game studies or podcast studies. This thesis rectifies this omission by providing the first large scale analysis of gaming podcasts in scholarship. It applies constructivist grounded theory in a mixed methodological approach. To do so, it draws on 23 case studies of specific gaming podcasts, case studies that consist of interviews with gaming podcast creators, surveys of audiences, and textual analysis of shows and related paratexts. Through these I offer a comprehensive examination of the gaming podcast industry and answer key questions related to who is creating and consuming these shows, how these creators and listeners engage with the podcasting medium, and why they chose to do so. In doing so this work showcases how this subfield is representative of broader trends in digital media and labour. While the conditions these creators endure recall Silvio Lorusso’s concept of the ‘entreprecariat’, the ways in which audiences engage with these creators’ shows emphasise the importance of the perception of creator ‘authenticity’. In foregrounding these trends, the thesis provides significant contributions to the fields of game studies, podcast studies, and media studies, and also demonstrates the need for continued research into the specific subfield of gaming podcasts
Methods for Optimising Short-term Production Scheduling in Open-pit Mines
No full textOpen-pit mine production planning involves decision-making for material extraction and allocation, divided into strategic and tactical planning. Strategic planning focuses on long-term economic value, while tactical planning addresses productivity and ore quality over shorter periods. This thesis contributes to tactical planning from both deterministic and stochastic perspectives. The deterministic approach solves static optimisation models with a focus on ore quality, while the stochastic approach manages uncertainty to ensure robust production plans under varying conditions.
Tactical planning models often involve numerous binary variables and bilinear constraints, posing computational challenges. Equipment uncertainties further complicate these models, making exact methods impractical. Traditional stochastic programming methods require many scenarios, adding to computational complexity.
To address these challenges, this thesis enhances the computational efficiency of a non-linear mixed integer programming model, enabling rapid responses to mining disruptions. A deterministic planner, Predictive CE, was developed using a sliding-window strategy, cross-entropy method, and probabilistic heuristic. Numerical tests show Predictive CE solves short-term non-linear production planning problems in minutes, producing solutions comparable to Gurobi, which struggled with large problems even after 10 hours. Predictive CE outperformed two alternative methods in speed, with quality gaps of 1.22% and 2.92%.
For managing operational uncertainty, a stochastic decision-making framework is proposed, featuring a robust planner, a discrete-event simulation module, and a dynamic truck-dispatching heuristic. The robust planner, central to this framework, optimises productivity under uncertainty. Simulation results show it can enhance productivity by up to 31.7% compared to a nominal planner, which only considers deterministic conditions
Ventriculostomy – Related Infections: Prognosis and Diagnosis in the Neurosurgical Intensive Care Unit
No full textExternal ventricular drains (EVDs) are commonly used in the management of acute neurological injury. Ventriculostomy – related infection (VRI) is a common complication associated with the presence of EVDs. Despite how common VRI is reported to be, there is minimal data regarding how a diagnosis of VRI affects long term outcomes in patients with EVDs. This is due to heterogenous and poorly validated diagnostic criteria for VRI, and confounding from the primary neurological diagnosis.
This thesis contains three studies which attempt to address some of the gaps in the literature on VRI. Firstly, we performed a systematic review to assess the relationship between a diagnosis of VRI and clinical outcomes. We found that a diagnosis of VRI was not associated with increased mortality, and had no adverse effect on functional neurological outcome. Secondly, we performed a study of registry data to assess the association between VRI and clinical outcomes, and found that a diagnosis of VRI was not associated with poor functional neurological outcome or mortality. VRI was associated with increased ICU and hospital length of stay, and increased insertion of VP shunts. Finally, we performed a prospective study using 16S rRNA PCR to assess whether standard diagnostic methods for VRI were adequate. We found a low incidence of positive PCR, which correlated best with CSF culture results. We also found no cases of “culture-negative VRI”, and that in patients with no microbiological evidence of VRI, the incidence of abnormal CSF findings was high.
These studies suggest that a diagnosis of VRI as defined by standard diagnostic criteria may not affect mortality or functional neurological outcome. It also shows that VRI is likely overdiagnosed and therefore overtreated. Future research with multi-centre cohort studies would help to establish a more accurate definition of VRI, to help better direct treatment and prevention strategies
Look on the Bright Side: Exploring the Role of Episodic Future Thinking in Anticipatory Anhedonia.
No full textAnhedonia, the diminished capacity to experience pleasure, is a debilitating symptom that impacts motivation, social engagement, and quality of life. While traditionally linked to psychiatric disorders, it is increasingly recognised as a key feature of frontotemporal dementia (FTD). This thesis investigates the multidimensional nature of anhedonia and its cognitive underpinnings across four studies.
Chapter 2 identifies distinct motivational profiles in dementia syndromes: global motivational impairment in behavioural variant FTD (bvFTD), a primarily anhedonic profile in semantic dementia (SD), and executive/apathy-related disturbances in Alzheimer’s disease (AD), with syndrome-specific links to functional decline. Chapter 3 further characterises anhedonia, revealing widespread impairments across anticipatory and consummatory dimensions in bvFTD and SD, while consummatory pleasure is relatively preserved in AD. Correlational findings highlight novel associations between anhedonia and everyday behavioural changes. Chapter 4 explores cognitive mechanisms, showing that deficits in episodic future thinking are associated with anticipatory anhedonia in FTD, suggesting an impaired ability to imagine positive future events. Chapter 5 compares anhedonia in bvFTD and mood disorders, demonstrating that consummatory anhedonia may distinguish neurodegenerative from affective conditions.
Together, the work presented in this thesis underscores the importance of recognising anhedonia as a core clinical feature of FTD, with significant implications for diagnosis, management, and quality of life. By elucidating the cognitive and behavioural underpinnings of anhedonia, this work paves the way for more targeted interventions aimed at improving patient outcomes and supporting caregivers
Evaluating Sleep Health in National Surveillance Systems: Gaps, Tools, and Strategies for Improved Monitoring
No full textIntrodcution
Sleep health is a multidimensional framework that contains several distinct but related domains. The integration of sleep health into public health surveillance systems is limited. Therefore, the aims of the thesis were to i) evaluate the current state of national surveillance systems in monitoring the sleep health of adults and ii) identify and assess the suitability of available tools for measuring sleep health in national surveillance systems.
Methods
A scoping review was conducted in Chapter 3 to identify existing national surveillance systems monitoring sleep health. Chapter 4 examined associations between sleep health indicators and sociodemographic factors and health conditions using cross-sectional data from the Australian Health Survey. Finally, in Chapter 5, a systematic review was carried out to identify and evaluate the validity and reliability of sleep assessment tools for use in health surveillance.
Results
Chapter 3 revealed that national sleep health surveillance was conducted in only 51 out of 199 countries examined. There was also a large disparity in surveillance between high-income and low- and middle-income countries. In Australia, surveillance only captured two sleep-related indicators: sleep duration and sleep medication use. Chapter 4 revealed that 16.8% and 15.4% of Australian adults experience short and long sleep, respectively, while 16.7% of adults with a long-term mental health condition used sleep medications for more than six months. Furthermore, sleep duration and sleep medication use were not significantly associated with chronic health conditions. Finally, Chapter 5 identified 57 sleep assessment tools that had been partially validated in general population samples and only two tools measured all domains of sleep health.
Conclusion
Overall, the thesis provided several practical and policy-related strategies and suggestions for future research to improve the monitoring of sleep health in national surveillance systems
Introducing the Time Factor into the Economic Framework of a Static General Equilibrium Model
No full textTime is an important ‘factor’ or ‘input’ into many economic activities, but up to now, the issue of time valuation has been considered mostly in a partial equilibrium framework such as in the context of travel time savings valuation. This does not allow for a more general consideration of the issue of time valuation especially in the wider context of an economy where almost any economic activity ‘takes time’. In a general equilibrium framework, however, the issue of time valuation seems to be neglected. This is because despite the fact that both production as well as consumption activities ‘take time’, production time is often considered only implicitly via the representation of the labour input: as a flow of labour service through time. Capital-time or machine-time, on the other hand, is ignored or masked under the representation of this input in the form of a stock rather than a flow (of capital services). Flow requires time, whereas stock is ‘timeless’. Therefore, it can be said that time is almost ‘absent’ in a (static) general equilibrium framework where, not only with regard to the issue about capital stock versus capital service flow (or utilization rate), in the long run as well as in the short run, but also with regard to the consideration of other so-called ‘fixed’ input, such land, natural or environmental resource stocks. These stocks are often taken into consideration but only with regard to the measurement of the (static) wealth of an individual or of a nation, but not with regard to the flow of the income which is derived from the activities of the individual or the nation (activities take time). In this paper, we consider the time factor in the framework of a ‘comparative static’ general equilibrium economic model because even here the operation of the time factor is still present and important and can affect the valuation (or costing) of many economic activities albeit in an implicit and subtle way
Insect-plant interactions of the Sydney Region
No full textThis data set contains the interactions and behaviours of of insects (Honey bees and hover flies) with plants recorded in Sydney, NSW between Winter 2019 and Autumn 2022We surveyed 30 sites across four seasons (Winter 2019-Autumn 2020) during favorable weather conditions (sunny/partly cloudy, winds 10°C). Sites were randomly visited within each three-month seasonal period.
At each site, we conducted a 20-minute, 100-meter transect survey, recording all insect-plant interactions within 2.5 meters of the transect line. An interaction was defined as an insect making contact with any plant part or hovering ≤10 cm above a plant for >2 seconds. Plants were identified to species level using the NSW Flora Online system.
Insects were collected via sweep net for identification, with survey timing paused during capture. Hover flies were identified to species level where possible using Thompson's (2011) unpublished keys, with expert verification by Andrew Young. Due to taxonomic complexity, Melangyna species (subgenus Austrosyphus) were treated collectively as Melangyna indet. Only honey bees (Apis mellifera) and Melangyna indet. had sufficient interaction numbers for analysis. All specimens are housed at The University of Sydney
Developing Chimeric Antigen Receptor T cells for the Treatment of Acute Myeloid Leukaemia
No full textAML is the most common acute leukaemia in adults with a high incidence of relapse following allogeneic HSCT. CAR T cells have shown remarkable outcomes in R/R B-cell leukaemia/lymphoma and MM. However, replicating this success in AML has been challenging chiefly due to heterogeneity of AML and lineage specific antigen expression in AML within and between patients, leading to immune escape and treatment failure.
CD123 is a leading target as it is frequently overexpressed in bulk and LSCs, with relatively lower expression on myeloid cells. Others in our lab have shown that PiggyBac CAR T cells targeting CD123 with natural ligand IL-3 recognition domain are effective in vitro. However, the discovery of CAR T derived lymphomas in treated patients prompted us to seek alternative gene modification systems. In this thesis, I explored 2 main themes, namely (i) to improve the genetic safety of CARIL3 therapy; and (ii) to increase the efficacy of anti-AML CAR T therapy.
Chapter 3 describes the pre-clinical development of CARIL3 using alternative lentiviral and PiggyBat systems with a focus on maintaining efficacy while exploring differences in gene integration patterns.
Chapter 4 looks at TIM-3 as another potential target with the aim of combining with CARIL3 to reduce the risk of antigen escape. The issue of fratricide due to expression of TIM-3 on T cells was overcome by CRISPR/Cas9 KO.
Chapter 5 explores whether the TIM-3 knockout could also improve efficacy of CARIL3, since TIM-3 is studied as a T cell exhaustion marker. The theme of genetic safety is again explored, by using CRISPR-Cas9 directed knock-in into the TIM-3 locus to minimise the risk of random integration.
While further work is required to enable safe and efficacious CAR T cells against AML in the clinic, the work in this thesis presents several proof-of-concept strategies taking significant steps towards realising this goal
Ngurra Barayagai (Song Belonging to Country)
No full textNgurra Barayagai (Song belonging to Country) takes the form of an insider researcher’s perspective
and cultural lens of a Darug song woman’s point of view. This thesis is practice-based research and
is documentation of my lived experience, while wogga (sewing) a virtual budbili (possum skin
cloak/rug) creating an anchor for the reader to visualise the many different aspects of a Songline and
how it can be repaired in a city like Greater Sydney. It has included field trips, yarning, ngara
(imaginative knowing), oolnga (intuition and gut-knowings) and wingarra (deep thinking).
This thesis is creating formal documentation of the language from Country, in all its different forms,
which it communicates to its people. It is creating a record of the lived experiences of some of the
Darug people communicating with their environment as a form of Country’s song. By gathering the
many different aspects of Songline repair, I aim to create new discussions and insights, evoke deeper desire for greater connection into this ancient fields of knowledge and bring back true respect
for our amazing past, present and future Australian culture.
Through the methodology I will wogga the different cultural lenses together, creating a common
ground, like a call and response to non-indigenous writings as a way of bringing balance to the
wogga of knowledge shared in these academic systems. The thesis is filling the gaps in our current
education systems, and providing alternative views to the colonized curriculum, which has presented
a one-sided approach to Australia’s history, and in turn influenced our society today and how
Australia promotes itself.
The outcome of the PhD is shedding new light on Ngurra Barayagai (Song Belonging to Country) that
is still present and ongoing for some Darug people who wish to create a better environment for all
living life forms to come