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Associations between advanced glycation end products and cardiometabolic health
No full textAbstract not currently available
The structure of a relationship: The asymmetry of labour and trade regulation in international economic law
No full textAbstract not currently available
Investigating the effect of HIV infection on TCR repertoire diversity and Mycobacterium tuberculosis-specific T cell function in Malawian adults
Get PDFThe burden of tuberculosis (TB) is huge, posing a significant health threat worldwide, particularly in HIV-endemic regions such as sub-Saharan Africa. Coinfection with HIV is a major risk factor for development and progression to active Mycobacterium tuberculosis (Mtb) disease. People living with HIV (PLHIV) remain at more risk of developing lower respiratory tract infections including TB than HIVuninfected individuals, despite successful coverage of antiretroviral therapy (ART). HIV depletes and impairs the function of Mtb-specific T cells crucial in controlling Mtb infection. However, the impact of HIV on T cell receptor (TCR) usage in alveolar T cells is incompletely described. Characterisation of TCR repertoire is essential for understanding the mechanisms of recognition and control of Mtb infections by T cell adaptive immunity.
To investigate the Mtb antigen-specific TCR diversity and clonality in the airway and blood and assess the impact of HIV and ART on TCR diversity, peripheral blood and bronchoalveolar lavage (BAL) samples were collected from PLHIV ART–naïve, on ART (≥3 years) and HIV-uninfected adults recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Alveolar and peripheral blood lymphocytes were stimulated with Mtb antigens and analysed using flow cytometry and TCR bulk sequencing.
Notably, Mtb-specific TCR repertoires from PLHIV displayed a reduced diversity and clonality compared to HIV-uninfected individuals in both the airway and blood. Moreover, ART was associated with the restoration of TCR clonotypes in PLHIV. Additionally, lower frequencies of Mtb-specific CD4 IFN-γ and TNF-α producing cells were observed in both blood and airway in PLHIV on ART and ART naïve compared to HIV-uninfected individuals. Significant alterations in TCR Vβ expression patterns were noted in CD4+ T cells in PLHIV compared to healthy controls. Vβ1, Vβ7.2, and Vβ23 were higher, while Vβ9 and Vβ18 were lower in blood and airway in PLHIV than in HIV uninfected individuals. In CD8 T cells, no significant differences were found in TCR Vβ expression in the PBMC compared to BAL. However, in the lung, Vβ5.1, Vβ16, and Vβ17 were increased, while Vβ14 was decreased in PLHIV. Furthermore, CDR3 length distribution analysis showed a higher and more diverse distribution of TCR amino acid lengths of Mtb-specific T cells in BAL and PBMCs in HIV-uninfected individuals compared to PLHIV. The elevated TCR Vβ in the lung and blood in PLHIV suggests their potential involvement in HIV immune response whilst depletion of certain TCR Vβ clones in Mtb-specific CD4 and CD8 T cells in the lung and blood may indicate HIV-induced alteration in the repertoire associated with increased TB risk.
These findings suggest a more restricted TCR repertoire in PLHIV compared to healthy controls, with alterations in the frequency of certain families that may impact antigen recognition and specificity. This could lead to a reduced ability to mount protective immune responses against infections, including Mtb, in PLHIV. Identifying highly used and expressed TCR Vβ segments provides insights into mechanisms of host protective immunity in HIV and TB and may offer crucial targets for vaccine development and preventive therapies
Characterization of peripheral immune dysregulation and brain neuroimmune pathophysiology in the Df(16)A+/- Mouse Model of 22q11.2 Deletion Syndrome, a high genetic risk factor for schizophrenia
Get PDFSchizophrenia (SCZ) is a severe and chronic neurodevelopmental disorder that imposes a profound global health burden. Among its complex genetic underpinnings, the 22q11.2 Deletion Syndrome (22q11.2DS) stands out as the highest-known genetic risk factor, with approximately 25-30% of affected individuals developing a psychotic disorder. Recent research in SCZ has undergone a paradigm shift, moving beyond purely neurocentric models to embrace growing evidence that implicates immune dysregulation and neuroinflammation as critical etiological processes. While 22q11.2DS is known to confer a complex immunological phenotype, including foundational T-cell deficits and a high incidence of autoimmune disorders, the functional consequences of this genetic 'first hit' on immune reactivity and central nervous system (CNS) vulnerability is not well understood. Therefore, the primary objective of this thesis was to systematically characterize immune dysregulation in the Df(16)A+/- mouse model of 22q11.2DS to test the hypothesis that the genetic deletion programs a dysfunctional response to subsequent inflammatory challenges, thereby providing a plausible biological substrate for neuropsychiatric risk.
This investigation utilized the Df(16)A+/- mouse model, which carries a chromosomal deletion syntenic to the human 22q11.2DS critical region. Our experimental strategy involved a comprehensive profiling of the peripheral and central immune systems at a homeostatic baseline and following provocation with distinct immune stimuli, including a sustained Toll-like receptor 7 (TLR7) agonist (Aldara) and an acute Toll-like receptor 3 (TLR3) agonist (LMW-Poly(I:C)). Given the limited characterization of the Df(16)A+/- immune profile and the incompletely elucidated mechanisms linking 22q11.2DS to psychiatric risk, this thesis employed both hypothesis-driven and exploratory analytical frameworks to systematically characterize the immune phenotype. Primary analytical techniques included multi-plex immunoassays (Luminex), multi-parameter flow cytometry, and quantitative immunohistochemistry. This central analysis was supported by the development of a high-throughput, objective morphometric pipeline to robustly quantify glial reactivity and neuronal cytoarchitecture within the hippocampus.
Our results demonstrate that the Df(16)A+/- genotype is not immunologically silent but confers a "first hit" of subtle, multi-system dysregulation. Peripherally, this is defined by a "central deficit, peripheral compensation" model, with foundational T-cell developmental deficits in the bone marrow and thymus that are compensated for in circulating blood and spleen populations. This cellular alteration is mirrored by a rewired baseline molecular milieu, characterized by increased inter-animal heterogeneity and a less interconnected systemic cytokine network. Centrally, this state corresponds to a latent glial vulnerability, defined by a subtle but significant reduction in the morphological complexity of hippocampal microglia, anatomically co-localized to the dorsal CA1 and dentate gyrus.
Subsequent immune challenges revealed this vulnerable baseline dictates a "second hit" of a profoundly dysfunctional and uncoupled neuro-immune response. The systemic reaction to the TLR7 challenge was both attenuated in magnitude, with blunted splenomegaly and pro-inflammatory cytokine upregulation, and qualitatively dysregulated, exemplified by the paradoxical downregulation of IFN-alpha and the collapse of the organized inflammatory network. Critically, this peripheral impairment was associated with a complete uncoupling of the glial inflammatory cascade in the dorsal hippocampus: wildtype mice mounted a coordinated neuroinflammatory response, whereas Df(16)A+/- mice exhibited a dissociated cascade where microglia adopted a morphologically reactive state in the complete absence of a canonical astrocyte (GFAP+) response. This microglial response was itself dysfunctional, occurring without the expected upregulation of the functional protein Iba1. This glial uncoupling was directly associated with the neuronal findings: Df(16)A+/- mice exhibited an altered parvalbumin-positive (PV+) interneuron response, lacking the significant change in cell counts observed in wildtype animals following the challenge. Findings from an acute TLR3 challenge, qualified by a severe physiological confound of hypothermia, also pointed towards a rewired inflammatory program by revealing a paradoxical central myeloid response.
The central conclusion of this thesis is that the 22q11.2DS-relevant genetic deletion establishes a "first hit" of homeostatic instability that dictates a functionally impaired "second hit" response to immune challenges. This work links this high-impact genetic risk factor to a specific CNS vulnerability, defined by an uncoupled neuroinflammatory cascade, where microglia activate but astrocytes fail to respond, and a corresponding genotype-specific PV+ interneuron response, where the significant change in cell counts seen in wildtype animals was absent in the Df(16)A+/- mice. This integrated phenotype provides a novel and plausible biological substrate for the increased neuropsychiatric risk observed in the human 22q11.2DS population
The structural transformation of the public sphere in Scotland: print culture, class conflict, and opinion formation, c.1850-1920s
Get PDFAs seen from the perspective of antagonistic Scottish print publics, how did the commercialisation of the press after the repeal of the ‘Taxes on Knowledge’ change the dynamics of class conflict, critical democratic deliberation, and opinion formation? The thesis reconsiders Habermas’s narrative of public sphere transformation (examined in Chapter 1) in the late nineteenth and early twentieth centuries through a series of case studies of periodicals printed in Glasgow, including the daily Glasgow Advertiser (1783-), Thomas Johnston’s ILP-aligned weekly Forward (1906-1959), and the Marxian monthly the Socialist (1902-1924). Through readings of the clashing post-bourgeois commercial and proletarian (earlier plebeian) print public spheres, the thesis contributes to comparative historical studies of distinct cultural formations, to Habermasian theory and public sphere studies, and to the history of education in Scotland. Chapter 2 analyses the Glasgow Herald (as the Advertiser became called) and its publishing company George Outram & Co., arguing that the proprietors resolved the dilemma of maintaining an organic community of readers for the mother-publication while pursuing the financial opportunities of an expanded reading public by segmenting the offering with the evening paper Glasgow Evening Times. I analyse the cultural fragmentation effects of commercial print culture, and the Glasgow Herald’s defensive strategies of containment via public opinion management, policing, and directed educational efforts by focussing on its mediation of the 1919 Battle of George Square and debates on post-war reconstruction. Chapter 3 analyses the Socialist which projected a socialist public sphere model, but actually constituted an intervention-driven proletarian counterpublic directed at the ideological and educational needs of the labour movement. I highlight continuities with plebeian radicalism in its educational praxis, and suggest that this formation became entangled in an ambiguous cultural politics which made it prone to isolation from wider working-class culture and legitimising constitutional discourses. Chapter 4 analyses the Forward’s distinctive cultural practices through advertisements, public notices, discussion- and legal-advice columns, showing a cross-class public approximating a deliberative Kantian public sphere model fusing morality with politics and political representation with enlightenment. Through debates on adult education in Forward, and following Raymond Williams, I argue that the labour movement contributed to cultural democratisation in Britain through hegemonic contestation. In the Conclusion, I propose further research into the emergence of critical populism
Fostering intrapreneurship in Scotland: internal and external factors, influences and tensions
Get PDFThis research investigates how intrapreneurship is facilitated in Scottish organisations across different sectors, drawing upon four strands of literature: entrepreneurship, human resource management, organisational behaviour, and organisational theory. The overarching aim is to explore how intrapreneurship is understood and enabled in organisations, emphasising the internal organisational dynamics, as well as external shocks and influences.
The study reviews literature across individual, team, and organisational levels affecting intrapreneurship while considering external environmental impacts, synthesising these strands into a conceptual model. A comparative multi-case study approach was employed, investigating three organisations in Scotland through semi-structured interviews and documentary analysis of organisational and government policies. Interviews were conducted with management and employees at each level in the case organisations. Thematic analysis and an abductive approach were adopted to identify and analyse recurring patterns informed by the conceptual framework.
As intrapreneurship is a complex multilevel construct, institutional logics were adopted as a lens to allow for an in-depth understanding of sectoral and industry differences in the intrapreneurship pursuit to be examined. The empirical findings show the enabling mechanisms of intrapreneurship, along with organisational tensions and competing logics. It is evident that top-down antecedents or enabling conditions are necessary to enable bottom-up ‘organic’ intrapreneurial activity. The findings demonstrate the influence of unexpected external events, pushing organisations to pursue intrapreneurship, developing antifragility and facilitating organic intrapreneurship. A multilevel model of intrapreneurship is presented, which considers all influencing factors and enabling mechanisms in its facilitation.
This research contributes to knowledge, policy and practice, building upon the growing body of research on intrapreneurship. It moves beyond the individual level of analysis to provide insights into the multilevel causal mechanisms that facilitate intrapreneurship, revealing the tensions organisations face in enabling it and emphasising the need to navigate these tensions and achieve harmony. Intrapreneurship is highlighted as a key driver of innovation in the cross-sectoral cases with the potential to create change from within existing organisations. Robust evidence is provided as to how intrapreneurship may unlock untapped potential in existing organisations in Scotland and further afield
Substance use, self-harm and suicide risk: investigating professionals’ perspectives and the role of alcohol factors
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Examining student mothers' and female academics' experiences of higher education in the United Arab Emirates through an Organisational Culture lens
Get PDFIn this PhD by Publication thesis, I present a portfolio of ten publications: eight journal articles and two book chapters, centred on women in higher education in the United Arab Emirates (UAE). I use arguments to extend the existing research and discourse in the field of women’s accessibility to higher education, specifically in the UAE, a small but wealthy Arabian Gulf country. In the UAE, as in several other GCC (Gulf Cooperation Council) countries, women outnumber men studying in higher education (70% to 30%, according to latest figures1) and there is near gender parity in the workforce, including in academic institutions. These statistics are often showcased as evidence of the high status of women in the country. The empirical research carried out in the studies represented in this portfolio curates work completed over a period of around six years; between 2017 and 2023. The studies centre upon the experiences of two groups of women: students who are mothers, and women academics (many of whom are also mothers). Nine of the publications are empirically data driven, while one used secondary data sets from institutions across the country. I believe that the synthesis of these articles in one submission helps to concretize the status of women in university by bringing together the experiences of these two key stakeholder groups of women in higher education. By exhibiting the work together I am able to consider the organisational culture and structures which impact both groups of women, including the structural aspects not currently addressed and which continue to remain roadblocks into women’s academic lives. This portfolio contributes to understanding the barriers and challenges which women - both students and academics – encounter. These are important to understand and are often overlooked in the face of much lauded statistics of women’s participation in higher education in the UAE. Bringing together the empirical evidence from these publications, along with a conceptual line of reasoning through an organisational culture lens, I argue that statistics of gender parity in higher education are no substitution for consideration of gender equality within this setting. In short - it may be that women are thriving in parity terms in spite of organisational structures and organizational culture, rather than because of them. Understanding the complexity of these tensions is important. By combining work from two distinct demographic groups in this submission, there is novelty in that the focus then becomes broader than challenges facing particular groups of women (although this is of course important) and instead allows for more of an institutional focus. This, I would argue, is more likely to facilitate the provision of concrete recommendations to address issues of gender inequity in practical terms
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