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Understanding the formation, function and inhibition of multinucleated giant cells in giant cell arteritis
No full textGiant cell arteritis (GCA) is the most common form of vasculitis in patients over 50 which can lead to irreversible blindness and strokes if not properly treated. GCA is characterised by immune mediated destruction of the medial layer of small blood vessels followed by aberrant repair leading to intimal hyperplasia and narrowing of the vessel. Multinucleated giant cells (MGCs) are a hallmark of disease pathology. Despite these cells being observed close to sites of both media destruction and intimal hyperplasia, their role and formation in GCA pathogenesis have not yet been fully explored. Furthermore, reliable models to investigate the early stages of GCA pathogenesis, particularly the migration of circulating monocyte precursors and the generation of MGCs, remain scarce. Accordingly, this thesis seeks to elucidate the mechanisms underlying the development and functional roles of MGCs and their precursors.
To address this gap in knowledge, this thesis employed spatial transcriptomics to characterise macrophages and MGCs within distinct vascular layers and to elucidate the mechanisms underlying their development and functional roles. The results showed that macrophages in the intima of GCA vessels were transcriptionally similar to MGCs. Furthermore, cell deconvolution analysis of MGCs showed that these cells were transcriptionally akin to an undifferentiated macrophage suggesting they could be both pro- and anti-inflammatory in nature.
Furthermore, it was important to understand the mechanisms involved in MGC formation. This thesis showed that GCA like MGCs could be generated by stimulating monocytes with GM-CSF+IFNg. This culture produced both Langhans, and foreign body giant cells as observed in GCA tissue. These cultured cells produced markers observed in the tissue such as MMP9 and CTSD.
Differences in MGC formation by cultured monocytes from healthy controls and GCA patients suggested that there are differences in circulating monocyte precursors of MGCs. Flow cytometric analysis, RNA sequencing and epigenetic profile analysis of these monocytes revealed that GCA monocytes express high CCR5 and GM-CSF receptor on their surface. Analysis also showed differences in H3K427me3 and H3K4me3 profiles in GCA monocytes compared to healthy controls.
Lastly, as CCR5 was shown to be highly expressed on GCA monocytes, it was assessed in the context of MGC formation. CCR5 and its ligands CCL3, and 5 could be observed in GCA tissue localized to and surrounding MGCs. CCR5 modulation by small molecules and monoclonal antibodies (such as maraviroc and Leronlimab respectively) were added to the previously described culture. This inhibition led to a large reduction in the number of MGCs observed in culture suggesting a role for this chemokine receptor in the formation of MGCs.
In summary, this thesis established a role of MGCs in GCA pathogenesis. It presented the first in vitro model of GCA MGC formation from enriched monocytes, enabling investigation of their initiation and modulation. It also identified differences in protein expression and epigenetic modifications between healthy and GCA monocytes and implicates the chemokine receptor CCR5 in MGC formation, highlighting CCR5 modulators such as Maraviroc and Leronlimab as potential therapies. Future work should explore GCA monocyte co-culture systems and develop 3D models to extend these findings
An exploration of metachronous colorectal lesion predictors from a bowel screening population
Get PDFThe 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
Investigating NF-κB signalling and its regulator Bcl3 in colorectal cancer
No full textAbstract not currently available
Three chapters on corporate financial decisions
No full textCorporate decision-making is shaped by the interplay of internal managerial dynamics and external forces, such as globalization and climate risks. This study examines three critical dimensions of this complex environment, integrating behavioral and neoclassical perspectives to provide a comprehensive understanding of corporate policies.
First, it explores how CEOs influence corporate cash management, focusing on the transferability of cash management styles during CEO transitions. Using a dynamic partial adjustment model, the findings reveal that high-cash-style CEOs tend to increase excess cash levels in new firms, while low-cash-style CEOs adapt to existing policies. These insights highlight the conditional persistence of managerial traits and their impact on firm outcomes.
Second, the study investigates the role of global connectedness in cross-border mergers and acquisitions (M&A). By leveraging the DHL Global Connectedness Index, it demonstrates that trade breadth and information flows drive international deal activity. However, the findings also caution against potential downsides, as highly connected environments may encourage lower-quality acquisitions.
Finally, it assesses the effects of climate risks, specifically extreme heat exposure, on M&A dynamics. Firms with higher heat exposure face reduced acquisition likelihood, diminished bargaining power, and long-term underperformance, underscoring the importance of integrating climate risks into corporate finance frameworks.
This research contributes to the understanding of managerial influence, globalization, and climate finance, offering practical insights for corporate leaders, investors, and policymakers navigating today’s interconnected and climate-conscious world
Impact of collagen architecture on breast cancer epithelial cell behaviour
No full textAbstract not currently available
Investigating professional development of content and language teachers in English Medium Instruction (EMI) contexts in China
Get PDFWith the global advancement of the internationalisation of higher education, English Medium Instruction (EMI) has gained momentum in non-Anglophone contexts such as China, where EMI programmes are surging to align with goals such as attracting government funding, enhancing university rankings, and improving students’ English proficiency and career prospects. However, a range of challenges faced by stakeholders (students and teachers) may jeopardise the realisation of these goals. While student-related issues have been widely recognised, challenges faced by teachers remain insufficiently explored. Specifically, content teachers often struggle linguistic and pedagogical challenges when teaching from L1 to English, while English for Academic Purposes (EAP) teachers face transitioning challenges from general English (EGP) to EAP.
Teacher professional development (PD) is therefore recommended to address these challenges. However, institutional support remains limited in practice, which may undermine the ultimate goal of EMI in ensuring students’ academic success (McKinley & Rose, 2022). Furthermore, collaboration between content and EAP teachers is suggested as a promising PD format (Lasagabaster, 2022; Ploettner, 2019), enabling content and EAP teachers to synergise disciplinary and linguistic expertise to better support student learning. However, collaboration remains largely at the pilot stage (Lasagabaster, 2018), with limited relevant research on its effectiveness, leaving multiple unaddressed issues in practice.
This study investigates the current state of PD opportunities and collaboration between content and EAP teachers across different types of EMI provisions (EMI university, EMI college and EMI programme) in China. Using a multi-method qualitative approach, data were collected through document analysis of PDrelated documents and interviews with content teachers (n = 20), EAP teachers (n = 20), and PD leads (n = 5). The study offers both objective and subjective insights into how PD and collaboration are perceived, structured, and experienced.
Key findings reveal institutional and individual factors influencing teachers’ PD and collaboration respectively, highlight significant variation across EMI provision types, and stress the need for structured mechanisms and leadership support to facilitate effective PD and also teacher collaboration. The study also underscores the critical role of EAP teachers in supporting students' academic English and calls for more equitable PD investment across teaching cohorts. It concludes by advocating for policy and institutional reforms to support more sustainable and collaborative PD practices. Ultimately, this study emphasises that the long-term success of EMI hinges on recognising teachers’ endeavours made for bettering EMI teaching quality and calls for a more holistic support system which ensures the empowerment of teachers and academic achievements of students
The factors impacting secondary school teachers’ continuance intention to use Madrasati platform in Saudi Arabia
Get PDFDuring the rapid outbreak of the COVID-19 pandemic, most countries enforced stay-athome policies, which led to an increase in distance working. Accordingly, e-learning was utilised to replace face-to-face education, with many educational organisations across the world switching to online teaching and learning. In Saudi Arabia (SA), the option for elearning was not widely supported in public schools. The Ministry of Education (MoE) developed an online learning management system (LMS) named Madrasati to support the educational process during school closures. However, a large proportion of teachers chose to continue using Madrasati even after schools returned to face-to-face teaching, making it part of their post-pandemic approaches to teaching and learning. This study aims to investigate the reasons and motivations associated with the post-COVID-19 usage of Madrasati. This is of particular interest given that, internationally, LMSs such as Madrasati typically feature more prominently in further and higher education than they do in elementary and secondary school education.
To thoroughly address the research question, this study adopts an explanatory sequential mixed-methods approach, wherein both quantitative and qualitative data were gathered in an organised sequence. First, a proposed model for a continued use of e-learning platforms was developed, primarily informed by the Decomposed Theory of Planned Behaviour (DTPB) and other relevant e-learning studies. In the first phase, a large-scale survey was conducted with 304 secondary school teachers in SA, who completed an online questionnaire. At this stage, Structural Equation Modelling (SEM) was applied to evaluate the proposed model, utilising two main techniques: the measurement model and the structural model. In the second phase, follow-up interviews were undertaken with 19 secondary school teachers, with a reflexive thematic analytical approach used to clarify the quantitative findings and to gain a deeper understanding of the rationale behind their decisions regarding the continuance of Madrasati use.
The obtained results confirmed that the proposed model demonstrated a good fit with the quantitative data, verifying the validity and reliability of its instruments. The survey findings identified significant factors influencing teachers’ intentions to continue using Madrasati, including learning content quality, perceived usefulness, social influence, and self-efficacy. Most teachers demonstrated favourable attitudes towards the platform, with social influence-particularly from peers and students—emerging as a strong predictor of continuance intention. In contrast, qualitative data from the interviews revealed some concerns that could hinder the platform’s continued use, such as insufficient professional training, limited technical support, and inadequate internet infrastructure, particularly in rural areas.
From an academic perspective, the proposed model may provide a useful tool for researchers in the field of technology adoption in education who wish to examine factors influencing the intention to adopt LMSs and technological platforms in diverse contexts. In addition, practical recommendations were presented to Saudi educational stakeholders and Madrasati’s developers to implement methods that could increase teachers’ motivation to continue using the platform
Low resource, model-based fault tolerant system for the control of planetary exploration rovers
No full textAbstract not currently available
The ballad of Motel Fresno: reimagining narrative poetry through music and performance
No full textAbstract not currently available
Biphotons for nonlinear imaging
Get PDFThe harnessing of the nonclassical properties in photon pairs generated by the process of Spontaneous Parametric Down Conversion (SPDC) to enhance two-photon interactions has long intrigued researchers. Their use in light-matter interactions has been proven to improve efficiency either by increasing the rate of generation or by suppressing noise. Namely, the processes of Entangled Sum Frequency Generation (eSFG) and Entangled Two Photon Absorption (eTPA) have been shown to produce more photons when stimulated with entangled photons than the classical versions of the effects. This has only been effective so far at very low intensities, which, alongside the inability to reproduce previous experimental results, has caused debates about the usefulness of the effect. In the presented work, I aim to shed light on the topic by employing a carefully crafted source of entangled photon pairs to improve two-photon effects. I attempt to demonstrate, through a series of experiments, that the quantum enhancement can be observed at an order of magnitude higher than previously thought possible. To solidify the results, a direct comparison of the quantum effect was conducted by investigating the performance of the phenomenon when it is stimulated by classical radiation from a laser. Our results confirm a quantum improvement in a regime previously considered impossible, and they enabled us to examine the ramifications of the effect on imaging. By doing so, we consider real-life microscopy applications, and therefore, we can set limits to the effect
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