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Dissecting the interplay of cardiomyocytes and cardiac fibroblasts using human stem cell models of disease
Get PDFThe cardiac fibroblast is an important cardiac cell type whose main role is to maintain the extracellular matrix of the heart and provide structural support for cardiomyocytes. During disease, cardiac fibroblasts become activated to myofibroblasts. This process is a key hallmark of the pathological remodelling known as cardiac fibrosis - resulting from persistent myofibroblasts and excessive deposition of matrix proteins. Cardiac fibrosis is associated with a majority of cardiovascular diseases as well as increased mortality and morbidity. Reversing the myofibroblast phenotype provides an avenue to reduce cardiac fibrosis and restore normal cardiac function. This has been explored to a certain degree using
rodent models but has yet to be fully explored using human cells.
The primary activator of myofibroblasts is TGF-β, however, mechanical stress has also been linked to this process. In this work, we investigated whether inhibition of TGF-β receptor 1 or decreasing tensile strength in vitro could reverse activated myofibroblasts back to a quiescent cardiac fibroblast phenotype. This was explored using both primary human cells and human induced pluripotent stem cells (iPSC).
Cardiac fibroblasts and myofibroblasts have also been investigated for both their direct and indirect effects on cardiomyocytes. Again, this has been explored predominantly using animal models. Optical mapping is a method often utilised in the study of arrhythmogenesis to interrogate the disruption of electrical wave propagation in the heart. Recently, it has been advanced to map human iPSC derived cardiomyocyte (hiPSC-CM) monolayers enabling study of disease phenotypes and drug testing in vitro using human models. The work presented here aimed to investigate the effects of quiescent cardiac fibroblasts and activated myofibroblasts on cardiomyocyte electrophysiology and contraction using human iPSC-derived cells and optical mapping
The epigenetic control of the establishment and transmission of long-term priming in tomato
Get PDFTomato (Solanum lycopersicum) is a major crop world-wide however its production is heavily limited by fungal pathogens such as Botrytis cinerea. Due to the toxicity of postharvest pesticide application, alternative control methods such as priming are being investigated. Here, it is demonstrated that priming with the broad acting elicitor β -amino butyric acid (BABA) results in long-lasting induced resistance (IR) in fruit and progeny of tomato plants only when initiated at an early developmental stage. Whole genome bisulfite sequencing analysis revealed seedling-specific changes, which occurred in the context of lower global CHH methylation levels. Large differences were observed in the transcriptome and methylome following early and late BABA-treatments suggesting a greater epigenetic imprinting capacity of young plants. Importantly, grafting experiments demonstrated that BABA-IR is transmissible from primed rootstocks to unprimed scions. In these resistant scions, a subset of mobile 24 nt small RNAs associated with genes were identified which display an enhanced expression in response to B. cinerea infection in fruit. These results suggest a functional association of a systemic signal with long-lasting IR in tomato. Additionally, investigations were conducted on the ability of strawberry seedlings (Fragaria x ananassa) to be chemically primed against B. cinerea, with large phenotypic differences seen in strawberry compared to tomato. This PhD therefore addresses current knowledge gaps on the long-lasting nature of priming including its maintenance and transmission. Elicitor screenings have investigated the influence of developmental stage on the plant’s imprinting capacity and stress memory formation. Through use of integrated omics approaches, (epi)genetic markers of long-lasting priming in tomato have been identified which may also serve as targets for durable resistance in other crops
Contribution of the endothelial protein CLEC14A to the pathogenesis of liver disease and liver cancer
Get PDFThe endothelium is a crucial component of the liver microenvironment. Hepatic sinusoidal endothelial cells (HSEC) that line the liver sinusoids form a unique specialised microvasculature. I investigated the expression of CLEC14A in the human liver and described how it is upregulated on sinusoidal endothelium in hepatocellular carcinoma (HCC). It can also be found on larger vessels supplying HCC and in bridging fibrosis in chronic liver disease. Flow-based adhesion assays with HSEC revealed that CLEC14A mediates the adhesion of neutrophils and in vitro angiogenesis studies revealed that CLEC14A promotes the migration and tube formation of HSEC.
I have evaluated CLEC14A as a serum biomarker in HCC, however, the detection of CLEC14A in the serum of cirrhotic non-HCC patients limits its value as a HCC surveillance tool in this cohort. I have shown that low shear stress upregulates CLEC14A on HSEC and CLEC14A is also upregulated by hypoxia and these conditions have the opposite effect on Multimerin 2, a ligand of CLEC14A. I have also narrowed down the region of Multimerin 2 where it interacts with CD248 showing that it is at a distinctly different site from where VEGF binds MMRN2.
I have presented digital spatial profiling data that support a role for CLEC14A in HCC tumour angiogenesis and suggest it may also influence the recruitment of natural killer cells. In addition, high CLEC14A expression is associated with poor tumour differentiation and vascular invasion. This work has indicated that CLEC14A is a novel target in pathological angiogenesis in liver disease and HCC, and also contributes to the immune microenvironment in liver disease
South Carolina in the early American republic: Lowcountry planters’ international republicanism and the French Revolution, 1789-1801
Get PDFThe thesis explores the reasons and chronology of the South Carolina elite’s ideological support for Revolutionary France in the 1790s. Historians depict South Carolina as an anti-French Revolution conservative and Federalist state, contrasting to the other Southern States they deem more Jeffersonian. They also argue that the elite’s supposedly adverse reaction to French revolutionary developments originated from their social and political conservativeness and their anxiety over how the examples of the French and Haitian Revolutions might endanger the state’s plantation and political system. Furthermore, they contend that, by mid-1794, the little elite support that the French Revolution had first enjoyed was defunct. The thesis challenges this historiography. It argues that pro-French elite support, Jeffersonian and moderate Federalist alike, was prompted by the state’s historical background and by its international republican ideology toward France; it also reveals that despite or partly because of planter anxiety over control over the plantation system and strong disquietude over French abolitionism and the Haitian Revolution, support for France occurred much more extensively and for a significantly longer time than hitherto advanced. From 1789 to 1795, this support for Revolutionary France was very prevalent in all state institutions: the government, the Society of the Cincinnati, Charleston’s municipality and democratic-republican society, and local federal officials, largely consisted of and were controlled by elite supporters of the French Revolution. A significant political Francophilia remained significant even during and after the Hamiltonian hiatus of 1795-1797. The thesis also resolves the historiographical contradiction that portrays South Carolina in the 790s as an archconservative, anti-French Revolution, and Federalist state that, suddenly, and for no apparent reason, shifted in an incredibly short time to democratic-republicanism from 1799 onwards, elected Jefferson as President in 1800, altered the constitution to give universal suffrage to white men, in 1810, and became America’s fiercest democratic-republican state until the Nullification Debates of the early 1830s, and beyond.
The thesis utilizes an extensive and varied range of primary sources, including many that historians of South Carolina never discussed. They comprise private and public correspondence, orations and pamphlets, administrative records, gazettes, and memoirs. The thesis explores the characteristics of South Carolina’s pro-French elite Lowcountry culture and planters’ reactions to national and international events connected to the French Revolution. Chapter One analyzes how colonial and revolutionary South Carolina developed a fertile ground for French support between its founding. in 1670, and 1789. Chapter Two examines pro-French support in the context of consensual politics in the United States and France after the 1791-1793 radicalization of American and French politics. Chapter Three explores elite reactions to the Neutrality Proclamation. Chapter Four investigates the elite’s control of Charleston’s democratic-republican society. Chapter Five studies responses to the Jay Treaty, Franco-American relations collapse, France’s republicanism recantation, and the Haitian Revolution. In conclusion, the thesis finds that the South Carolina Lowcountry elite of the 1790s displayed significant and long-lasting pro-French Revolution sentiment
"Allowed to care”: a nested case study exploring positive experiences of primary aged children during the Covid-19 pandemic
Get PDFThe COVID-19 pandemic has had considerable and pervasive impact on children, and it is undeniable that many have experienced significant negative effects. Several long-term school closures resulted in children engaging with learning and teaching online or being among the small minority of children who remained able to attend school, due to having a ‘key worker’ parent or being classed as ‘vulnerable’.
Review of the rapidly extending corpus of published research literature consistently indicates some cases in which children have been judged to have experienced relatively positive outcomes since the COVID-19 pandemic. Existing research in this area depends predominantly on surveys, with more emphasis on the negative impact of the pandemic.
My own nested case study aims to ‘sift for gold’ during this difficult time to find positive exceptions and learn what can be taken forward to inform provisions for these and similar children. Through semi-structured interviews, this research explores the perceptions of four nested cases, each comprising a triad of a child, one of their parents and a member of school staff, about the child’s experiences during the pandemic and what was valued and beneficial within their educational and home experiences. Use of Reflexive Thematic Analysis (RTA) supports a deep understanding of both shared perspectives and individual differences among participants.
Key themes were identified across the case studies relating to the children’s progress: improved wellbeing; self-development/personal growth; development of positive relationships; and greater engagement and progress with learning. Further themes were abstracted, relating to mechanisms that contributed to the recognised progress: a different school environment during the closures; being at home during the closures; quality time, support, and attention from adults; structure, consistency, safety, and boundaries; development of positive relationships; and hobbies and enjoyable activities.
Key implications are therefore: creating a sense of safety through structure, consistency, and boundaries; prioritising spending quality time with children, enjoying activities and nurturing bonds; strengthening the curriculum’s focus on wellbeing and social connections, while promoting greater flexibility in school practices, providing higher levels of adult support when needed, and nurturing parent-school relationships. EPs are well placed to support the implementation of approaches that align with these implications
Individual differences in adults’ mindreading: psychometric challenges and the role of social motivation
Get PDFThe last four decades have witnessed extensive scientific investigation of mindreading (or ‘theory of mind’), that is, the socio-cognitive capacity to attribute mental states such as beliefs, desires and intentions to oneself and others. The present research was motivated by the observations that despite most adults having a conceptual understanding of mental states, adults exhibit substantial variation in how and to what extent they engage in mindreading and, secondly, that comprehending the nature of such variation requires the consideration of motivational factors. We investigated individual differences in mindreading in community adult populations both in terms of the accuracy of mindreading, or ‘contextually justified mindreading’ (see chapter 2), as well as in terms of the processes involved (see chapter 3). To achieve the latter, a unique approach was developed to capture individual differences in the structure of adults’ mindreading, irrespective of response accuracy. Instead of relying on existing measures with inadequate psychometric properties, we sought to refine existing measures (see chapters 2) and to develop a novel measure of mindreading validated across two independent samples (see chapter 3). This exposed that there are reliably measurable, content-irrelevant processes and strategies that individuals employ when engaging in mindreading. Finally, this research assessed the role of individual differences in mindreading alongside social motivational factors (see chapters 2 and 4), revealing that there were positive associations between mindreading and social motivation, while both were still distinguishable constructs. The results also showed unique associations between individual differences in social motivation (but not mindreading) and social competence and mental health (see chapter 4). The present findings challenge past epistemological assumptions about how mindreading can be operationalised and measured and provide support for the notion that researchers interested in mindreading should consider social-motivational factors alongside mindreading
Search for rare exclusive hadronic decays of the W boson with the ATLAS experiment
Get PDFThe search for rare exclusive hadronic decays of the Wboson in the , and final states is presented. This search was performed using up to 140 fb of proton collision data collected by the ATLAS experiment at a center-of-mass energy of =13 TeV. These decays can serve as clean probes of the QCD factorisation formalism and, in the future, could offer a new way to perform the W boson mass measurement, through fully reconstructed final states. Upper limits at 95 % CL are set on the branching fractions of the decays: B() < 1.9x10, B() < 1.7x10 and B() < 5.4x10. These results correspond to the first experimental constraints on B() and B(), and the most stringent upper limit to date on B(). This analysis was enabled by the use of dedicated triggers and of a novel, data-driven non-parametric background modelling technique. Detailed characterisation and validation studies of this novel background modelling method are also presented
Development of raman spectroscopic point of care diagnostics for the detection of key targets of disease
Get PDFInflammatory bowel disease (IBD) and cardiovascular disease (CVD) represent two distinct yet urgent healthcare concerns. IBD, characterised by chronic inflammation of the gastrointestinal tract, poses a significant burden on the affected individuals. Both conditions require early and accurate diagnostic methods to optimise patient care and treatment outcomes. Conversely, CVD continues to be a leading global cause of morbidity and mortality, necessitating innovative approaches to diagnosis and monitoring. Here, we explore the transformative potential of Raman spectroscopy (RS) as a rapid and non-invasive diagnostic tool in the assessment of saliva and blood plasma. The multidimensional approach combining RS with multivariate analysis unveils distinct molecular profiles thus enabling early and accurate disease diagnosis. Classification accuracies of >88 % are demonstrated between three sample types applied to healthy, CVD and follow-up blood plasma. Similarly, in IBD, classification yields accuracies >90 % over four sample types applied to saliva and tissue. This further extends into biomarker discovery, unveiling novel CVD- and IBD-indicative molecular signatures. Feature extraction, inherently connected to classification results, indicates an increase in circulating cytokines, a hallmark of inflammation in both CVD and IBD. Extracellular vesicles (EVs), as biomarkers serve as key carriers of disease-specific biomolecules, therefore, rendering them invaluable in diagnostics and personalised treatment. Conventional EV isolation methods suffer from several limitations such as, low throughput, sample loss, limited scalability and EV damage thus this has led to the exploration of alternative EV isolation techniques. The developed methodologies harness the power of RS to redefine the paradigm of disease diagnosis and risk stratification and as a means of increasing diagnostic accuracy, bridging the translational gap, and facilitating the clinical integration of RS-based diagnostics via a novel lab-on-a-chip (LoC) platform for the isolation and separation of disease-indicative EVs from biofluids. The developed platform marks a significant advance in utilising the diagnostic potential of EVs, offering a streamlined and efficient approach to their isolation and analysis
Epidemiology of and health services for people living with HIV and comorbidities of non-communicable diseases
Get PDFPLWH are increasingly experiencing comorbidities of non-communicable diseases (NCDs). This could be due to complex interactions of HIV and non-HIV mechanisms (i.e. antiretroviral therapy [ART], persistent viral presence, and behavioural and psychosocial risk factors). Most countries provide HIV care through specialised HIV/infectious disease clinics or sexual health clinics; thus, care for NCD comorbidities is often separate from HIV care with little to no integration, leading to fragmented care. Fragmented care can lead to drug-drug interactions, polypharmacy and negatively impact quality of life and clinical outcomes. The aim of this thesis is to understand the risk of NCD comorbidities among PLWH and determine how care for NCD comorbidities can and should be improved; the NCDs focused on in this thesis are cardiovascular disease (CVD), diabetes (DM), hypertension (HTN), chronic kidney disease (CKD) and mental health conditions.
Using a UK-based matched retrospective cohort study design, three research projects were conducted: 1) to determine the risk of DM, HTN, CKD, stroke, ischaemic heart disease (IHD), myocardial infarction (MI), peripheral vascular disease (PVD), heart failure (HF) and a composite measure of CVD in PLWH compared to people without HIV; 2) to determine the risk of depression, anxiety, severe mental illness (SMI) and a composite measure of mental health conditions in PLWH compared to people with HIV and; 3) to determine if age-related conditions occur prematurely and/or are attenuated and/or accelerated among PLWH. Using semi-structured interviews with healthcare professionals (HCPs) and PLWH in Tanzania, two qualitative analyses were conducted: 1) to identify the barriers and facilitators of PLWH receiving optimal care for HTN and DM in a fragmented healthcare system and; 2) to identify the preferred integration model for HIV, DM and HTN care and the associated barriers and facilitators for the preferred model.
PLWH were found to have a 28% increased risk for DM, 37% for HTN, 242% for CKD, 42% for stroke, 55% for IHD, 50% for composite CVD, 94% for depression, 38% for anxiety, 218% for SMI and 63% for composite mental health compared to people without HIV after matching and adjusting for confounders. Additionally, PLWH experience early onset of CVD and HTN and an exponential increase in CKD over time indicating possible premature and accelerated ageing. Many barriers were found for PLWH to receive optimal care for DM and HTN within the current model of care in Tanzania; most related to organisational and healthcare system factors (i.e. fragmented services, no protocol for NCD screening, lack of access to diagnostic equipment for NCDs, poor continuity of care for NCDs); however, syndemic factors of poverty, stigma and poor mental health were found to be cross-cutting barriers impacting each component of the care pathway. HCPs and PLWH preferred for DM and HTN care to be integrated within HIV clinics in Tanzania which would create little to no additional barriers to care; however, existing barriers to do with costs of NCD medication, lack of NCD medication and equipment would need to be improved for the preferred model to be effective.
The epidemiology findings from this thesis should highlight the need for prevention strategies and changes in policy and clinical care to improve care for PLWH with or at risk for developing CVD, DM, HTN, CKD and mental health conditions; however, future research is needed to better understand which mechanisms contribute to these higher risks. The qualitative findings from this research should inform both quick wins and long-term system changes to improve DM and HTN care for PLWH in Tanzania; though, procurement of NCD medication and equipment must be improved and reductions in stigma and poverty must be prioritised
The consuming power of territories: a grounded theory exploration of symbolic violence and territorialized consumption in a post-conflict city
Get PDFIn a world where territorial boundaries have long been a source of division and conflict, this research unveils a transformative understanding of the complexities of territoriality within the realm of consumer behaviour and marketing. With roots embedded deeply in the traumatic experiences of the Bosnian war and its post-conflict transition, this research explores how seemingly inconspicuous boundaries, such as the Inter-Entity Boundary Line (IEBL) going through the city of Sarajevo, profoundly influence consumption patterns.
Central to this thesis is an exploration of how major disruptive events, a war in this particular case, reshape the significance of places and, by extension, impact consumption patterns in ways that, this study argues, have been overlooked. Informed by critical marketing, this thesis explores the otherwise neglected domain of territorial consumption in marketing, using an interdisciplinary approach that links cultural geography with marketing. It looks into how we perceive, navigate, and are influenced by the boundaries around us, ultimately contributing to the way marketing discipline understands and engages with territory.
Using grounded theory method, this study uniquely integrates a "category-centred" grounded theory analysis, focusing on the relationships between emerging codes/categories, with the "case-centric" approach of narrative inquiry. By combining these aspects, it maintains the integrity of individual narratives on the one hand, while enriching the understanding of categories that arose within the grounded theory framework, on the other. The presented qualitative data encompasses oral life stories, participant observations, visual data, and archival (secondary) data from the 1992-1995 war in Bosnia and Herzegovina.
Through the comparison of data and literature, “territorialized consumption” is conceived as the core category. Territorialized consumption, as conceptualized in this study, refers, at the outset, to the process by which territorial boundaries—both tangible and intangible—profoundly influence, mould, and delimit people’s consumption behaviours and patterns. The process, however, does not stop here. This core category entails territoriality, which, this study argues, is an active subject which continuously conditions people’s consumption behaviour, while, simultaneously, 'consuming' individuals. In this dynamic, individuals are not just consumers of territories; they are also consumed by territoriality, that is by the power, violence, and authority acting in the territory, with visible and invisible boundaries as their multifaced agents.
The original contribution to knowledge lies in the unveiling of this two-way relation between people and territory challenging the conventional dichotomy between individuals as subject/consumers and territories as objects to be consumed.
Three key categories were identified within the formulated theoretical framework:
Legitimisation: The data posits that territories must first be legitimized, accepted, and recognized. Legitimisation serves as the foundation for examining territoriality within disrupted places as it demarcates boundaries employed as control strategies. Spatial memory, which is a constant recollection of past trauma during daily encounters with a place, serves to further legitimize territoriality. This interplay between the past and present transforms these places into transitional territories, reinforcing and re-experiencing the trauma within these newly legitimized spaces. This dynamic illustrates the original contribution to knowledge, which is the idea that territories consume individuals, reversing traditional views.
Maintenance: This category delves into the persistence of territoriality. It is illustrated through two processes: ownership and othering. Ownership refers to the establishment and acceptance of control over certain territories, essential for maintaining new boundaries. Othering involves distinguishing between 'us' and 'them,' often employed to sustain territorial boundaries by differentiating between insiders and outsiders. The strategic manipulation of symbolic markers plays a critical role in establishing and upholding territorial boundaries, distinguishing between the 'self' and the 'other.' The relationship between ownership and othering demonstrates how they work together to uphold and reinforce the territorialized consumption, with ownership providing the structure, and othering helping maintain the boundary by emphasizing distinctions.
Expression: Data reveals that territorial boundaries are often internalized, becoming a normalized, albeit unrecognized, form of daily violence. Yet, responses to territorialized consumption are not binary. Instead of strictly accepting or naturalizing territorial norms, individuals often challenge these boundaries, suggesting reactions to territorial demarcations are multifaceted and exist on a spectrum.
In conclusion, it is argued that this thesis successfully achieves the primary objective of grounded theory methodology: the development of a theory. Drawing from diverse and rich data sources, it offers a theoretical framework that delves into the realm of territoriality and consumption within disrupted contexts. It is also proposed that the relevance of this research is enhanced by its shedding light on overlooked contexts often marginalized in mainstream marketing, particularly those from non-Western perspectives. As the global landscape continually struggles with major disruptions, such as the widespread of armed conflicts and the recent pandemic, the insights offered by this research become even more critical. By examining the dynamics at stage in territories marked by boundaries (‘soft’ ones in particular), this study, in line with critical marketing thinking, offers scholars a lens through which they can understand and navigate the complex interplay between territory and consumption. This thesis, therefore, contributes both to the academic discourse and to real-world applications, particularly in understanding and addressing the challenges posed by disruptions and mutations in the experience of territory
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