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The effect of prolonged glucose and insulin stimulation on mitochondrial function in endothelial cells
No full textAbstract not currently available
Transforming museum exhibits using interactive mixed-reality
Full text linkMuseums play a crucial role in preserving and communicating cultural, historical, and scientific knowledge. However, traditional exhibition methods often limit visitor engagement and comprehension. This research investigates how mixed-reality (XR) technologies (integrated with Artificial Intelligence (AI) and Computer Graphics (CG)) can transform visitor experiences within museum environments, with a focus on the Hunterian Museum’s Science Collection.
Building on these insights, a prototype mobile and mixed-reality application was designed and developed to enable immersive exploration of artefacts in 3D, interactive storytelling, and adaptive learning experiences. The system architecture integrated wearable interfaces, edge computing, cloud services, and AI-driven modules for speech recognition, natural language processing, and personalized recommendations.
After finishing the implementation of my App, functional and performance evaluations are operated. It identified optimal solutions for enabling natural user interaction, while user studies demonstrated significant improvements in engagement, comprehension, and satisfaction compared to traditional exhibition methods. The findings indicate that AI-enhanced XR applications can provide inclusive, dynamic, and educational museum experiences, bridging the gap between physical artefacts and visitor understanding. This research contributes a practical framework for integrating immersive technologies into museum practice and offers insights for future developments in adaptive, user-centered digital heritage experiences
Hydrological responses to wetland changes in the Yangtze River Basin
Full text linkAs the most productive ecosystems in the world, wetlands play a vital role in carbon cycling, climate change mitigation, socio-economic development, and natural disaster protection. The Yangtze River Basin (YRB) contains 40% of the national wetlands and the most frequent floods in China. In recent decades, the abundant wetland resources in the YRB have experienced substantial changes due to the climate change and human activities, significantly affecting the flood risk. Due to the lack of a long-term time series wetland dataset with comprehensive categories for the YRB, the effects of wetland variations on flood risk, as well as improved assessments of past and future flood risk incorporating wetland dynamics, remain underexplored. Moreover, wetland-related flood risk mitigation efforts in the YRB are less widely adopted. It is crucial to address these gaps for enhancing the sustainable wetland management and flood risk mitigation in the YRB.
This thesis aims to achieve three primary objectives: 1) to establish a long-term time series wetland classification dataset with the comprehensive categories in the YRB and analyze driving forces of their variations; 2) to investigate the long-term wetland effects on the flood risk in the YRB based on an improved GIS-based multi-index flood risk assessment model incorporating wetlands input; and 3) to predict the future flood risk with wetland effects in the middle-lower YRB under climate change and socio-economic scenarios.
The Long-term Wetland Classification Dataset for YRB (LTWCD_YRB) with nine wetland categories from 1984 to 2021 was created by using the Random Forest machine learning classifier on the Google Earth Engine platform with 30m resolution Landsat images. The LTWCD_YRB revealed that: 1) the total wetland area of the YRB in 2021 was larger than that in 1984, with a constant increase in human-made wetlands and fluctuating natural wetlands; 2) aquaculture ponds expanded the most by 4,987 km2, while inland marshes in the source region exhibited the most fluctuations; and 3) seasonal changes in wetlands were prominent in the Poyang Lake Basin, Dongting and Honghu Lake Basin, and YRB source region; and 4) human activities were found to be more dominant than natural driving forces in affecting wetlands. The LTWCD_YRB offers a consistent agreement of wetland area variations with the other satellite-based wetland datasets in the YRB.
To investigate the long-term effects of wetland variations on flood risks in the YRB, this thesis developed an improved GIS-based multi-index flood risk assessment model incorporating the wetland input obtained from the LTWCD_YRB. The findings indicated that: 1) wetlands in the Taihu Lake Basin, Wanjiang Plain, Poyang Lake Basin, and Dongting and Honghu Lake Basin could mitigate flood risks, while wetlands in the Sichuan Basin have aggravated but limited impacts on flood risks; and 2) Precipitation in the Taihu Lake Basin and Poyang Lake Basin, runoff and vegetation cover in the Wanjiang Plain, GDP in the Taihu Lake Basin, population density in the Taihu lake Basin, Dongting and Honghu Lake Basin, and the Sichuan Basin are dominant flood risk indicators under wetland effects. The wetland-related suggestions to mitigate flood risks including maximizing stormwater storage capacity of wetlands and increasing vegetation coverage in urbanized and precipitated regions.
The flood risk prediction of the middle-lower YRB applied the improved flood risk model to assess the flood risk from 2021 to 2100 under the Shared Socioeconomic Pathways (SSP) 2 - Representative Concentration Pathways (RCP) 4.5 and SSP5-RCP8.5 scenarios. The results indicated that: 1) the high and very high flood risk areas will totally cover 38% and 40% of the total study area under the SSP2-4.5 and SSP5-8.5 scenarios by 2100, respectively; 2) the overall flood risk of the MLYRB was predicted to become severer by 2100 under both scenarios; and 3) there would be a prominent northward expansion of the high and very high flood risk areas in Jiangxi, Hunan and the southern part of the Taihu Lake Basin in Jiangsu.
In summary, this thesis provides the data support for the long-term wetland variations in the YRB, develops an improved flood risk model to investigate the long-term wetland effects on the flood risk and predicts the future flood risk incorporating wetland dynamics in the YRB. The efforts of thesis contribute to the sustainable wetland conservation and flood risk mitigation in the YRB, aligning with the United Nations Sustainable Development Goals
Investigating the potential importance of Hedgehog signalling in conferring Venetoclax resistance in AML
Full text linkHedgehog (Hh) signalling pathway is a highly conserved pathway, which plays a crucial role in the development, maintenance and regeneration of human tissues. Its role in the primitive and definitive haematopoiesis has been extensively studied. Its activity has been proven to be a critical mechanism in the pathogenesis of tumours, either solid or haematological. It has a vital role in promoting the proliferation and survival of acute myeloid leukaemia (AML) cells, including leukaemia stem cells (LSCs). Moreover, it contributes to therapy resistance. Several Hh signalling pathway inhibitors have been generated and are involved in AML clinical trials. The outcomes of these trials are promising. Glasdegib is a Smoothened (SMO) inhibitor, which has been approved in combination with low-dose Cytarabine (LDAC) for newly diagnosed cases of AML in patients who are not fit for extensive chemotherapy. This follows the promising results of the BRIGHT AML 1003 trial.
The introduction of Venetoclax, a BCL2 inhibitor, into clinical practice marked a revolution in the treatment of leukaemia, particularly since the anti-apoptotic B-cell lymphoma 2 (BCL2) proteins were observed to be overexpressed in different types of leukaemia and are associated with chemoresistance. Testing Venetoclax for the newly diagnosed AML patients in the VIALE-A and VIALE-C trials demonstrated promising outcomes and superiority over low-dose chemotherapy alone regimens. Thus, in AML, Venetoclax has been approved for use in combination with Hypomethylating agents (HMA) (such as Azacitidine or Decitabine) or LDAC in newly diagnosed AML patients who are unfit for intensive chemotherapy.
Before that time, Glasdegib regimens were more involved in clinical trials and clinical settings; however, the promising efficacy achieved by Venetoclax resulted in the widespread adoption of the Venetoclax-based regimens. Venetoclax resistance has been a critical challenge hindering the efficacy of several leukaemia-treatment protocols.
This thesis aimed for the repurposing of the clinically approved drugs, Glasdegib and Venetoclax, to combat therapy resistance. This work investigated the potential involvement of the Hh signalling pathway in Venetoclax resistance in AML and whether its role in Venetoclax resistance is dependent on anti-apoptotic BCL2 proteins or not.
Venetoclax-resistant (VE-RE) cell line models have been established to investigate the potential mechanisms of resistance with particular focus on the role of Hh pathway. Inducing resistance was accomplished by exposing the Venetoclax-sensitive cells of MOLM-13 cells to increasing concentrations of Venetoclax in an intermittent (group 1) or continuous (group 2) manner. Venetoclax resistance was validated in VE-RE MOLM-13 groups 1 and 2 by comparing their half-maximal inhibitory concentration (IC50) to Venetoclax with that of the wild-type MOLM-13. There was an approximately 209-fold and 418-fold increase in the Venetoclax IC50s in VE-RE MOLM-13 group 1 and 2, respectively.
VE-RE MOLM-13 groups 1 and 2 cells were profiled at the transcriptomic and genomic levels to identify potential mechanisms of Venetoclax resistance. Additionally, Venetoclax-treated (VE-TR) MOLM-13 cells at 2nM, 4nM, and 6nM were profiled, as well, to determine the trend of change and the onset of the mutations, as it is believed that Venetoclax resistance develops gradually over time, rather than immediately upon exposure to Venetoclax. The expression of BCL2 family members and Hh signalling pathway was found to be deregulated. BCL2, Myeloid cell leukaemia-1 (MCL1), BCL2 Like 1 (BCLxL), Suppressor of Fused (SUFU) and Patched 1 (PTCH1) were significantly changed from the sensitive cells to the resistant cells.
Screening VE-RE cells for the potential causes underlying Venetoclax resistance revealed interesting, promising contributors. Based on the observations reported in clinical studies, these contributors provide valuable insights into Venetoclax resistance. Thereby, further investigations are warranted to explore their therapeutic implication in VE-RE AML. Among these potential contributors are Mitogen-Activated Protein Kinase Kinase Kinase Kinase 1 (MAP4K1), KIT Proto-Oncogene (KIT), Mesothelin (MSLN), S100 Calcium Binding Protein A4 (S1004A), N-Myristoyltransferase 2 (NMT2), Mouse Double Minute 4 (MDM4) and Transmembrane BAX Inhibitor Motif Containing 4 (TMBIM4). Several deregulated genes were found to have a significant association with adverse patient survival based on multiple AML datasets.
VE-RE MOLM-13 groups 1 and 2 cells were tested against Glasdegib alone and in combination with Venetoclax. Based on our preclinical results, the combination experiments between Glasdegib and Venetoclax have improved the sensitivity of the wild-type (Bliss synergy score of 23.40) and VE-RE MOLM-13 cells of both groups to Venetoclax (Bliss synergy score of 8.59 and -5.33, respectively). Studying the cell cycle kinetics changes upon adding Glasdegib to Venetoclax revealed a significant increase in the percentage of cells in the sub G0 phase in wild-type MOLM-13 and VE-RE MOLM-13 groups 1 and 2.
This combined effect can be explained by either inducing the quiescent leukaemic cells from G0 phase by Glasdegib to be targets for the action of Venetoclax, Glasdegib-mediated apoptosis, or Glasdegib-induced downregulation of anti-apoptotic BCL2 family proteins.
The Hh signalling pathway was found to depend, to some extent, on anti-apoptotic BCL2 family proteins in inducing Venetoclax resistance. This was shown by the role of Glasdegib in the downregulation of BCL2, MCL1, and BCLxL. This was detected following the treatment of wild-type MOLM-13, VE-RE MOLM-13 groups 1 and 2 by two concentrations of Glasdegib.
Venetoclax resistance is a collaboration of multiple mechanisms that carry variable intensities upon continuous or intermittent exposure to Venetoclax. Continuous exposure was concluded to cause a higher degree of Venetoclax resistance.
Finally, this work established a valuable fact, in which Hh signalling pathway is involved in the emerging Venetoclax resistance. Furthermore, activation of Hh signalling in VE-RE cells can occur in a canonical or non-canonical manner. Glasdegib-mediated blocking of the canonical activation of the Hh signalling improves the apoptotic effect of Venetoclax on the VE-RE MOLM-13 cells.
SUFU, which encodes for a GLI Family Zinc Finger (GLI) sequestering protein, is a valuable biomarker that warrants further investigation, particularly as it is significantly downregulated in VE-RE MOLM13 of both groups. Moreover, it has been observed from studying its effect on patient survival that its low expression has a significant association with adverse patient survival in the early follow-up period in cohorts of either AML or other malignancies
Energetics as a system of cadence: four studies of Schoenberg, Brahms, Boulez, and Cage
Full text linkThis thesis shows how Andrew Eason’s Schoenbergian closing concept can be used on a broader repertoire of non-tonal music to provide formal readings. It shows this by using the Schoenbergian closing concept, which this study refers to as the Schoenbergian cadence, to analyse Schoenberg’s music and three other composers, and how the Schoenbergian cadence applies to music beyond the strict focus of Eason’s “Cadence as Gesture in the writings of Arnold Schoenberg”. The Schoenbergian cadence is defined in both material and non-material terms, and this study makes its analyses with the understanding that this music is of a repertoire which is either historically or conceptually related to that of Schoenberg, and which uses the same cadence concept is analysable with the same approach. At the end of his conclusions, Eason writes that his essay would be useful for analysts in forming a new path into non-tonal music. It is my intention that this study forms that new path into non-tonal music for composers. Specifically, I refer to composers who have training in a Western-European, classical or post-classical approach to composition, who would take classes in harmony, counterpoint, and form. It is my intention that the approach to the music which is taken in this study, would give these composers and students of composition a way into the piece of non-tonal music’s repertoire explored herein
Roman Catholicism and the senses in early modern English drama
No full textAbstract not currently available
Low power compact dual mode detectors for nuclear security applications
Full text linkThe transportation and use of illicit Special Nuclear Material is a challenge that must be addressed in an increasingly nuclear world. To this end, different monitoring techniques of key nuclear signatures, such as neutron and gamma radiation, are being investigated to improve the likelihood of the detection of this material.
This thesis details the work undertaken to achieve the goal of creating a low power and sturdy detector solution that can be used for longer term passive monitoring or active field interrogation. This is possible using dual (or even triple) mode detectors, which are detectors that can use pulse shape discrimination (PSD), to separate gamma and neutron radiation species, using different timing characteristics that arise from each form of radiation. The detectors chosen for use in this investigation were the inorganic scintillation materials CLLBC and CLYC, and the organic scintillation materials EJ-276 and EJ-299-50.
Inorganic scintillators are primarily sensitive to gamma radiation and thermal neutrons, with these materials commonly having a high 6Li enrichment, allowing for the thermal capture of these neutrons. Organic scintillators are sensitive to gamma radiation and fast neutrons, which have energies in excess of 1MeV. The EJ-299-50 material alters slightly from these definitions, as whilst it is organic in nature, it also has a high enrichment of 6Li, allowing it to act as a triple mode detector.
Both photomultiplier tubes (PMTs) and silicon photomultipliers (SiPMs) were used as photon detection technologies for recording scintillation photons throughout this investigation, with PMTs forming the significant majority due to operational difficulties with the available SiPMs. This was undertaken to evaluate the performance of each technology, as SiPMs are the natural choice for lower power performance. This is due to the lack of vacuum components and dynode chains required by a PMT, and a lower operating voltage of ∼40V. This is a significantly lower voltage than the ∼2kV required by a PMT. It was therefore necessary to determine the differences between each technology and how these would impact later designs.
Both digital and analogue processing methods were investigated, with digital methods expressed as discrete values processed using high speed digitisers, and analogue methods consisting of continuous voltage waveforms that would only be expressed digitally at a final output stage. The decision was made to attempt a comparative study, with the results recorded using digital methods in combination with a PMT considered the benchmark. This was due to the greater signal stability presented by the PMT, whilst the SiPM and analogue methods presented more opportunities for noise or faults to enter the system. Unfortunately each of three SiPM arrays used at various points during this investigation failed for separate reasons, and it was not possible to take sufficient SiPM results to determine a clear comparison between the technologies.
Each detector material was investigated and characterised to determine which material would make for the most effective prototype. Key results such as the detector energy resolution and gamma efficiency were also calculated. For CLLBC, CLYC, EJ-276 and EJ-299-50 the energy resolution at 662keV was determined as 5.6%±7.6 × 10−3%, 9.3%±0.04%, 20%±0.26% and 22.2%±0.21% respectively. The intrinsic gamma efficiency, also at 662keV, was determined to be 17.6%±8.8% and 13.6%±6.8%, for CLLBC and CLYC respectively. The use of a time-of-flight measurement allowed for the determination of neutron efficiency for the CLLBC, CLYC and EJ-276 materials, as EJ-299-50 was not available at the time of this measurement, with neutron efficiencies of 0.22%±0.05%, 0.31%±0.07% and 0.53%±0.12% determined respectively. This efficiency was calculated across the entire available neutron energy range which would affect each efficiency, due to the speciality of each material at detecting different neutron energies. The neutron efficiency of EJ-299-50 was unable to be calculated as there was not a characterised neutron source of known neutron emission rate available when this material was available, and as such would be an area of future interest.
The digital methods were used as a benchmark, with traditional figure-of-merit (FOM) analysis, which calculates the value of separation between the respective neutron energy regime and gamma species for each material, determining a FOM of 3.69±0.029 for CLLBC, 1.82±0.096 for EJ-276, 2.02±0.025 for EJ-299-50 and 2.5±0.1 for CLYC. However, the decision was made during this work to focus upon the analogue electronic methods, as it was believed the less intensive computing demands would decrease the power requirements, and allow for a better continuous passive interrogation prototype.
Electronic simulation results demonstrated that each of the chosen analogue PSD methods functioned as intended. These methods were the time-over-threshold method, which records the time a waveform is above a specified level, the zero-crossing method, which compares the time at which different waveforms cross a zero point, and the charge comparison method, which compares the amount of charge contained within predetermined time intervals. However due to manufacture delays and unforeseen noise contributions, the constructed prototypes did not produce results that matched the simulated outcomes. This meant that the current prototypes needed an additional round of redesign to prioritise noise suppression and signal amplification.
Overall, each of the available scintillation materials have been characterised to a greater extent which can be applied to later analogue PSD designs. This can be seen in combination with the electronic simulations that demonstrate the efficacy of each method, meaning that the choice of detector material and analogue PSD method can be made based on the user requirements. The designed analogue solution in this case did not operate as intended, but each method showed great promise for future development and investigation of low power analogue PSD solutions
Digital inclusion in British Columbia’s public libraries
Full text linkThis dissertation explores the role of libraries in British Columbia in supporting digital inclusion. The research question is: What is the role of British Columbia’s public libraries with respect to digital inclusion? Within that role, what do we need to do to accomplish digital inclusion, and what are the barriers that may prevent us from accomplishing it?
I used Nussbaum's Capability Approach as a theoretical framework to explore the issues surrounding digital inclusion and libraries. Further, I used Futures Studies to guide the interviews, using the 7 Questions method.
The research applies a qualitative approach. Eight library staff were interviewed to identify current and future challenges and conflicts faced by public libraries. Semi-structured interviews allowed exploration of the participants' perceptions of past and potential future challenges in supporting digital inclusion and the changes that need to be made if libraries are to better respond to the digital future. Braun and Clarke's approach to thematic analysis was used to analyse the data.
The findings suggested that the challenges cluster around:
• Challenges with access, from access to stable funding to digital resources,
• Governance in that libraries have become a type of essential service to communities, and would benefit from clearly articulated roles and more formal connections to government
• Building community, which relates to the library’s role as a community educator and connecting community with information and culture.
The findings further suggest that to determine the library’s role with regards to digital inclusion, one must first determine the library’s role in general as both are very much tied together. The implications of the study are that the Capability Approach enables a way of looking at the role of the library and what libraries can do to support digital inclusion. Developing minimum standards based on that, would be beneficial to libraries by providing consistency and a goal to strive towards. Future Studies provided libraries with a way of examining, understanding, and responding to the challenges
From measurement to management of kidney function: population-based insights into biomarker discordance, risk factors, and outcomes
No full textChronic kidney disease is a major risk factor for cardiovascular diseases and mortality, yet both the measurement of kidney function and the management of kidney-related risk in the general population require further exploration. This thesis aims to move from measurement to management of kidney function by examining modifiable behaviours, identifying patterns of kidney function and their associations with adverse outcomes, and evaluating treatment strategies and their potential cardiorenal benefits.
A total of five published manuscripts were included in this thesis to achieve the above aims. These studies utilized data from the UK Biobank and several Swedish national registers.
The first study in Chapter 4 presents a systematic review and meta-analysis of intervention studies in generally healthy populations, examining how changes in physical activity influence kidney-related biomarkers. Higher physical activity was consistently associated with higher serum creatinine, while other biomarkers showed little or no change. The second study in Chapter 5 uses UK Biobank data to examine how changes in physical activity relate to changes in kidney function in more than 11,000 participants free of chronic kidney disease at baseline. The findings differed by biomarker. When rapid decline was defined using creatinine-based estimated glomerular filtration rate (eGFR), lower physical activity appeared protective, whereas cystatin C-based eGFR showed the opposite pattern, with higher activity associated with lower risk. The creatinine-cystatin C based eGFR showed no clear association.
The following two studies in Chapters 6 and 7 focus on discordance between creatinine-based and cystatin C-based eGFR. Chapter 6 synthesises evidence from 18 studies and shows that individuals with lower cystatin C-based eGFR relative to creatinine-based eGFR have substantially higher risks of mortality and cardiorenal events, while those with higher cystatin C-based eGFR tend to have lower risks. Chapter 7 extends this work in a large UK Biobank cohort, showing that 15.5% of the study population has discordantly lower cystatin C-based eGFR and that this discordance is strongly associated with all-cause mortality, particularly in older (65 years and above) and obese (BMI≥30 kg/m2) people, independent of established risk factors.
The last study in Chapter 8 shifts to pharmacological management in type 2 diabetes, comparing oral fixed-dose combination therapy with loose-dose combinations using Swedish national registers. In a propensity score matched cohort of 27,766 people, fixed-dose combinations were associated with a lower risk of heart failure, especially in older adults (65 years and above), with 47% of this benefit being mediated by improved medication adherence. No clear differences were observed for other cardiovascular or kidney outcomes.
In conclusion, this thesis provides population-based evidence that selection of kidney function biomarkers may play an important role in evaluating health outcomes, while intraindividual discrepancies in kidney function may reveal distinct physiological or pathological processes. In addition, pharmacological strategies may affect cardiorenal risk. Key limitations include reliance on estimated rather than measured GFR, potential residual confounding, the inability to establish causality inherent to observational analyses, and limited generalisability to more diverse populations
Integrated photonic circuits on SOI and SiNOI platforms for high-sensitivity sensing and reconfigurable multi-passband filtering
No full textIntegrated photonics offers compact and energy-efficient platforms for label-free biochemical sensing and agile spectrum control. This thesis establishes a unified design framework on silicon on insulator (SOI) and silicon nitride on insulator (SiNOI) that links two capabilities: enhancing light-matter interaction for refractometric sensing while constraining excess loss, and realising reconfigurable multi-passband photonic filters with predictable, programmable spectra. The work combines electromagnetic and coupled-mode modelling, reconstruction equivalent chirp design, heater-matrix control, foundry-compatible fabrication, and system-level characterisation using optical frequency comb sources and thermo-optic tuning. It demonstrates that sensitivity enhancement and spectral programmability can be obtained through spatially distributed design and algorithmically coordinated actuation, rather than by accepting large insertion-loss penalties.
For sensing, three-slot hybrid plasmonic waveguides are engineered to localise the evanescent field at the analyte interface while routing most optical power through low-loss analyte sections. This architecture supports stable C-band operation and provides a route to array-scalable sensors intended for monitoring biomolecular binding and concentration changes in microfluidic lab-on-chip diagnostics.
For filtering, phase-shifted sampled Bragg grating devices are synthesised using the reconstruction equivalent chirp (REC) technique to spatially decouple reflection points, enabling independent control of multiple passbands. Integrated micro-heater matrices provide reconfiguration and algorithm-assisted phase synthesis, combining self-adaptive differential evolution with local optimisation, coordinates multi-parameter tuning to obtain low-ripple spectra. Three architectures validate the framework: a dual-passband filter based on coupled phase-shifted cavities, a programmable four-phase shift sampled Bragg grating (4PS-SBG) on SiNOI enabling selectable multi-passband and stopband responses, and a cascaded superstructure grating with a microring resonator enabling optical-domain frequency multiplication and hopping.
Overall, the thesis provides design rules for co-optimising waveguide confinement, photon distribution, and heater matrix control in integrated photonics, underpinning scalable programmable photonic circuits and future heterogeneous integration with on-chip light sources
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