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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)ThesisThe aim of this thesis is the development of microscopy-compatible electronic devices to advance the field of biosensing in two main directions. First, the development of a platform that allows electrical and optical studies of membrane proteins at the single molecule level. We have fabricated InAs nanowire field-effect transistors and PEDOT:PSS organic electrochemical-transistors on 170 μm thick glass slides for their integration with fluorescence microscopes. Each electronic device was fabricated at the bottom of a circular well sealed with a lipid bilayer. A wide range of membrane proteins can be inserted into this lipid bilayer, most of which work as pores or active pumps for the transport of ions across the membrane. This platform allows simultaneous electrical and optical studies of such proteins, achieving single-molecule resolution when a single protein is inserted in the bilayer. We present the fabrication procedures for these devices and the creation of a lipid membrane over them, as well as electrical characterization and ion sensitivity measurements. The development of novel hardware to achieve electrical contact with the devices while performing fluorescence microscopy is also presented. We demonstrate the viability of our platform via the correlation of electrical and optical signals in response to ion concentration and lipid bilayer rupture. We also present a computational model that provides insight into this system and propose future optimization steps towards the incorporation of membrane proteins into the system. Second, the creation of a sensor that allows electrical detection of a moving target at the single molecule level. In this thesis, we present a theoretical model to determine the feasibility of detecting an actin filament or microtubule passing in close proximity to a carbon nanotube field-effect transistor. This platform would allow the detection of moving biomolecules without the need to physically attach the molecules to the electronic devices. Our results showed that electrical detection is possible given the right experimental conditions. This would enable tracking of large numbers of molecules at once, an important advance for applications where the detection of biological agents is relevant, such as biocomputation.
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(2022)ThesisThe inflammatory artery diseases atherosclerosis and abdominal aortic aneurysm (AAA) are major causes of morbidity and mortality and there is significant attention towards identifying and targeting prominent inflammatory mediators underpinning these cardiovascular diseases. In the first chapter, the role of the pro-inflammatory and pro-oxidant enzyme myeloperoxidase (MPO) in inflammatory artery disease was studied. A clinical study showed that while circulating plasma MPO levels were not different in AAA patients versus healthy controls, immunohistochemistry showed that the MPO protein was prevalent in human AAA tissue. In the angiotensin II (AngII)-infusion model of AAA and atherosclerosis in apolipoprotein-E gene-deficient (ApoE–/–) mice, administration of 2-thioxanthines (2-TX), a clinically-trialled MPO inhibitor, significantly inhibited AAA but not atherosclerosis. Paradoxically, MPO gene-deficiency did not affect AngII-induced AAA but attenuated atherosclerosis. Notably, 2-TX significantly inhibited AAA in ApoE–/–MPO–/– mice, indicating 2-TX protects against aortic disease in the absence of MPO. The role of MPO in the diabetes-accelerated atherosclerosis in ApoE–/– mice was also examined. While MPO gene-deficiency did not impact on the degree of diabetes it significantly reduced diabetes-accelerated atherosclerosis at the brachiocephalic artery and aortic sinus, but not aortic arch, indicating that MPO exhibits site-specific effect on atherosclerosis. A second chapter focused on semicarbizide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), a pro-inflammatory enzyme that facilitates the vascular recruitment of activated leukocytes. Treatment of AngII-infused ApoE–/– mice with a clinically-viable SSAO/VAP-1 inhibitor significantly protected against AAA and atherosclerosis, independent of alterations to plasma lipid levels. A third chapter tested the therapeutic efficacy of apolipoprotein A-I (ApoA-I), the major cardioprotective protein in high-density lipoproteins, and a class of immunomodulatory nanoparticles (INPs), which selectively target and disable a pro-inflammatory monocyte subset. Although ApoA-I treatment did not impact on the development of arterial disease in AngII-infused, aged ApoE–/– mice, INPs provided significant protection against AAA and atherosclerosis in these mice. This novel research provides new insights on the roles of MPO and SSAO in AAA and atherosclerosis and identified clinically-viable inhibitors of MPO and SSAO and a class of biodegradable immunomodulatory nanoparticles as potential new therapeutics for treating inflammatory artery disease.
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(2023)ThesisMuch evidence indicates that maternal obesity programs a range of complications in offspring, highlighting the need to identify beneficial interventions. The present thesis examined if the programmed effects of maternal obesity on offspring are exacerbated by exposure to a high-fat, high-sugar ‘Cafeteria’ (Caf) diet and investigated the effects of a healthy diet intervention in adulthood. The first study examined whether a diet switch intervention could reverse the adverse effects of an unhealthy postweaning diet in male and female rat offspring born to dams fed standard chow or a high-fat, high-sugar, Caf diet. Weanling offspring from Caf dams were smaller and lighter, yet had more retroperitoneal (RP) fat, particularly in males. Maternal obesity enhanced the impact of postweaning Caf exposure on adult (14-week-old) body weight, RP fat, liver mass and plasma leptin in males but not females. Maternal Caf diet significantly increased relative expression of ACACA and Fasn in male and female weanling liver, whereas PPARα was increased in males from Caf dams. Hepatic CPT-1 expression was reduced in adult males from Caf fed dams. The results underline the sex-specific detrimental effects of maternal obesity on offspring; maternal obesity exacerbated the obesogenic phenotype produced by postweaning Caf diet in male, but not female offspring. A subset of rats from this first cohort were maintained on their postweaning diets until 22 weeks of age, when postweaning Caf groups were switched to chow for a further 5 weeks. Switching from Caf to chow in adulthood suppressed energy intake below groups maintained on chow. Consequently, body weight and adiposity fell in switched groups, but remained significantly higher than chow-fed controls. The diet switch improved a deficit in place recognition memory observed in Caf-fed groups, with no significant change over time in chow-fed groups. Importantly, the effects of the switch did not differ between offspring born to chow or Caf-fed dams. Thus, in these older adult offspring a healthy dietary intervention led to benefits regardless of prior exposure to maternal obesity. To complement these data, our second study investigated if the programming effects of maternal obesity were aggravated by offspring exposure to a Caf diet when introduced in adulthood. Male and female offspring from lean and obese dams were weaned onto chow until 9 weeks of age; siblings were then either continued on chow or switched to Caf diet for 5 weeks. Offspring from Caf dams were smaller than those from chow dams at birth, and exhibited greater adiposity, plasma glucose and leptin levels at weaning in both sexes. Offspring of Caf dams exhibited elevated liver triglyceride content at weaning but no significant changes in the liver antioxidant enzymes GPx, SOD, and CAT. The switch to Caf diet elevated body weight and fat mass, with more pronounced effects in females than males. As in our first study, adult males (14 week old) from Caf-fed dams exhibited increased body weight, adiposity, and plasma insulin and leptin levels relative to offspring from chow dams. In female offspring, only RP fat mass and plasma insulin were increased by maternal obesity. Moreover, there were behavioural effect of maternal obesity (reduced anxiety-like behaviour) on offspring. Thus, the effects of maternal Caf diet exposure were absent until a cafeteria diet challenge in adulthood, indicating that Caf diet-induced maternal obesity programs a latent vulnerability to obesogenic diet exposure in offspring, particularly in males. Further studies are needed to investigate the beneficial effects of reprogramming strategies such as healthy diet intervention in offspring, which are likely to be influenced by the duration, timing and mode of intervention.