Visualising infections across scales

The ability to visualise biological structures and processes at the microscale has been instrumental in the development of modern medicine and the control of disease. In recent years, technological innovations have enabled imaging of large, mesoscale tissues, from organs to whole mammalian organisms. However, the development of these methods demonstrates the inherent weaknesses of imaging modalities designed to function at specific length scales. While modern microscale methods enable imaging at resolutions beyond the diffraction limit of light, resolving objects tens of nanometers apart, the field of view and working distance of these systems prevents analysis of mesoscale samples. Conversely, cutting-edge mesoscale imaging methods are capable of imaging whole mice, but lack the resolution of modern confocal microscopes. Holisic analyses are crucial in understanding biological processes and only by designing imaging pipelines capable of coupling high resolution microscopy with large sample mesoscopy can we develop a complete understanding of processes occurring within organisms. Influenza A virus (IAV) exemplifies the need for multiscale imaging approaches. Viral replication is governed by microscale, intracellular processes, while pathology and spread on the scale of the whole lung dictates virus transmission and patient outcomes. Here, I develop methods for imaging tissues across length scales, primarily using IAV as a model pathogen. On the mesoscale, I develop means of visualising infections in whole murine lungs, as well as skin, nerve, and bone tissue without the need for sectioning. On the microscale, I develop computational tools and laboratory assays capable of visualising interactions between viruses, elucidating the processes governing the emergence of viral strains with pandemic potential. By designing holistic imaging pipelines capable of analysing IAV infections across scales, these insights develop a more complete understanding of the spatial context of IAV infection, the interactions between viral populations, and the relationship between microscale processes and meso- and macroscale pathology

Essays on crowdfunding

This thesis consists of three independent chapters: I examine the role of crowdfunding as an alternative financing tool, with a particular focus on the impact of external shocks, industry-specific responses, and the role of sustainable crowdfunding campaigns. The first chapter investigates the influence of the COVID-19 pandemic on crowdfunding campaigns in the UK, analysing key metrics such as success rates, number of backers, campaign duration, funds raised, and campaign’s location. It uses crowdfunding data from Crowdfunder, FundRazr, Indiegogo, and Kickstarter, COVID-19-related data from the Official Coronavirus Disease Situation Dashboard, and population data from the Office for National Statistics. Using OLS and LPM, the findings reveal that the pandemic did not lead to an increase in the number of backers or the raised amount; however, campaigns with shorter durations and lower goal amounts had higher success rates. The second chapter extends this analysis by examining the differential impact of COVID-19 on campaigns requiring physical gathering. I then investigate the impact of the pandemic across various crowdfunding industries, including cultural, creative, and entertainment sectors, using a DiD model and data from four major crowdfunding platforms—Crowdfunder, FundRazr, Indiegogo, and Kickstarter. The chapter reveals that campaigns reliant on physical gatherings show a decrease in funds raised, while entertainment campaigns report an increase. This chapter offers new insights into how external shocks, such as a global pandemic, influence crowdfunding campaigns differently across industries. Heterogeneity analysis suggests the following: (1) campaigns following keep-it-all raised fewer funds, had fewer backers, and had a lower success rate; (2) campaigns with higher duration raised less money, had a lower success rate, and had fewer backers; (3) campaigns with higher goal amount had no impact on the raised amount, number of backers, or the success rate. The third chapter explores the role of crowdfunding in supporting sustainable campaigns, focusing on campaigns aimed at promoting environmental and social responsibility. I further investigate whether sustainable campaigns initiated by females have increased the success, the raised amount, or the number of backers of campaigns. Despite growing global interest in sustainable development, such initiatives often face challenges securing traditional funding. This chapter applies OLS and LPM and uses data from UK-based crowdfunding campaigns between 2018 and 2022 to investigate whether campaigns with a sustainability focus are more likely to succeed in crowdfunding markets. The findings indicate that while sustainable campaigns do not necessarily outperform others in terms of success rates or raised amounts, campaigns initiated by women face particular challenges. Overall, this thesis contributes to the literature by providing a comprehensive understanding of how crowdfunding responds to external shocks, industry-specific variations, and the growing need for financing sustainable ventures. Chapters two and three used manual classification to provide a unique dataset. The findings offer practical implications for both policymakers and practitioners interested in leveraging crowdfunding for social, economic, and environmental sustainability

Development of spatio-temporal data fusion frameworks for point and gridded soil moisture data

Monitoring soil moisture can play an important role in helping to inform researchers, regulators, and landowners about the available water content of the soil for agriculture and vegetation. However, the capacity to observe soil moisture is constrained by practical and financial limitations, making it challenging to observe continuously across space and time. We can only monitor soil moisture at a finite number of spatial locations and time points. One of the most accurate methods for measuring soil moisture is to use in-situ sensors. However, the high cost of deploying these sensors extensively means that soil moisture data tends to be collected from a sparse network of monitoring points. Given the limited in-situ sensor data, it becomes essential to explore the benefits of utilising other data sources, such as satellite data, by developing and using data fusion techniques. Data fusion allows for the integration of different data sources, enhancing the ability to make informed decisions and understand environmental phenomena with more precision, despite the limited direct monitoring of soil moisture. The research question is motivated by the in-situ soil-moisture data provided by SEPA in Elliot Water and the satellite images provided by Copernicus. It is necessary to develop a data-fusion method for point data and gridded data, so that the accuracy of the in-situ data can be combined with spatial and temporal information from satellite data to generate a fine-resolution map with uncertainty quantification. This thesis introduces three INLA-based data-fusion methods in Chapter 3, 4, and 5, which include a spatio-temporal regression with misaligned covariates, a spatial data fusion method, and a spatio-temporal data fusion method. A comprehensive simulation study varies sensor density, grid resolution, percentages of missing grid data, and temporal window length k. Across scenarios, joint fusion consistently outperforms point-only and grid-only baselines in RMSE. This thesis also introduces an XGBoost-based constrained ensemble method with conformal prediction in Chapter 6, developed to merge in-situ point and satellite gridded data under different spatio-temporal supports. This thesis presents the background, motivation, model development, and application of the novel data fusion methods, addressing the gap in the literature by accounting for spatio-temporal change-of-support problems. Results are presented throughout to demonstrate the use of the data fusion model in soil moisture data

An exploration of metachronous colorectal lesion predictors from a bowel screening population

The rising incidence and mortality rates of colorectal cancer (CRC) continue to impact patients and burden healthcare systems worldwide. Multiple factors contribute to increasing CRC risk and, while modifiable ones such as improving diet, and smoking cessation are within an individual’s control, non-modifiable factors such as age and a genetic propensity for CRC remain major causes of the disease. This led to many countries adopting national screening programs to promote the early detection and prevention of CRC. Many modalities can be used for screening, but several countries (including the United Kingdom (UK)) begin with a quantitative faecal immunochemical test (qFIT) and, should a positive result be found, a colonoscopy is recommended. Not only do screening colonoscopies detect CRC but also find pre-malignant polyps from which most CRC is derived. These are removed opportunistically as a mode of prevention; however the presence of polyps is associated with ongoing future risk of polyps and CRC, leading to the need for surveillance. In 2020, the British Society for Gastroenterology published updated guidelines (BSG2020 Guidelines) for the surveillance of patients who underwent a screening colonoscopy. They define a “high-risk” patient as one whose colonoscopy revealed two or more polyps where at least one was advanced, a serrated polyp larger than 1cm or with dysplasia, an adenoma larger than 1cm or with high-grade dysplasia, or five or more polyps. According to BSG2020 Guidelines, “high-risk” patients are recommended to undergo a second colonoscopy for surveillance of metachronous polyps or CRC within three years of the screening colonoscopy. However, with only 20-50% of “high-risk” patients developing metachronous polyps, coupled with the endoscopy services backlog in the UK, these risk stratification guidelines are not sufficient. This thesis aimed to identify a suitable tool to improve the current BSG2020 Guidelines for risk stratification within a bowel screening population. Initially, Fusobacterium nucleatum, was investigated with relation to the detection of metachronous polyps or CRC, through detection by a novel technique, TempO-Seq™. Numerous evidence of the involvement of F. nucleatum in CRC is available, implicating it in supporting tumorigenesis and metastasis. F. nucleatum+ patients revealed an immune-oriented whole tissue transcriptomic profile, however, spatial transcriptomics revealed a poor adaptive immune response in those patients. Similarly, there was no association between lymphocytic markers (CD3+ T cells, CD4+ T cells, and CD8+ T cells) and the detection of metachronous polyps or CRC in patients with a known F. nucleatum status, although the stimulation of patient-derived organoids with inflammatory cytokines led to an increase in cell viability. Ultimately, F. nucleatum in this cohort was not associated with the detection of metachronous polyps or CRC. However, mutational analysis of adenomas from these patients revealed mutations in multiple Wnt pathway-associated genes. At the protein level, E-Cadherin and β-Catenin were not associated with the detection of metachronous polyps or CRC. However, the high expression stemness marker and Wnt regulator SOX9 in the cytoplasm was associated with the detection of metachronous polyps or CRC. Patients with high SOX9 protein expression demonstrated a proliferative transcriptomic profile, with multiple anti-microbial pathways being positively enriched. Finally, the addition of SOX9 protein expression to current BSG2020 Guidelines significantly improved risk stratification. This research provides a basis for the use of additional stratification methods to improve the rate of prediction of metachronous polyps or CRC, using simple well-established methods like immunohistochemistry

Investigation of the possibilities for host modulation therapy for periodontal treatment

Background: Periodontitis is a globally prevalent chronic inflammatory disease characterized by immune dysregulation and alveolar bone loss. Conventional therapies, while effective in many cases, often fail to achieve complete resolution, particularly in patients with systemic comorbidities or aggressive disease phenotypes. This has led to increasing interest in Host Modulation Therapy (HMT), which targets the underlying immunopathogenesis rather than the microbial component alone. Aim: This thesis investigates the potential of HMT in periodontal care, focusing on bonemodulating cytokines and the RANK/RANKL/OPG axis. It seeks to evaluate the feasibility of repurposing denosumab, a monoclonal antibody against RANKL used in osteoporosis, as a therapeutic adjunct in periodontitis. Methods: Two research questions were addressed. First, salivary concentrations of OPG, RANKL, and inflammatory cytokines (IL-1β, IL-6, IL-8, TNFα) were analysed in systemically healthy individuals with varying periodontal status (health, gingivitis, periodontitis) before and after treatment. Second, an exploratory clinical study assessed periodontal changes in a patients initiating denosumab therapy. Biomarker quantification was performed using multiplex immunoassays, and clinical inflammation was assessed using the Periodontal Inflamed Surface Area (PISA) metric. Results: OPG was variably detectable across health and periodontal disease states, while RANKL levels were consistently below detection thresholds. IL-1β showed a consistent reduction following treatment, suggesting its potential as a marker of therapeutic response. In the sample studied there were no significant correlations between cytokine levels and PISA. The denosumab study was limited by recruitment challenges and evolving prescribing guidelines, but provided valuable insights into the complexities of studying biologic agents in dental populations. Conclusion: HMT represents a promising adjunctive strategy in periodontal therapy, particularly for high-risk individuals. While current evidence supports the biological plausibility of targeting host pathways, further research is needed to validate targets, optimise delivery systems, and establish long-term clinical efficacy. The integration of personalised medicine and biomarker-guided care may enhance the future role of HMT in periodontal practice

Measurement of the t¯tH(b¯b) process using the ATLAS detector with an effective field theory interpretation

The associated production of a Higgs boson with a top-quark pair (t¯tH) provides a direct probe of the top–Higgs Yukawa coupling, the largest coupling in the standard model. Constraining this process is essential for testing the standard model and for probing possible contributions from physics beyond the standard model. This thesis presents a measurement of t¯tH production in the H → b¯b decay channel, using the full Run 2 dataset, 140 fb−1 of proton-proton collision data at a centreof-mass energy of √ s = 13 TeV, collected by the ATLAS detector at the LHC. Included in this analysis are: novel machine learning methods, improved modelling and reconstruction techniques, dedicated high pT uncertainty extrapolation and more. An excess of events over the non-t¯tH background is found with an observed (expected) significance of 4.6 (5.4) standard deviations. The t¯tH cross-section is measured to be σttH¯ = 411+101 −92 fb = 411 ± 54 (stat.) +85 −75 (syst.) fb, for a Higgs boson mass of 125.09 GeV, consistent with the standard model prediction of 507+35 −50 fb. The cross-section is also measured differentially in bins of the Higgs boson transverse momentum within the Simplified Template Cross-Section framework. This analysis is then re-interpreted in the Standard Model Effective Field Theory framework. The three main operators governing the ttH production in this framework, OtG, Otϕ, OϕG, are investigated and constraints are applied to their respective Wilson coefficients ctG, ctϕ, cϕG. Improvements in precision of the Wilson coefficients were seen in individual quadratic fits compared to early Run-2 (2016) studies, particularly with ctϕ = 2.55+2.22 −2.15, whose contributions are unique to the t¯tH production mode, sees improvements in precision by a factor of 2

Novel surface termination for advanced diamond electronics

Diamond is an interesting semiconductor for high-power and high-frequency devices due to its ultra-wide bandgap, high carrier mobility, and superior thermal conductivity. However, traditional doping is limited by the deep energy levels of most impurities, which limit carrier activation at room temperature. As a consequence, despite its exceptional intrinsic properties, relatively few reproducible and high-performance diamond field-effect transistors have been reported in recent literature. This motivates the exploration of alternative doping strategies, such as hydrogen-terminated diamond with surface transfer doping. Hydrogen-terminated diamond provides a conductive two-dimensional hole gas (2DHG) with low activation energy and relatively high carrier mobility, making it highly attractive for electronic devices. At the same time, the surface conductivity of H-diamond is highly sensitive to surface chemistry, oxide interfaces, and fabrication processes, posing significant challenges for achieving stable and controllable device operation. In this work, different surface terminations have been explored for negative electron affinity (NEA) and positive electron affinity (PEA), to clarify their respective roles in enabling surface transfer doping or suppressing surface conductivity. Subsequently, the behaviour of different contact metals on H-diamond was examined, with emphasis on their ability to form reliable ohmic contacts. The influence of different oxide layers and deposition methods on H-diamond transfer doping was studied, revealing that thermal ALD HfO₂ can enhance the 2DHG by promoting transfer doping, whereas electron-beam–deposited Al₂O₃ with prior in-situ annealing effectively suppresses surface conductivity without degrading the hydrogen termination. Building on these findings, accumulation-channel hydrogen-terminated diamond MOSFETs were successfully fabricated using an optimised and reproducible process flow. The devices exhibit normally-off, enhancement-mode operation with an Ion/Ioff ratio of 10⁷, achieving drain current densities exceeding 35 mA/mm at room temperature. These results demonstrate a viable pathway towards stable and controllable diamond MOSFETs, addressing key technical barriers that have limited progress in the field. A stable and reproducible Au-based fabrication process was established for hydrogen-terminated diamond devices, providing a robust contact platform for the demonstrated enhancement-mode MOSFETs

Preclinical investigation of the BCL-2 family protein MCL-1 as a potential therapeutic target in breast cancer

Abstract not currently available

The search for strangeonium resonances: partial wave analysis of polarised photoproduction reaction γp → ηφp at the GlueX experiment

The strong force gives rise to a large hadron spectrum, many areas of which are still not well understood. Progress in mapping out these regions is vital for building better models of the strong force and verifying the predictions of its quantum field theory, Quantum Chromodynamics. This thesis focuses on the study of the so-called strangeonium states, which are mesons with s¯s quark content, and in particular on members of the φ meson series φ(1680) and φ3(1850). The former is a radially excited vector that has been seen by both e⁺e⁻ collider and photoproduction experiments, but whose reported mass does not match between the two, with observations from photoproduction being systematically higher; the latter is a tensor that has not been measured since the 1980s and never in experiments with high statistical power. The data analysed in this thesis was collected at the GlueX experiment, which has produced the world’s largest photoproduction dataset to date since starting to run in 2016. A 9 GeV linearly polarised photon beam incident on a liquid hydrogen target was used to produce a variety of mesonic and baryonic resonances. The GlueX spectrometer allows both neutral and charged final states to be exclusively reconstructed with good resolution and angular acceptance. Results from the partial wave analysis of decay channel γp→ηφ p→K⁺K⁻γγ p are presented. After signal was isolated from background using a combination of event selection criteria and statistical subtraction via the sPlot method, an extended maximum likelihood fit to angular decay distributions allowed the extraction of partial wave amplitudes. A partial wave consistent with the φ(1680) was observed, but no clear evidence of a φ3(1850) was found. The obtained amplitudes indicated a preference for natural parity exchange. A fit to the intensity of the wave identified as the φ(1680) resulted in a Breit-Wigner mass more compatible with the e⁺e⁻ measurements. A cross-section was also calculated, allowing an order-of-magnitude estimate that matched the existing predictions. The results provide evidence against the additional vector meson states that have been previously hypothesised to explain the higher observed mass of the φ(1680) in photoproduction. They should also aid the development of models of the strangeonium spectrum

Control of hybrid superconducting quantum circuits based on advanced nanomaterials

Abstract not currently available