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(1998)Journal ArticleThe first results obtained using a SOI device for microdosimetry applications are presented. Microbeam and broadbeam spectroscopy methods are used for determining minority carrier lifetime and radiation damage constants. A spectroscopy model is presented which includes the majority of effects that impact spectral resolution. Charge collection statistics were found to substantially affect spectral resolution. Lateral diffusion effects significantly complicate charge collection
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(2008)Journal ArticleThe concept that macrophages can become foam cells as a result of a disturbed balance between the uptake of cholesterol from lipoproteins and cholesterol efflux is generally accepted. ABCA1 and ABCG1 are two cholesterol transporters that may act sequentially to remove cellular cholesterol, but currently their combined role in vivo is unknown. We report here that targeted disruption of both ABCA1 and ABCG1 in mice, despite severe plasma hypocholesterolemia, leads to massive lipid accumulation and foam cell formation of tissue macrophages. A complete ablation of cellular cholesterol efflux in vitro is observed, whereas in vivo macrophage-specific reverse cholesterol transport to the feces is markedly decreased. Despite the massive foam cell formation of tissue macrophages, no lipid accumulation was observed in the vascular wall, even in mice of 1 year old, indicating that the double knockout mice, possibly because of their hypocholesterolemia, lack the trigger to attract macrophages to the vessel wall. In conclusion, even under hypocholesterolemic conditions macrophages can be converted into foam cells, and ABCA1 and ABCG1 play an essential role in the prevention of foam cell formation.
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(1998)Journal Article
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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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(2023)ThesisSensory signals informing about frictional properties of a surface are used both for perception to experience material properties and for motor control to be able to handle objects using adequate manipulative forces. There are fundamental differences between these two purposes and scenarios, how sensory information typically is obtained. This thesis aims to explore the mechanisms involved in the perception of frictional properties of the touched surfaces under conditions relevant for object manipulation. Firstly, I show that in the passive touch condition, when the surface is brought in contact with immobilised finger, humans are unable to use existing friction-related mechanical cues and perceptually associate them with frictional properties. However, a submillimeter range lateral movement significantly improved the subject's ability to evaluate the frictional properties of two otherwise identical surfaces. It is demonstrated that partial slips within the contact area and fingertip tissue deformation create very potent sensory stimuli, enabling tactile afferents to signal friction-dependent mechanical effects translating into slipperiness (friction) perception. Further, I demonstrate that natural movement kinematics facilitate the development of such small skin displacements within the contact area and may play a central role in enabling the perception of surface slipperiness and adjusting grip force to friction when manipulating objects. This demonstrates intimate interdependence between the motor and sensory systems. This work significantly extends our understanding of fundamental tactile sensory processes involved in friction signaling in the context of motor control and dexterous object manipulation tasks. This knowledge and discovered friction sensing principles may assist in designing haptic rendering devices and artificial tactile sensors as well as associated control algorithms to be used in robotic grippers and hand prostheses.
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(2022)ThesisLess than 10% of patients with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years. One of the characteristic features that drive the aggressive nature of PDAC is its multicellular, heterogeneous, and fibrotic microenvironment. We previously identified a cytoskeletal protein, βIII-tubulin, as a novel therapeutic target in PDAC. However, the PDAC cell survival mechanisms controlled by βIII-tubulin were previously unknown. We also identified a major gap in the ability of human PDAC preclinical models to accurately mimic the 3D multicellular architecture and stroma of the disease. Thus, the aims of this work were (1) to evaluate the pro-survival role of βIII-tubulin in PDAC; (2) to establish a new patient derived tumour explant model that maintains all features of the PDAC microenvironment; and (3) to use the tumour explant model to test the clinical potential of silencing βIII-tubulin expression as well as two stromal targets that had been previously explored by our lab: solute carrier 7A11 (SLC7A11) and heat shock protein 47 (HSP47) Here, we identified that silencing βIII-tubulin in pancreatic cancer cells activated extrinsic apoptosis and increased their sensitivity to extrinsic apoptosis inducers including tumour necrosis factor-α (TNFα), Fas-ligand (FasL), and TNF-related apoptosis inducing factor (TRAIL). We next established the patient derived PDAC tumour explant model. We cultured whole-tissue tumour explants from PDAC patients for 12 days and demonstrated that explants maintained their 3D multicellular architecture, proliferative state, and collagen fibrosis. We also demonstrated the ability to deliver chemotherapeutics and siRNA-nanoparticles to the tumour explants. Finally, we tested the utility of this model to investigate the clinical potential of silencing three different therapeutic targets. We showed that therapeutic silencing of βIII-tubulin combined with TRAIL increased extrinsic apoptosis, decreased cell proliferation, and decreased tumour cell number. Inhibition of the stromal target SLC7A11 reduced tumour cell number and inhibited activity of stromal cancer-associated fibroblasts. Silencing of another target, HSP47, also led to a reduction in tumour cells and decreased cell proliferation. Overall, this work has discovered a previously unexplored role of βIII-tubulin as a brake on extrinsic cell death and has developed a new human PDAC preclinical model with utility in the drug development and precision medicine pipeline.
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(2022)ThesisCardiovascular disease (CVD) is the leading cause of global mortality. Two forms of CVD are acute coronary syndromes (ACS) and heart failure (HF). Patients with either are prone to repeat hospitalisations, which are detrimental to both patients and the healthcare system. Traditional care models are suboptimal in preventing readmissions. Mobile health interventions (MHIs) are attractive due to the computing power and convenience of the smartphone. Firstly, the literature regarding MHIs in CVD is systematically reviewed and meta-analysed. MHIs improved medication adherence in ACS patients and hospitalisation rates in HF patients. The review noted limitations of published trials and identified features of successful MHIs, which were incorporated into the design of a novel smartphone app-based model of care (TeleClinical Care, TCC). TCC allows home measurement of blood pressure, heart rate and weight by patients. The readings are automatically transmitted to a central server, where clinicians can identify abnormalities and intervene accordingly. A pilot RCT comparing TCC and usual care (UC) to UC alone was performed (n=164). Patients using TCC had fewer readmissions at 6 months (41 vs. 21, hazard ratio 0.51, P= 0.015), and were more likely to be adherent with medications (75% vs. 50%, P= 0.001) and complete cardiac rehabilitation (39% vs. 18%, odds ratio 2.9, P= 0.02) compared to patients in the control arm. A process evaluation of the RCT was subsequently undertaken, which identified several contributory factors to TCC’s success, such as a helpful orientation protocol for team members, and high background rates of HF outreach service and cardiologist follow-up in both trial arms. Via a series of interviews, methods to improve the future delivery of TCC were identified, particularly relating to its integration into mainstream healthcare. Patterns of smartphone ownership among cardiac inpatients were also examined. Age, sex, diagnosis, and private health insurance subscription influenced smartphone ownership. These data will help identify patients who may be excluded from MHIs. The thesis contains a cost-effectiveness model of TCC if applied widely. When enrolment exceeds 237 patients, TCC will reduce healthcare costs relative to UC, resultant to readmission prevention. Enrolment of 500 patients is projected to save $100,000 annually. In conclusion, TCC is demonstrated as a feasible, beneficial, safe, and cost-effective intervention for patients with CVD.
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(2022)ThesisSecreted by pancreatic β-cells, insulin is the major anabolic hormone, regulating the metabolism of fats, proteins, and carbohydrates. Defects in insulin production or action can lead to diabetes characterized by derangements in glucose handling and metabolic disease. Diabetes affects 420 million people worldwide, increasing morbidity, mortality and placing a burden on healthcare of nations. There is a need for rapid and accurate monitoring of insulin levels to optimize diabetes management and facilitate early diagnosis of insulin related chronic diseases. Conventional strategies such as HPLC, MALDI-TOF, ELISA, etc. used for insulin detection are not suitable for point-of-care testing (POCT) as they are expensive, and require sample preparation, sophisticated instruments, and skilled personnel. Our goal was to develop techniques to allow POCT for insulin in real time. In this study we developed two lateral flow assays (LFAs) based POCT platforms using aptamers as the biorecognition molecules for colorimetric and fluorescent detection of insulin. A range of conditions were tested such as concentrations of aptamers, reporter molecules used, volume of sample required, and assay time to obtain quantify insulin levels using a standard LFA reader. The colorimetric LFAs had linear detection range of 0.01-1 ng.mL-1 and LOD of 0.01 ng.mL-1. The fluorescent LFAs exhibited a linear detection range of 0-4 ng.mL-1 and 0.1 ng.mL-1 LOD. Various signal amplification strategies were incorporated, ie., gold-silver amplification technique and rolling circular amplification (RCA) to further enhance the signal. The developed colorimetric LFAs were successfully used for insulin quantification in rat blood, human blood, and human saliva samples. Although insulin levels were quantified within 12 min, some issues arose such as coagulation, need for dilution, and non-uniform flow through the test strips. Further work is required to optimize blood handling to progress an insulin POCT in real time. Future work could develop a multiplexed strip for detection of different analytes such as HbA1c, glucose, and C-peptide for better management of diabetes, along with a smartphone reader App. This research goes some way to addressing the challenge of providing a reliable and rapid approach for highly sensitive and specific detection of insulin for POCT applications.