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(2022)ThesisIn the last 40 years there have been many strides taken towards better and more selective cancer treatment using nanoparticles. Nanoparticles can have inherent passive accumulation in tumour cells, known as the enhanced permeability and retention effect (EPR) which makes them a strong therapy candidate; however this effect is not as well defined or effective as once thought. There is a large variance of efficacy between different patients due to the heterogeneity of tumours, therefore a more targeted nanoparticle systems needs to be designed to increase selectivity and efficacy. This thesis describes the design, synthesis, and characterisation of 20 novel ellipsoidal polymersomes decorated with peptide ligands for selective targeting of medulloblastoma, a childhood brain cancer. These ligands were FSRPAFL 1 a medulloblastoma cell targeting peptide and T7 26 a transferrin targeting peptide designed to aid in crossing the blood brain barrier (BBB). A new synthetic method was designed to attach the peptide ligands post self-assembly, so the peptides were attached to the hydrophilic corona rather than the hydrophobic membrane of the polymersomes. Analysis of these polymersomes showed more ligand available for binding but this did not translate to increased cell association due to an over saturation of ligand. The ratio and density of the targeting peptide 1 and BBB peptide 26 was altered on the surface of the polymersomes and it was found that the polymersomes with 100% T7 ligand showed rapid and high cell association with two different subtypes of SHH medulloblastoma (DAOY and UW228) as well as high association with brain endothelial cells that make up the BBB (HBEC-5i) making it a promising candidate as a drug delivery system for SSH medulloblastoma. Finally, linearly conjugated dual peptides made up of both targeting peptide 1 and T7 peptide 26 sequence, were synthesised and attached to the polymersome hydrophilic corona and analysed against the non-conjugated dual-functionalised peptide polymersomes. There was no significant difference between the two ligand conjugation method analysed but further research should be conducted to confirm this. The work described in this Thesis has shed light on the multitude of nuances that make up the composition of mono and dual functionalised peptide nanoparticle systems and how these can influence biological function. Future work will allow for a better understanding of fundamental questions about targeted nanoparticles therapies and how ligand characteristics directly impact biological function, selectivity and efficacy.
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(2022)ThesisRear-end crashes are a major part of road injury burden, accounting for one-third of all vehicle-to-vehicle crashes in New South Wales, Australia. Close following or driving with short headways is a key cause, yet the role of driver behaviour in rear-end crash risk is not well researched. The primary aim of this research was to develop a better understanding of rear-end crashes by assessing headways on Australian roads and investigating driver behaviour and performance associated with close following in crash and non-crash scenarios. Two systematic reviews of headway were conducted. First, a review of research on headway identified the need for a consistent and accurate definition of headway, so the thesis puts forward an improved definition. The second review identified the range of external factors that increase the risk of short headway and increase crash risk including speed, task engagement, lead vehicle type, traffic conditions, road characteristics, weather/visibility, drug use, driving fatigue, innovative lane markings, and various warning systems. These factors were then explored in New South Wales data on rear-end casualty and multiple vehicle crashes. The modelling of these associated factors were confirmed as contributing factors in rear-end crashes, congruent with the review of headway. Higher speed, free flowing traffic, volitional task engagement, low cue environments, and collision warning lead to longer headway. Despite lower fatalities, higher odds of injury were observed for rear-end crashes than other crash types. Rear-end crashes were more likely to lead to multiple vehicle crashes, which had a higher chance of fatality than other types of crashes. Finally, naturalistic driving study data was used to investigate headway during normal driving, exploring close following at different speeds and classifying potential risky driving at various headways. In 64 hrs accumulated across 2101 trips, short headways of under 1 s occurred in around 15% of driving. Common manoeuvres to avoid rear-end crashes when close following were changing lanes, or braking, almost always by the following driver. Headway was associated with both driver speed and posted speed limits, decreasing as posted speed limits increased. Over-the-speed-limit driving was observed in all headway scenarios, but especially in higher speed zones. The findings challenge the notion that rear-end crashes are less severe with low injuries. Road users should be made aware of how frequently safe headways are violated and severity of injury outcomes. Driver education, community engagement, application of driver assistance technology consistent with driver behaviour and safety campaigns need to focus on safer speed and headway management to reduce rear-end crash risk.
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(2022)ThesisFrom a child interrupting a conversation between her parents to ask "What's for dinner?" to a nurse interrupting a physician in the middle of a complex procedure with an urgent message, interruptions are an inevitable part of our daily lives no matter who we are, where we live, or what we do. Interruptions can have a variety of affects on people's performance and behavior. While interruptions may sometimes facilitate performance, often interruptions have negative consequences. For example, interruptions may result in people making more errors or forgetting to complete a prior task altogether. This thesis examines existing strategies to help mitigate interruption costs and explores the effects of interruptions within different decision environments. Chapter I introduces the topic by discussing a few theoretical frameworks of interruptions and reviewing prior research on what makes interruptions disruptive. One strategy to minimize interruption costs is to use what is called an interruption lag, which can be thought of as taking time to prepare for a pending interruption. Chapter II presents a novel experiment to systematically explore the potential benefits of interruptions lags and an alternative intervention (i.e. providing feedback) when interruption lags are not possible. Chapters III and IV discuss the results from three experiments and a final replication study that all focus on how interruptions affect people's decision making in unique environments. The environments consist of easy problems (i.e. basic arithmetic problems) and trick problems, designed in such a way to lead the reader down an incorrect path. Results from these studies were mixed. While there was some evidence that interruptions may make people more susceptible to falling for the trick answer, this finding was inconsistent across all the experiments. Chapter V applies the findings from the previous chapters to a medical context. This chapter presents novel medical cases that were developed with the help of a medical expert. These cases consisted of easy, hard, and trick cases designed for medical students. The goals of this chapter were to validate the cases and to investigate the effects of interruptions within the different case types. The final chapter (Chapter VI) concludes with a general discussion of the experimental findings, the theoretical implications of the results, and the broader implications of this research for the field of medicine.
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(2022)ThesisWellbeing, a key aspect of mental health, is defined as a state of positive subjective experience and optimal psychological functioning. This thesis presents a series of studies devised to comprehensively explore phenotypic, genetic, and neural correlates of wellbeing. The first study (Chapter 2) aimed to compare the heritability and stability of different wellbeing measures in the TWIN-E dataset (N~1600) to discern the most suitable approach for measuring wellbeing for subsequent gene discovery efforts. This twin-based study concluded that multi-item measures of wellbeing such as the COMPAS-W scale, were more heritable and stable than single-item measures. Wellbeing-associated variants were identified via genome-wide association studies (GWAS) and highlighted the need for larger sample size. The subsequent studies were conducted using population-scale data from the UK Biobank comprising ~130,000 participants with phenotypic and genetic data. Thus, in Chapter 3, I constructed a multi-item “wellbeing index” measure using UK Biobank data to investigate its relationship phenotypically and genetically (using GWAS, polygenic scores and LD score regression) with negative mental health indicators (e.g., neuroticism and loneliness), childhood maltreatment and psychiatric illness. I confirmed that SNP-heritability of wellbeing index was higher than both single-item measures and estimates previously reported (SNP-h2 = 8.6%). Moreover, I provide an overview of phenotypic and genetic correlations between wellbeing index and negative mental health indicators. In addition, childhood maltreatment and psychiatric illnesses were associated with reduced wellbeing, with evidence that genetic factors may influence their correlations. In Chapter 4, I investigated the genetic and phenotypic associations between wellbeing index and brain structure, using magnetic resonance image-derived phenotypes from the UK Biobank. This study found associations between wellbeing and volumes of brainstem, cerebellum and subcortical regions, and structural morphology of various cortical regions. Thus, wellbeing is associated with complex structural variations, each with a small effect. Together, this thesis explores the multifaceted nature of wellbeing, elucidating its phenotypic and genetic relationships with related phenotypes, childhood maltreatment, and psychiatric outcomes, and provides novel insights into the associations between wellbeing, its genetic signatures and brain structure.
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(2022)ThesisThere is an ongoing global threat of highly transmissible infectious disease outbreaks such as the COVID-19 pandemic. Consequently, the demand for effective, sustainable, and reusable personal protective equipment (PPE) is high for the protection of the frontline workers and community, especially with possible vaccine-resistant variants emerging. However, the commonly used PPE, especially protective clothing, and face masks, has several drawbacks and improvement areas. In this thesis, three state-of-the-art reviews (Chapters 2A, 2B, and 2C) identified the challenges and limitations of commonly used protective clothing and face masks. Potential new materials, technologies, and strategies were also addressed to overcome the limitations and challenges. Lastresort strategies were outlined to help people navigate their choices during mask shortages. In addition, it was revealed that the multifunctional performance of PPE could be significantly enhanced with the application of advanced materials such as graphene and metal nanoparticles (NPs). Accordingly, in Chapters 3 and 4, reduced graphene oxide (RGO) and copper (Cu)/silver (Ag) NPs incorporated cotton and silk fabrics were developed by a facile dip and dry method using a silane crosslinking agent followed by chemical reduction and vacuum heat treatment. The developed fabrics demonstrated excellent multifunctional activities such as hydrophobicity, electroconductivity, Joule heating capacity, heat dissipation, thermal stability, mechanical stability, UV shielding, and washing durability. Especially, the RGO- and Cu-NPs-embedded cotton and silk fabrics exhibited the best multifunctional performances with high washing durability among all other fabric samples. To further assess the potential of protective clothing, antimicrobial activity and biocompatibility of the developed fabrics were investigated in Chapter 5. The graphene and Cu/Ag NPs incorporated fabrics showed excellent activity against bacteria (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus) and fungus (Candida albicans). On top of the antimicrobial activity, the developed fabrics showed low cytotoxicity, making them a potential candidate for application in next-generation PPE. During COVID-19, due to the massive global shortage of disposable masks/respirators, cloth masks became a mainstay and showed hope of being a sustainable alternative to medical masks. Chapter 6 provides a comprehensive study using violent respiratory events (sneeze) and evaluating all dimensions of protection (respiratory droplet blocking efficiency, water resistance, and breathing resistance) to develop a blueprint for the optimal design of a high-performing reusable cloth mask that can outperform a disposable surgical mask. The results reveal that droplet blocking efficiency increases by ∼20 times per additional fabric layer. A minimum of 3 layers with a combination of cotton/linen (hydrophilic) for the inner layer, blends for the middle–layer, and polyester/nylon (hydrophobic) for the outer–layer is required to resemble the performance of surgical masks. The fabrics' average thread count and porosity should be greater than 200 and less than 2 %, respectively. Overall, the developed graphene/NPs incorporated multifunctional fabrics, and face mask design proved to be a breakthrough to prevail over the limitations of the conventional PPE materials. They hold great promise to be applied to a broader range of PPE and could provide a sustainable PPE solution globally.
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(2022)ThesisThis thesis focuses on the development and applications of magnetic resonance electrical properties tomography (MREPT), which is an emerging imaging modality to noninvasively obtain the electrical properties of tissues, such as conductivity and permittivity. Chapter 2 describes the general information about human research ethics, MRI scanner, MR sequence and the method of phase-based MREPT implemented in this thesis. Chapter 3 examines the repeatability of phase-based MREPT in the brain conductivity measurement using balanced fast field echo (bFFE) and turbo spin echo (TSE) sequences, and investigate the effects of compressed SENSE, whole-head B_1 shimming and video watching during scan on the measurement precision. Chapter 4 investigates the conductivity signal in response to short-duration visual stimulus, compares the signal and functional activation pathway with that of BOLD, and tests the consistency of functional conductivity imaging (funCI) with visual stimulation across participants. Chapter 5 extends the use of functional conductivity imaging to somatosensory stimulation and trigeminal nerve stimulation to evaluate the consistency of functional conductivity activation across different types of stimuli. In addition, visual adaptation experiment is performed to test if the repetition suppression effect can be observed using funCI. Chapter 6 explores if resting state conductivity networks can be reliably constructed using resting state funCI, evaluates the consistency of persistent homology architectures, and compares the links between nodes in the whole brain. Chapter 7 investigates the feasibility of prostate conductivity imaging using MREPT, and distinctive features in the conductivity distribution between healthy participants and participants with suspected abnormalities.
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(2022)ThesisRodents learn to fear a stimulus (e.g., a light) that signals the imminent arrival of an innate source of danger (typically an aversive foot shock). They also learn to fear a stimulus (e.g., a noise) that signals a learned source of danger (e.g., the already conditioned fear-eliciting light). Following Pavlov (1927), the former type of fear is termed first-order conditioned fear, because the stimulus is paired with an aversive unconditioned stimulus (US). The latter is termed second-order conditioned fear, because the stimulus is paired, not with a US, but with an already conditioned stimulus. There are both commonalities and differences in the neural substrates underlying these two forms of fear. Both require neuronal activity in the basolateral amygdala complex (BLA), including activation of NMDA receptors, for their encoding, and both require CaMK signalling, gene expression and DNA methylation for their consolidation. However, de novo protein synthesis is required for consolidation of first-order fear but not for consolidation of second-order fear.
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(2022)ThesisA breakdown in B cell self-tolerance can lead to antibody-mediated autoimmune disease. This thesis aims to explore how B cell tolerance can be broken in two distinct, but complementary projects within the context of the Goodnow somatic mutation hypothesis. In both scenarios, B cells that escape self-tolerance and generate autoantibodies are referred to as “rogue” B cells. First, this thesis aimed to elucidate the precise steps undertaken by expanded rogue B cell clones in patients with chronic Hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis, an autoimmune disease characterised by the production of a rheumatoid factor cryoglobulin autoantibody. The rogue B cell clones in the HCV cryoglobulinemic vasculitis patients were confirmed to be the source of the autoantibody. The rogue B cell clone precursor antibodies failed to bind the HCV envelope glycoprotein E2, yet bound multimerised self-antigen IgG relative to membrane IgM density. These findings disfavour a molecular mimicry hypothesis, and instead indicate IgG immune complexes may be sufficient to drive recruitment of the rogue B cell clone precursors. Finally, the rogue B cells clones were found to carry somatic lymphoma-associated, non-immunoglobulin gene mutations and chromosomal aberrations, predicted to cause hyperactivation of the NF-kB signalling pathway and escape of B cell tolerance. This finding provides additional evidence in support of the Goodnow somatic mutation hypothesis. Second, this thesis examined rogue germinal centre (GC) B cells that arise in the absence of the receptor FAS. Rogue GC B cells loose specificity for the foreign antigen and incidentally generate autoantibodies. However, the accumulation of rogue GC B cells cannot be explained by our current understanding of affinity-based selection in the GC. This work revealed rogue GC B cells, unlike “conventional” GC B cells undergoing affinity maturation to the foreign antigen, can be identified by low expression of CD21 and high expression of B220 (CD21loB220hi). Moreover, rogue GC B cells were found to be rapidly entering cell cycle, enriched for a dark zone phenotype and T-cell dependent, reminiscent of positively selected GC B cells. Thus, rogue GC B cells typically removed by FAS, likely persist in the competitive GC microenvironment despite their loss of BCR specificity to foreign antigen, because they retain the capacity to undergo T-cell dependent positive GC selection.
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(2022)ThesisT cells are critical in the body's defence against viruses and cancerous cells. They specifically recognise viral or tumour antigens presented on antigen presenting cells using their T cell receptor (TCR). Antigen binding triggers the TCR, transmitting signal intracellularly and resulting in the recruitment of a plethora of signalling proteins to the membrane. The signal is transmitted by post-translational modifications, such as the phosphorylation of tyrosine residues in intracellular tails of receptors, resulting in the recruitment of signalling proteins via their interaction domains. The spatial organisation of signalling proteins at the membrane determines the effector response of the T cell and is therefore critical for understanding the complex array of T cell responses. In this thesis, I develop a novel microscopy technique that reports on the nanoscale locations of signalling proteins and their binding kinetics to receptors at the T cell membrane. This technique utilizes the SH2 interaction domains of various signalling proteins which selectively and transiently bind to phosphorylated tyrosines on receptors. This transient binding results in the stochastic blinking necessary for super-resolution microscopy. Using this technique, termed protein point accumulation in nanoscale topography (pPAINT), I investigate the binding of multiple signalling proteins, achieving multiplexed imaging both simultaneously and sequentially with a combined microfluidic and microscopy approach. In the second half of this thesis, I apply pPAINT to study how chimeric antigen receptors (CARs) signal in T cells. In CAR-T therapy, patient cytotoxic T cells are isolated and transduced with a CAR construct that recognises tumour antigens, and are then reintroduced into the patient where they find and eliminate cells expressing the CAR target antigen. CAR constructs are made up of an antigen recognition domain fused to various intracellular signalling motifs from the TCR complex and co-stimulatory receptors, such as CD28, which are crucial for T cell activation. The first-generation of CARs contained an intracellular tail of the TCR, the CD3ζ chain, but it has been the second-generation CARs, with the addition of co-stimulatory receptor signalling domains, that have proven clinically effective. However, CAR therapy is not successful in all patients; limitations reducing their efficacy include inefficient recognition of low antigen densities, finite persistence in the body and off-target side effects in patients. It follows that a detailed knowledge and understanding of CAR activation and signalling is needed to optimise CAR design. In this thesis I use pPAINT to gain a unique perspective on how different generations of CARs signal upon activation, identifying key similarities and differences to signalling from the standard TCR. Signalling was investigated in CAR-T cells generated in a similar way to clinically used CAR-T therapies. In doing so, unique signalling mechanisms utilized by CARs were identified that will be valuable for the development of more effective chimeric antigen receptors. The results demonstrate that although CARs utilise the signalling domains of the TCR and co-stimulatory receptors, the pattern of adaptor protein recruitment is different from that of T cells stimulated through the TCR and co- stimulatory receptors. Specifically, I found that whilst hubs of signalling proteins spatially diverged from clusters of activated TCR, they were instead closely colocalised with activated CARs. The incorporation of the CD28 coreceptor in CAR design improves signalling protein recruitment patterns, however, the patterns of protein binding were still vastly different to co-stimulated T cells. Collectively, the results indicate that CARs utilize a signalling pathway unique to that of costimulated T cells, in a mechanism that may have ramifications in the functional responses exhibited by cells used in CAR-T therapy.
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(2022)ThesisWith widespread access to combination anti-retroviral therapy (cART) and HIV suppression, life expectancy among people living with HIV (PLHIV) is increasing more than ever. According to UNAIDS, there were 8.1 million older PLHIV (i.e., 50 years of age and over) in 2020 globally. Although HIV-associated dementia has become rare in the cART era, mild neurocognitive impairments remain prevalent among PLHIV (~30% in virally suppressed). With aging, there is an increasing concern that HIV may precipitate neurocognitive abnormal aging because HIV is associated with increased markers of aging (e.g., immunosenescence and hyper-coagulopathy) and multiple age and HIV-related comorbidities (e.g., cardiovascular diseases). Importantly, these comorbidities occur at an earlier age and at a higher rate among PLHIV compared to age-matched HIV-negative persons. Earlier, more severe and more rapidly progressing neurocognitive impairment would have major public health consequences for the millions of PLHIV and the healthcare system. The overarching aim of this PhD thesis is to determine whether having chronic stable HIV infection and suppressive ART is associated with abnormal cognitive aging including premature cognitive aging (HIV and age synergistically/addictively lead to much lower cognitive performance at a younger age compared to controls), accentuated cognitive aging (HIV and age synergistically/addictively lead to much greater prevalence and severity of neurocognitive impairment), and/or accelerated cognitive aging (HIV and age synergistically/ addictively lead to much more rapid progression of neurocognitive impairment). To address these questions, we used a range of scientific methodologies including a systematic review, and several types of advanced statistical analyses using national and international longitudinal cohort data. First, to contextualise the potential public health consequences of cognitive aging in PLHIV, we conducted a narrative review of the burden of established dementia risk factors among PLHIV. We identified that the burden of several major dementia risk factors is much greater among PLHIV than in the general population. Second, we conducted the first-ever systematic review evaluating the current evidence for premature, accentuated and accelerated cognitive aging among PLHIV. We determined moderate evidence for premature cognitive aging and strong evidence for accelerated cognitive aging, while accentuated cognitive aging had not been optimally assessed. Lastly, addressing the previous literature major limitations (low sample size, cross-sectional study design, low proportion of older PLHIV, and inadequate controls/norms), we quantified the profiles of cognitive aging in four longitudinal studies of PLHIV. We demonstrated robust trends for premature cognitive aging among PLHIV compared to age-matched HIV-negative persons. We also demonstrated that older PLHIV had a higher risk for both neurocognitive impairment and neurocognitive decline compared to younger PLHIV, while controlling for normative age effect. These results are indicative of both accentuated and accelerated aging, although our research identified the need for longer-term studies using very large sample size to assess these trends especially in PLHIV older than 70+. Based on these findings, we discussed implications for clinical practice and future research directions.