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Illiberalism in its epoch: The emergence of modern illiberalism as a consequence of the Global War on Terror
Get PDFThe aim of this thesis is to look at the extent to which the Global War on Terror (GWOT) played a role in the emergence of the phenomenon of modern illiberalism.
While 9/11 was undoubtedly a paradigm-shifting event in global and local politics, this work argues that the GWOT was a specific ideological response to those attacks. Moreover, the particulars of that response contributed to the rise of modern illiberalism in various ways.
In order to best understand how the GWOT played a role in the emergence of modern illiberalism, it was necessary to examine modern illiberalism in practice. This work includes case studies and analyses of Orban’s Hungary, Putin’s Russia, and the 'counter-jihadist' ideology of the Islamophobic terrorist Anders Behring Breivik. It examines how the consequences and dynamics of the GWOT, often functioning inadvertently, shaped key aspects of their methods, beliefs, and reactions.
It concludes the GWOT was a major contributing factor to what this work terms the ‘epoch of illiberalism’ that describes a significant aspect of global politics. That is not to say that illiberalism would not exist if not for the GWOT, as it obviously preceded it, but, rather, that without the GWOT, modern illiberalism, as a phenomenon in itself, would be both quantitatively and qualitatively different
The use of pre-implantation perfusion techniques of kidney grafts to increase organ utilisation and the investigation of regenerative cell therapy
Get PDFDespite the advancements in solid organ transplantation, including an ever-increasing living donation programme, there remains a significant shortfall of utilisable grafts to meet the demand. In the United Kingdom, NHS Blood and Transplant released a mission statement entitled “2030: Meeting the Need," highlighting key areas to focus efforts on and tailor technologies. Within this statement, organ utilisation was highlighted as a critical area for improvement and development.
There have been significant developments in recent years with regard to deceased donation in how organs are assessed, transported and prepared for transplantation with organ utilisation in mind. Despite these advancements, the rate of organ decline remains high, and tools and technologies that allow clinicians to assess organs, providing more confidence to accept and utilise offered organs, are vital to improving our utilisation rates. Furthermore, pre-implantation therapeutics may improve grafts from those deemed unsuitable for transplantation to those considered utilisable in certain circumstances.
Ex-vivo normothermic perfusion (EVNP) is one such technology that delivers warmed, oxygenated blood with added nutrients to a kidney graft before implantation, allowing for a period of assessment, and potentially mitigates against some of the critical issues within deceased donation, such as ischaemic reperfusion injury.
The implementation of a clinical EVNP service is then described. Herein we describe the mechanisms by which the technology was introduced as a clinical service to assess the viability of marginal grafts, including the requisite training and trust approval. Obstacles and pitfalls are also discussed, including the sourcing of blood products, staffing considerations and the perfusion of grafts with variant anatomy.
This thesis first outlines the risks evident when high-risk donor kidneys and recipients combine. Retrospective analysis demonstrated that although graft survival and function are satisfactory, this high-risk combination is associated with delayed graft function, prolonged length of stay in hospital and increased use of secondary care within the first 90 days posttransplant.
This is followed by a report of the successful implantation of seven kidneys as a result of this novel assessment tool. This includes grafts in the deceased donor setting with severe acute kidney injury, poor perfusion and in the context of dual kidney transplantation. Furthermore, the use of this technology to assess arterial reconstruction in two cases of living donor nephrectomy for renal artery stenosis is detailed. To our knowledge, this series includes examples of world-firsts in the use of this technology to expand the donor pool of utilisable grafts.
A systematic review is then conducted which sets the scene for a study in which adiposederived regenerative cells (ADRC), harvested from donor peri-renal tissue, were delivered via EVNP technology to discarded human kidneys. Perfusion characteristics and urine output were unchanged with ADRC treatment, as were histological features of acute tubular injury. RNA sequencing, however, highlighted differential gene expression to guide further mechanistic evaluation. Of note, no adverse events were found with the delivery of this regenerative therapy.
In summary, EVNP is a valuable assessment tool in transplantation decision-making, with the potential to improve organ utilisation. Furthermore, it provides an opportunity to deliver therapeutic agents, such as regenerative cell populations, as described herein
Elucidation of the role of methylarginine metabolism in regulation of nitric oxide production and inflammation
Get PDFAtherosclerosis is a major global health issue, and inflammation is important in its pathogenesis. Many atherosclerosis risk factors lead to reduced nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA), an independent cardiovascular disease risk factor and NO synthase inhibitor, is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). DDAH2 is the isoform present in the immune system. A deeper understanding of ADMA metabolism could help reveal new therapies for atherosclerosis. However, it is debated if DDAH2 hydrolyses ADMA. There is evidence that DDAH2 has NO-independent cellular functions, and research in our group showed that DDAH2 regulates macrophage functions.
This thesis initially aimed to investigate the role of DDAH2 in regulating inflammation in atherosclerosis models. However, this was derailed by limitations imposed by the Covid-19 pandemic. Therefore, models of inflammation were used. Genes and mechanisms associated with inflammation and atherosclerosis were investigated.
RAW 264.7 murine macrophage cell line and bone marrow-derived macrophages (BMDM) were validated for suitability to study the DDAH-ADMA-NOS pathway. To better understand the functions of DDAH2, a macrophage-specific Ddah2 null mouse model was re-derived and validated. RNA sequencing data previously generated by our group from peritoneal macrophages of the same model was re-analysed and revealed almost 5,000 genes to be DDAH-dependent and required for normal immune response. More than 200 Reactome pathways appeared enriched, with apoptosis being the most enriched. The in silico data was validated in vitro in DDAH2-knockout peritoneal macrophages from the macrophage-specific Ddah2 null mouse model. Inferred hypotheses were investigated in DDAH2-Knockout BMDMs from the macrophage-specific Ddah2 null mouse model with confirmatory studies on C57BL/6J BMDMs using ADMA.
The in vitro analysis in the BMDMs showed no conclusive evidence supporting the in silico data that DDAH2 regulates the investigated genes (except Il17a), nor did ADMA alter the gene response to LPS. Il17a was shown by the in silico analysis to be regulated by DDAH2 and was validated in vitro in peritoneal macrophages by both RT-qPCR and ELISA. Given the significant role of IL17A in inflammation and its existing use in treating systemic inflammatory conditions such as psoriasis, this thesis proposes DDAH2 as a potential therapeutic target for inflammatory diseases in general and atherosclerosis in particular
Genetics of the interactions between the human malaria parasite Plasmodium falciparum and Anopheles albimanus
No full textAbstract not currently available
Original web dramas and Chinese subscription video-on-demand services: patterns and benefits
Get PDFSubscription video-on-demand (SVOD) services not only serve as new distribution channels for television content but also transform industry practices and protocols. This study focuses on three leading services in China – IQIYI, Youku, and Tencent Video –to understand how they established themselves and how they are reshaping the existing drama industry. The study proposes three main research questions that explore the reasons why Chinese SVOD services invest in original drama production, how these investments impact the production and distribution of dramas, and what strategic implications arise from these changes. The study spans the fields of TV studies, strategic management, production, and distribution. It seeks to enhance understanding of industrial practices in the Chinese SVOD industry and builds upon existing theories, which have primarily focused on US-based SVOD services.
The study involved semi-structured in-depth interviews with 24 practitioners and utilised document analysis for triangulation. It reveals that Chinese SVOD services primarily invest in original drama productions to enhance cost efficiency, secure market power and resources, and build brands and ecosystems. In terms of content production, audience fragmentation, datafication, and regulation are highlighted as major factors influencing creative decisions. Chapter 6 shows that Chinese SVOD services prioritise ‘time delay’ as the core strategy to maximise income from advertisers and subscribers and develop more flexible scheduling strategies than those used in television. The 'online-first' strategy dominates domestically, with overseas distribution increasingly synchronised with domestic releases. Chapter 7 argues that Chinese SVOD services complement traditional television rather than replace it. The study also considers how these services promote the 'industrialisation' of drama production, outlines the ‘logics’ of their advertiser-supported model, confirms the of platformisation on content production, and examines potential power asymmetry issues
Genomic and transcriptomic approaches to investigating candidate genes associated with tick resistance in cattle
Get PDFThe cattle tick, Rhipicephalus (Boophilus) microplus, is able to transmit tick-borne diseases in cattle, which causes major production and welfare implications, particularly in tropical and subtropical areas. Problems associated with cattle ticks, such as decreased production yield, mortality, and costs of treatment are economically significant. Although resistance to ticks in cattle is moderately heritable (0.4), there are no genes or biomarkers commercially available that could be used for genomic selection. The aim of this study was to identify genes and pathways associated with tick resistance in cattle using a meta-analysis of previous studies, combined with single nucleotide polymorphism (SNP) based genotyping and long-read sequence-based transcriptomics.
Previous gene expression (GEX) and genome-wide association studies (GWAS) have identified a large number of potential genes or quantitative trait loci (QTLs) associated with tick resistance in cattle. However, different studies have found different sets of genes, using different experimental procedures and platforms. In Chapter 2, I aimed to integrate results from differential expression genes (DEGs) and QTLs from GWAS associated with host resistance to infestation with R. microplus in order to generate a list of genes which showed supporting evidence from multiple sources. I identified a set of 37 genes that were found in multiple studies, based on blood or skin gene expression and GWAS, including three transcription factors, 12 genes associated with immune function, nine with the extracellular matrix, six structural genes, and 13 other biological processes. This subset of genes was then used to investigate whether there was sufficient variability that they could potentially be used as targets of selection (Chapter 3).
To develop animals breed to be resilient to foreign invasion (pathogens and ectoparasites), it may be necessary to focus not only on genes associated with immune function but also on other types of pathways. The aim of Chapter 3 was to determine whether any of the genes shortlisted from Chapter 2 showed significant differences in genotypes between Scottish breed groups, including British (n=14), European (Continental) (n=10), and Hill (n=10) cattle. Focusing on breeds within Scotland provided a conservative estimate of variability of these genes. The genotyping was investigated from DNA extracted from spleen tissue samples from individuals collected from a single abattoir, by using the GeneSeek Genomic Profile (GGP) Bovine 100K SNP chip. A total of 88 SNPs were identified from the list of candidate genes, with 14 spread across six genes (HOXD1, SATB2, GIMAP7, ITGA11, PLA2G7, and PRKG1) presenting significant differences in genotype frequencies between the breed groups. Although most of the SNPs were located in introns that were not close enough to exons to expect linkage to mutations under selection, only a single amino acid changing variant was identified in PLA2G7-1 (missense mutation), with the other 13 being either synonymous changes within an exon (ITGA11) or located in introns. This list of SNPs was then used to classify gene expression patterns from skin and spleen samples from the same individuals in Chapter 4.
All of the previous studies identifying genes showing differential expression associated with resistance to ticks in cattle have focused on skin or blood samples in Chapter 2; however, immune functions are more pronounced in tissues such as spleen or lymph nodes. Chapter 4 was a pilot study aimed at identifying genome-wide patterns of gene expression (transcriptome profiles) in both skin and spleen tissue samples using GridION from Oxford Nanopore Technology (ONT). The data were analysed using a weighted gene co-expression network analysis (WGCNA) correlated with variation in the 14 significant SNPs from Chapter 3. In skin datasets, seven modules showed significant correlations with at least one of the SNPs in the skin dataset, which contained 2,297 genes, whereas there were ten modules in the spleen dataset (3,265 genes). Overall, I found different sets of co-expressed gene modules associated with variation in the SNPs in the two tissue types, with a wider range of modules associated with the spleen but also more pathways directly related to immune function. Nevertheless, both tissues identified multiple biological pathways and interactions between pathways correlated with genotype variation at the focal genes. From the large set of genes identified in these pathways, I found three genes (FN1, ATP9A, and ECM1) from the skin dataset and five (CR2, RHOT1, SRGN, GIMAP7, and LAPTM5 ) from the spleen dataset that overlapped with the list of 37 candidate genes identified in Chapter 2. Only one of these (GIMAP7) also showed significant variation on the SNP genotyping panel, suggesting that it could make a useful candidate to consider further. Here I provided preliminary evidence about candidate genes connecting the genotype and phenotype (gene expression) across different tissues (skin and spleen) and developed predictions about potential biomarkers. Further analyses to identify tissue-specific novel isoforms, alternative splicing and their respective biological functions in cattle could provide additional support for the utility of the genes identified for marker-based selection.
The integration of the genes or QTLs from multiple resources, the SNP genotype variation, and the transcriptome profiling in this study offer a potential panel of biomarkers which could be evaluated in pathogen and ectoparasite resistance in cattle studies and develop improvements for the future selection and breeding programs in cattle. The understanding of the genetic basis for resistance in cattle offers preliminary evidence that could impact beef and dairy production efficiency and product quality, especially in tropical and subtropical regions
Improving accuracy of polyoxometalate computational models
Get PDFGiven the growing materials and energy crises, where the Earth’s stock of precious, non-renewable metals and fuels being consumed by an ever-bigger population of human beings, it is more imperative than ever that we design smarter technology that is not only versatile, but also relevant to the problems we currently face; from being able to store renewable energy for long periods of time to finding alternative batteries to power our transportation, there is an ever greater need to develop electrochemically based methods of storing energy. Polyoxometalates (POMs) as a family of molecules are well-known for their ability to reversibly store large number of electrons per unit cage, solubility and structural durability under a wide range of environmental conditions, and studies show that alteration of the central heteroatom can further tune the oxidizing power of the species.¹
One of the main issues holding POMs back from being specially designed to exhibit the most desirable properties allowing for optimal deployment in key fields such as redox flow batteries is the lack of understanding surrounding their self-assembly mechanisms and, therefore, synthetic methods. Without this fundamental knowledge of how metal oxide reagents interact to yield unique structures under particular environmental conditions, we are left to rely on change discoveries to provide us with innovation. The first step towards building a greater wealth of knowledge is to refine our ability to simulate POM characteristics and properties using DFT, iteratively improving our calculations by benchmarking against empirical data; with this theory behind us, it should be easier to elucidate the mysteries hiding within the synthetic mixture.
With this investigation, we set out to establish how one can accurately model three species of POM: the well-known [X₂W₁₈Oₘ]ⁿ− Wells-Dawson (X = As, P, Se m = 60, 62), its hexalacunary variant [X₂W₁₂Oₘ]ⁿ− (X = As, P, Se m = 46, 48), and the wheel-shaped [X₈W₄₈Oₘ]ⁿ− framework these hexalacunaries can self-aggregate to form (X = As, P, Se m = 176, 184). After detailing the POM, computational chemistry, inverse design basics, and experimental details relevant to this work (Chapters 1, 2, and 3 respectively), we discuss our strategies and results with modelling the [X₈W₄₈O₁₈₄]ⁿ− POM wheel, highlighting how inclusion of only a few of the total number of countercations is sufficient for good empirical comparison (Chapter 5). Likewise, we repeat the same premise with the [X₂W₁₈O₆₂]ⁿ− Wells-Dawson and [X₂W₁₂O₄₈]ⁿ− hexalacunary species (Chapter 6), concluding that presence of several (but not all) countercations is essential for accurate replication of the POM structure but additional inclusion of protons within the framework will provide the best model for analysing regions of electron density and frontier orbital data. Finally, we review the available literature regarding computational modelling of POM UV-Vis spectra, arguing that the current level of theory is insufficient for accurate results and reviewing the available options (Chapter 7).
We also included results from a brief organic chemistry project we conducted over the course of this PhD thesis relating to the Ugi reaction which we, in the end, were not able to see through to completion (Chapter 8). Following this are the appendices for Chapters 10-13 (Appendix:1 – Appendix:4 respectively), collecting the vast number of tables, figures, and graphs produced by this work
Exploration of forensic mental health service users’ experiences of collaboration and strength-based approaches in their care
Get PDFAbstract available at each chapter
Prioritising new antihypertensive drug targets and understanding the genetic basis of disease modulation by antihypertensive drugs using Mendelian randomisation
Get PDFBackground:
Several critical gaps remain in understanding the detailed effects of antihypertensive drugs on cardiovascular, diabetic, and renal outcomes. This thesis aims to address these gaps using the Mendelian randomisation (MR) framework. The first objective is to systematically evaluate the causal effects of genetically predicted systolic blood pressure (SBP) and various antihypertensive drug classes on a range of cardiovascular, diabetic, and renal outcomes. The second objective is to discover if any detected associations are mediated through the transcriptions of genes encoding proteins targeted by the corresponding antihypertensive drug classes.
Methods:
Both established and newly developed drugs, as well as first-line and non-first-line therapies, were included in this study. Two-sample MR was conducted to investigate the causal effects of genetically proxied SBP reduction and antihypertensive drug classes on seven outcomes: coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), ischemic stroke, chronic kidney disease (CKD), and type 2 diabetes (T2D). Summary statistics were obtained from the largest European ancestry genome-wide association studies (GWAS). Sensitivity analyses (MR Egger, weighted median, simple median, negative control outcome) were performed to evaluate the robustness of the MR findings to potential biases. Summary-based MR (SMR), which integrates data from GWAS and eQTL studies, was performed to investigate if the detected drug-outcome associations were mediated through gene transcription. eQTL data were obtained from GTEx v8 for the main analysis, and from the eQTLGen consortium for the sensitivity analysis. To evaluate whether the observed associations were due to a shared causal variant or linkage scenario, the Heterogeneity in Dependent Instruments (HEIDI) test and colocalisation were performed.
Results:
Genetically proxied SBP reduction was associated with a lower risk of all the outcomes. The observed associations of genetically proxied calcium channel blockers, angiotensin-converting enzyme inhibitors, and beta-blockers with cardiovascular diseases were consistent with the findings from previous randomised controlled trials and observational studies. New associations were observed between the following genetically predicted drug classes and the outcomes: angiotensinogen inhibition and a decreased risk of CAD and ischemic stroke; loop diuretic and a decreased risk of CAD; endothelin receptor antagonists and a decreased risk of CAD and ischemic stroke; PDE5 inhibition and a lower risk of CAD, ischemic stroke, and CKD; sGC stimulation and a decreased risk of CAD, MI, and CKD. SMR analysis found significant associations of genetically increased GUCY1A3 expression in tibial artery with lower SBP and with a reduced risk of CAD (pSMR = 1.74×10⁻⁰⁶; pHEIDI = 0.664, H₄ = 0.99), genetically increased PDE5A expression in aorta with higher SBP and with increased risk of CAD (pSMR = 9.12×10⁻⁰⁶, pHEIDI = 0.338, H₄ = 0.48), genetically increased KCNH2 expression in the brain cerebellum was associated with higher SBP and increased risk of AF (pSMR = 6.02×10⁻⁰⁵, pHEIDI = 0.195, H₃ = 0.99).
Discussion:
The consistency of MR estimates across various methods enhances confidence in the results, contributing to the credibility of genetic approaches in pharmacological research. The SMR method applied in the studies to identify if the effect of a genetic variant on a phenotype is mediated by gene expression provides insights into the biological pathways involved in drug actions and potential targets for therapeutic interventions. Causal variants in GUCY1A3 and PDE5A suggest that these genes play a central role in BP regulation across different tissues, indicating that modulation of these genes’ expression could influence cardiovascular outcomes.
Conclusion:
This thesis makes a significant contribution to the field by offering new insights and perspectives through the use of Mendelian randomisation and the integration of GWAS and eQTL data using the SMR method providing a more detailed understanding of the genetic mechanisms underlying BP regulation and cardiovascular outcomes. The results from this thesis support the need for further research to validate and functionally characterise these findings followed by clinical effectiveness trials for clinical translation
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