Reality anchors: investigating the use of reality cues for socially acceptable immersive technologies in transit

Immersive technologies, such as virtual reality (VR) headsets, offer opportunities to transform time spent in transit by customising the user's reality with virtual content rendered anywhere around them. However, their widespread use remains limited due to the disconnect they create from the surrounding environment, reducing user’s awareness and ability to respond to social cues. To address this challenge, this thesis proposes the concept of Reality Anchors, which integrate cues from the real world into virtual environments to retain immersion and alleviate concerns about using immersive technology in transit. Through a series of studies, this research investigates how Reality Anchors can address awareness needs and support the adoption of immersive technologies in transit. Studies I and II identified barriers to adoption through surveys, confirming that immersive headset use in transit raises concerns about safety, awareness, and social acceptance. Rooted in users' lack of awareness of surroundings, other passengers, personal belongings, and journey progress, these concerns varied with journey length. Longer journeys, such as on flights, showed higher acceptance due to lower awareness needs and greater interest in entertainment, while shorter journeys, like those on buses, posed greater challenges requiring heightened awareness. These findings informed the design of initial Reality Anchors focused on addressing safety, awareness and social concerns. Building on this, Study III evaluated Reality Anchors using VR simulations of short transit journeys, identifying people and personal belongings as the most useful anchors. Study IV extended this exploration, investigating anchor usage in journey types categorised as self-managed and externally managed. Findings revealed that Reality Anchors must be flexible to accommodate changing user needs, with self-managed journeys requiring more anchor support. Finally, Studies V and VI bridge the gap between lab and real-world contexts. Study V explored asymmetric co-located passenger experiences, where passengers using different devices navigated real unexpected interactions. Study VI examined how passengers maintained awareness under changing real-world conditions. Together, these studies demonstrate the potential of Reality Anchors to reduce key safety, awareness, and social concerns. This thesis represents a first step toward enhancing immersive technology acceptance in transit environments and provides actionable recommendations for the future design of Reality Anchors

Rights in the era of ‘green’ market expansion: articulating radical demands

The unfolding planetary crisis confronts us with unprecedented challenges. As climate change and biodiversity loss accelerate, environmental and social movements across the planet increasingly turn to human rights, to tackle the problems global policy largely fails to address. More and more, rights are not only invoked to press governments towards more ambitious climate action, but also against the injustices resulting from our responses to the planetary crisis. A central feature of global climate law and policy are market-based solutions. While proponents praise them as the most efficient way to reduce emissions, market mechanisms favour historical polluters and are geared towards upholding the capitalist political economy that has caused the crisis in the first place. While rights-based litigation seeks to confront the multiple injustices caused or exacerbated by ‘green’ markets, rights’ transformative force remains ambivalent. While human rights are often seen as a device of resistance against capitalism’s excesses, their orthodox understanding is firmly rooted in Western-liberal individualism, centred on the human, property owning subject. Consequently, critical scholars have called into question human rights’ emancipatory potential or even accused them of being complicit in neoliberal globalisation. Looking at recent case law on climate and just transition permits to retrieve a differential understanding of rights, that neither uncritically endorses, nor entirely dismisses them. Climate and just transition litigation suggest that human rights are best conceptualised as oscillating between two poles: As a-legal, radical demands, they confront and challenge the given order – as authoritatively mediated decisions in the field of law, they consolidate the given political-economic set up. Understanding rights this way helps to inform our thinking about how we best employ them strategically

Investigating the associations between plasmodium infections and autoimmunity in sub-Saharan Africa

Autoimmune diseases affect 5- 8% of the global population and are known to occur due to a misguided immune response towards the host, consequently affecting several organs. Importantly, infections are considered key environmental triggers of autoimmunity and contribute to the onset of autoimmune diseases, though this idea remains controversial. In this research, I focus on malaria, a disease caused by Plasmodium species, which has been linked to autoimmunity through the induction of anti-self-antibodies, with higher levels of autoantibodies associated with disease severity. By contrast, there is evidence suggesting that autoantibodies play a crucial role in anti-malarial protection, with increased autoantibodies shown to inhibit parasite growth. Thus, autoantibodies play a dual role in protection and pathology. However, this raises a crucial question on whether the induction of autoimmune antibodies during malaria increases predisposition to autoimmune disease later in life. Herein, anti-citrullinated protein autoantibodies (ACPA) commonly associated with clinical diagnosis of rheumatoid arthritis and their corresponding native peptides were first screened using ELISA in mice infected with the model pathogen Plasmodium chabaudi. This approach was chosen to investigate whether Plasmodium triggers ACPA production, providing insights into the potential link between Plasmodium infections and autoimmunity. Subsequently, the impact of heightened antibody responses to both the native and citrullinated peptides on the development of a model of experimental arthritis in mice was assessed. Extending the findings to humans, serum samples obtained from individuals residing in areas with varying levels of malaria exposure were examined for the presence of autoimmune markers using ELISA and protein microarray assays. This was followed by assessing differential cellular immune phenotypes using flow cytometry. Interestingly, increased levels of antibody responses to both the native and citrullinated peptides were observed in the P. chabaudi-infected mice with levels comparable to those observed in a chronic experimental arthritis model. However, despite the elevated autoantibodies, under the experimental conditions used in our study, infection-induced autoantibodies did not appear to influence the outcome of either acute or chronic experimental arthritis in mice. Furthermore, expanding our findings to adults and children residing in malariaendemic areas, I observed that individuals living in high malaria transmission areas exhibited elevated antibody responses to both the native and citrullinated peptides compared to those in low transmission areas. Interestingly, a similar trend was observed in children, particularly children with uncomplicated and severe malaria who had increased levels of autoantibodies compared to healthy children. In addition, protein microarray data suggested that individuals from a high malaria transmission area had an overall increase in autoimmune reactivity. Notably, higher levels of antibodies against both the native and citrullinated peptides were also associated with increased frequency of atypical B cells (CD27⁻ CD21⁻CD11c⁺T-bet⁺) and a reduction in the levels of FOXP3 regulatory T cells. My research indicates that Plasmodium infection leads to a broad spectrum of autoantibodies, including responses to both the native and citrullinated peptides as well as extracellular antigens, mirroring a profile of increased autoantibodies typically observed in autoimmune diseases. Moreover, in this study, I report the presence of elevated antibody responses to these peptides in both Plasmodium infected mice and humans residing in areas of high Plasmodium falciparum transmission. Notably, the pre-existing autoantibody response to these peptides from a single Plasmodium infection episode did not modulate susceptibility to experimental autoimmune arthritis. Thus, the effect and role of chronic exposures to P. falciparum infections on the risk of developing autoimmune diseases in people living in endemic areas cannot be ruled out and should be determined

Epidemiology of Mycoplasma bovis in Scottish dairy herds

The bacterium Mycoplasma bovis (M. bovis) causes major economic losses to dairy herds resulting from increased mortality and morbidity, treatment costs, and reduced growth of young stock. There was limited knowledge on the prevalence of M. bovis in Scotland and no national monitoring scheme. Two studies were conducted; a longitudinal bulk tank milk (BTM) prevalence study and a cross-sectional seroprevalence study on dairy calves. In the longitudinal BTM prevalence study, one hundred and eighty-one dairy herds across Scotland participated in the study which required them to submit four BTM samples roughly three months apart that were tested for the presence of active M. bovis infection and for recent exposure. A short questionnaire on general herd management practices were issued to farmers to identify potential risk factors associated with seropositivity. At each of the four sampling points, the proportion of antibody positive herds were 76%, 71%, 83%, and 79%, and overall, 86% of herds tested seropositive in at least one of their four samples. Multivariable logistic regression identified herd history of M. bovis as a potential risk factor for the presence of M. bovis antibodies. The questionnaire results also provide an updated overview of the common structures and practices on Scottish dairy farms. Herds were then classified based on the antibody results of their four BTM samples using various methods. Sixty-one percent of herds tested consistently positive for all four samples, 15% consistently negative, and 24% transitional. When classified by k-means clustering of the optical density (OD) trend, the majority of herds had a stable trajectory (44%). A cross-sectional seroprevalence study was then carried out on a subset of herds from the BTM study (n=36) to determine if there was evidence of exposure to M. bovis in youngstock and if there was an association between the BTM and calf seroprevalence. Twenty calves were sampled on each farm (10 animals 4-8 months old and 10 animals 10-14 months old) and a BTM sample collected. There was evidence of youngstock exposure in most herds (58%), and this was associated with the BTM prevalence. The results of this thesis have demonstrated that M. bovis is likely endemic in Scottish dairy herds and has raised further questions on risk factors and within-herd prevalence estimates of M. bovis

AI-assisted, Raman Activated Cell Sorting (AI-RACS)

Abstract not currently available

Mitochondrial targeting for inhibition of fumarate hydratase

Abstract not currently available

Investigating cognitive-motor function in younger and older adults, using multimodal MRI

Abstract not currently available

Finite-dimensional DG-algebras and Reflexive DG-categories

Summary available

Elucidating the role of the TGF beta superfamily in metastatic spread of colorectal cancer

Colorectal cancer (CRC) is an aggressive disease and the leading cause of cancer death, characterised by high heterogeneity and various risk factors related to its etiology (1-3). During carcinogenesis, adenomatous polyps, which represent most premalignant lesions (85-90% of sporadic CRC), can develop into CRC (4-6). About 20-25% of CRC patients are diagnosed with metastatic disease, which is associated with poorer survival rates. CRC can spread to various tissues, including lymph nodes, liver, lungs, peritoneum, bones, and the central nervous system (7). The liver is the most common site for detecting metastatic CRC and is involved in 25% to 50% of cases. However, a rare form of CRC with bone metastasis occurs in 3% to 7% of patients; these individuals often have worse survival outcomes, with shorter survival times and limited treatment options (8-10). TGF-β and BMP signalling pathways are crucial mechanisms in tissue homeostasis, promoting cell proliferation and differentiation during crypt formation in the intestine (11-15). Dysregulation of these pathways in intestinal cells can impair their tumour-suppressing functions and facilitate tumour development (16-18). In particular, mutations in TGFBR2, BMPR1A, and SMAD4 have been identified as contributing to CRC carcinogenesis (2, 3, 19-23). Patients with consensus molecular subtype (CMS) 4, categorised based on gene expression signature, are associated with prominent activation of TGF-β, along with stromal infiltration, epithelial to mesenchymal transition (EMT), and angiogenesis, leading to poorer survival outcomes (19). In silico analysis of gene expression levels of TGF-β and BMP signalling components across CRC cell lines using the DepMap database, along with examination of key proteins and their phosphorylation statuses through Western blots, revealed that ligand activation occurs at various levels, with notable activation of upstream receptors such as TGFBR2, ACVR1B, and BMPR1A. Increased expression of signal transduction genes, including SMAD1, SMAD2, SMAD3, and SMAD5, was also observed. Interestingly, although phosphorylation of SMAD1/5/8 was detected in SW620 cell lines (a metastatic CRC cell line), SMAD4, a central element in signal transduction, was found to be downregulated. Apart from the differential expression of TGF-β and BMP signalling in CRC, the investigation of gene expression in these pathways within disease-free bone marrow (BM) cells using the Stemformatics database was also investigated to provide some insight into whether this morphogenic pathway is involved in metastatic spread to the bone. Here we demonstrated high levels of TGF-β and BMP signalling pathways in the bone marrow associated cells, indicating maintenance of homeostasis and serving as a baseline reference for further research. Assessment of epithelial SMAD4 expression in colorectal polyps using immunohistochemistry (IHC) and digital weighted histoscoring with QuPath revealed that low SMAD4 levels in adenomatous polyps correlated with higher grades of dysplasia, different histological subtypes, the presence of metachronous polyps, and served as a prognostic marker. This marker indicated an increased risk of developing metachronous polyps, particularly in the tubulovillous polyp subtype. Additionally, transcriptomic analysis of tubulovillous polyps showed that upregulation of genes involved in protein deubiquitination occurs in polyps with low SMAD4 levels, along with a likely enrichment in tyrosine metabolism, PPAR signalling, arginine and proline metabolism, leukocyte transendothelial migration, and basal cell carcinoma. In CRC, lower epithelial SMAD4 expression was strongly associated with higher tumour stages and increased tumour stroma. Moreover, lower SMAD4 expression in CRC tumours had prognostic significance, predicting decreased cancer-specific survival in CRC patients, especially in right-sided tumours. A combination of tumour SMAD4 levels and stroma percentages suggested that the worst survival outcome was in patients with low SMAD4 expression in the tumour and high stroma content. Transcriptomic analysis also identified downregulation of SOD3 and enrichment of aminopeptidase activity in this group. Differential expression patterns at gene and protein levels, along with phosphorylation activity, were observed across the complex crosstalk of MAPK/ERK, WNT/β-catenin, TGF-β/BMP, and PI3K signalling pathways in CRC cell lines. However, the mechanisms regulating SMAD4 activity in CRC remain unclear.Testing the TGF-β and BMP signalling inhibitor (LDN-212854) in combination with the standard chemotherapy (Fluoropyrimidine; 5-FU) showed synergistic effects on CRC cell viability, cell cycle arrest, cell proliferation, and cell recovery in an in vitro 2D study. Conditioned media from BM and hepatic cells influence changes in CRC behaviour. The 3D bioprinted SW620 spheroids in 2% alginate and 8% gelatin hydrogel supported physiological interactions, spheroid survival and growth, and were used for drug screening, demonstrating efficacy of the LDN-212854/5-FU combination in a more mechanophysical 3D system. Further development of this in vitro 3D model to become multicell by incorporating metastatic CRC culture with BM and hepatic niches would enhancefuture CRC research and drug discovery

Surveillance and Characterisation of the Humoral Immune Response to SARS-CoV-2 in UK Companion Animals during the COVID-19 Pandemic

The 2019 emergence of SARS-CoV-2, the causative agent of the COVID-19 pandemic, resulted in a global public health crisis. The virus is believed to have emerged from bats, via an intermediate animal species into the human population. This significant spillover has laid bare the significant gaps in the scientific community’s understanding of coronaviruses and the surveillance of viruses in animal species. Although SARS-CoV-2 can be considered primarily as a human pathogen, it has been shown to infect a diverse range of animal species, including white-tailed deer, mink and companion animals such as cats and dogs. These animal infections have resulted in severe pathologies in numerous cases, as well as rare instances of animal-to-human transmission. In human diagnostics, reverse transcription polymerase chain reaction (RT-PCR) testing has been the gold standard for identifying active SARS-CoV-2 infections throughout the pandemic. RT-qPCR can also be used to identify SARS-CoV-2 animal infections. This thesis outlines a series of SARS-CoV-2 RT-qPCR-confirmed cases in domestic cats, demonstrating a range of clinical manifestations and outcomes. The occurrence of severe and sometimes fatal infections in both cats and dogs not only raises concerns for animal health, but also for public health, given the close contact between pets and humans and previously documented cases of SARS-CoV-2 zoonosis. RT-qPCR’s utility in animals is limited by challenges in detecting asymptomatic or transient infections. As such, this thesis details the development of an enzyme-linked immunosorbent assay (ELISA) to be used alongside a pseudotype virus neutralisation assay (PVNA), to detect previous exposure to SARS-CoV-2 in companion animal populations. These assays were used in combination to test 5847 residual diagnostic feline samples, finding a neutralising antibody seroprevalence of 4.8%, alongside an ELISA seroprevalence of 13.7%. This large non-neutralising response is likely driven by the production of antibodies against viral epitopes that are not conducive to virus neutralisation, suggesting a complex humoral immune profile in cats following natural infection. Additionally, several demographic risk factors for SARS-CoV-2 seropositivity were identified in cats, including age and breed. A companion serosurvey in dogs, comprising a smaller sample size, demonstrated a comparable overall seroprevalence (4.3% neutralising and 14.3% seropositive on ELISA) but notably lower antibody titres, indicating a weaker humoral immune response relative to cats. Analysis of immune responses in both species showed variant-dependent patterns of antibody neutralisation, which implied the existence of at least two distinct SARS-CoV-2 serotypes. A small serosurvey was also conducted on pre-pandemic raccoon dog sera, uncovering evidence of antibodies against an unknown Betacoronavirus that were capable of cross-neutralising multiple SARS-CoV-2 variants. This finding provides insight into the potential role of raccoon dogs as hosts of coronaviruses with zoonotic potential and underscores the importance of expanded viral surveillance in wildlife. The findings outlined in this thesis emphasise the importance of adopting a One Health approach to pandemic preparedness, integrating human, animal, and ecosystem health research to provide a comprehensive understanding of coronavirus transmission and evolution. The data presented also highlight the requirement for enhanced surveillance of coronavirus infections in companion animals, bats, raccoon dogs, and other wildlife to better characterise the Coronaviridae family and identify potential emerging threats. This knowledge is essential for the understanding of the origins of human coronaviruses like SARS-CoV-2, as well as for informing vaccine strategies, veterinary diagnostics and public health messaging