VictorJuiz/thesis huggingface dataset:
"Love is tears": the charmolypic theological vision of C.S. Lewis

This dissertation examines the significance of tragi-comedy in the theological writings of C.S. Lewis. It describes Lewis’s approach in terms of charmolypi (joy-sorrow), a word derived from John Climacus. I argue that Lewis’s charmolypic theological vision can address a dilemma in Christian theology. Some critics suspect that Christianity promotes escapism from the tragic conditions of human life, while others claim that it negates or undermines joy and laughter. Thus, Christianity is criticized for being insufficiently sorrowful but also insufficiently joyful. Lewis’s view of Christianity as something charmolypic might show a way to resolve this dilemma.
This research is original because almost no scholarly attention has been given to tragi-comedy in Lewis’s writings. With the single exception of Terry Lindvall’s 1996 Surprised by Laughter, scholars have examined Lewis’s views of comedy and tragedy within the confines of his literary criticism, but the possibility that these genres may have implications for his theological outlook.
The significance of this dissertation is threefold. First, it is the first ever dissertation on C.S. Lewis submitted to the Faculty of Theology and Religion at Oxford University. Second, my archival work on an unpublished play Lewis wrote in 1942, analyzed in Chapter Three, is entirely new in scholarship on Lewis. Thirdly, the implications of my argument are significant. If Lewis’s charmolypic vision of Christianity is sufficiently tragic and comic, it can help address the present need for a theological imagination that properly affirms the sorrows and joys of human experience. Christian theology can learn something from Lewis about how to respond to both criticisms mentioned above in a persuasive and imaginatively compelling way.
The method used throughout this research is textual-interpretative and theological. It first interprets the primary texts in which Lewis, explicitly or implicitly, discusses tragi-comedy or depicts charmolypi and then examines the theological implications thereof.
The Introduction frames the dilemma and presents the thesis of this dissertation. Chapter One examines the “tragic horn” of the dilemma, and Lewis’s direct response to it. Chapter Two does the same with the “comic horn” of the dilemma. Chapter Three defines the central terms of the dissertation (tragedy, comedy, tragi-comedy), and relates them to the notion of charmolypi. Chapters Four through Seven survey how various theological doctrines are depicted as tragi-comic in Lewis’s writings. The Conclusion summarizes the overarching argument and delineates its contributions to Lewis scholarship and Christian theology.

Keywords: literary criticism
sorrow
drama
tragi-comedy
charmolypi
love
modern theology
C.S. Lewis
joy
Advisor: Ward, M
McGrath, A
Investigating age at onset in bipolar disorder

Bipolar disorder (BD) is a complex mental health disorder with a heterogenous clinical course, diagnostic delays, high relapse rates, and sub-optimal treatment outcomes. Age at onset (AAO) has been proposed as a useful specifier for defining more homogeneous BD subgroups that can inform clinical course and symptom profiles. This thesis aimed to investigate the utility of AAO as a clinical specifier by defining and validating AAO subgroups; identifying predictive factors for BD AAO; investigating the relationship between premorbid factors, AAO, and functional outcomes; and examining the association between AAO and mood instability.
Using mixed methods across four experimental chapters, this thesis provides novel insights into the role of AAO in BD. Chapter 2 presents a systematic review of AAO distributions in BD and provides a recommended AAO definition. Chapter 3 uses machine learning approaches to explore predictive factors for BD AAO. Chapter 4 investigates the potential pathways between premorbid factors, BD AAO, and functional outcomes using prospective data. Chapter 5 examines the association between AAO and mood instability using longitudinal mood monitoring data. Findings reveal a trimodal distribution of AAO in BD, with distinct early-life risk factors, which may represent potential causal pathways to clinical outcomes. Additionally, mood instability is identified as a promising target for intervention in the clinical trajectory of BD. These results have important theoretical and practical implications, informing early intervention strategies and providing further evidence for the distinctiveness of AAO subgroups.
The thesis concludes with a general discussion of the findings and implications for future research. Overall, this thesis provides valuable insights into the role of AAO in BD, highlights the importance of identifying more homogeneous subgroups to improve diagnosis and treatment outcomes, and underscores the need for continued research in this area.

Keywords: structural equation modelling
bipolar disorder
BD
machine learning
AAO
adolescent mental health
age at onset
Advisor: Geddes, J
Saunders, K
The design and mechanism of synthetic homing endonuclease gene drives

When humans and insects come into conflict, this can lead to significant ecological and public health challenges. Traditional pest control methods often rely on chemical insecticides, which can adversely affect the environment and non-target species. Genetic biocontrol through the use of gene drive may offer a radically more efficient and species-specific method of addressing pest harm. Synthetic homing gene drives, particularly those based on the CRISPR-Cas9 system, have been the focus of intensive research in recent years. However, there is much we do not understand about the fundamental nuclease processes that mediate gene drive functioning and how these are affected by transgene design. Here, we investigate through computational modelling how unintended nuclease processes affect gene drive performance. We find that certain complex self-limited gene drive designs (daisy-chain gene drives) are especially sensitive to effects that cause separate gene drive elements to segregate prematurely. Through a meta-analysis of experimental gene drive crosses, we evaluate the effect of sex and deposition on different gene drive outcomes. We developed a companion web tool that allows users to find the highest-quality data evaluating specific aspects of gene drive designs and experimental conditions. Lastly, we analyse Aedes aegypti gene drive performance with different nuclease expression patterns. This shows that identical homing gene drives can vary in their underlying mechanism of inheritance bias.

Advisor: Bonsall, M
Alphey, L
Cationic rhodium complexes with ortho-Aryl substituted DPEphos ligands and rhodium-diphosphine catalysed phosphine-borane dehydropolymerisation

Transition metal-phosphine chemistry is the underpinning theme of this thesis. Chapter One briefly introduces the subject, with particular focus on ortho-aryl substituted phosphines, the DPEphos ligand and agostic and anagostic metal-hydrogen interactions. A comprehensive presentation of the developments in the field of phosphine-borane dehydropolymerisation is then provided.
Chapter Two describes the synthesis, characterisation and structural studies of a range of Schrock-Osborn type complexes containing ortho-aryl substituted DPEphos ligands of varying steric bulk, namely [Rh(o-R-DPEphos)(NBD)][BArF4] [R = H, Me, OMe and iPr, NBD = norbornadiene and ArF= 3,5-(CF3)2C6H3]. These complexes were all shown to contain a Rh···H–C anagostic interaction with an ortho-aryl proton, which were studied experimentally and computationally. The reactivity of the Schrock-Osborn complexes, upon hydrogenation of the alkene fragment in acetone, resulted in a range of Rh(I) and Rh(III) products, depending on the phosphine ortho-aryl substituent. In the bulkiest, oiPr version, C–H activation is observed at the isopropyl group, which is shown to be reversible through reactivity with CO and D2. This reactivity was used to form the first reported complex that contains both an anagostic interaction and an agostic bond.
Within Chapter Three, the coordination chemistry of the di-ortho-fluorine analogue of DPEphos, o-F,F-DPEphos, is described in comparison with the parent o-H-DPEphos and the bulkier o-MeDPEphos. Rh···F interactions are observed in the Schrock-Osborn complex of o-F,F-DPEphos [Rh(oF,F-DPEphos)(NBD)][BArF4]. The hydrogenation products in 1,2-F2C6H4 solvent are also compared, revealing the formation of a Rh dimeric complex Rh(H)(fac-κ3-P,O,P-µ-CH-DPEphos)]2[BArF4]2 with a bridging C–H agostic interaction for the parent DPEphos. The coordination chemistry of bimetallic gold complexes with these ligands is also explored, including an example of through-space F-F interactions.
The final chapter details an in depth study of the dehydropolymerisation of primary phosphineboranes using a [Rh(dppe)]+ catalyst. The mechanism is probed using in-situ NMR spectroscopy, stoichiometric reactivity and polymer molecular weight variation studies. Exploiting the mechanistic insight, the synthesis and characterisation of the first block copolymer of poly(phosphinoboranes) is described, which is also shown to self-assemble in solution to form spherical micelles.

Advisor: Weller, AS
Molecular magnets in nanoscopic quantum devices: theory & experimental comparisons

Quantum devices are quickly becoming the centrepiece of a novel generation of technological systems that could affect every aspect of our life, though we still do not understand how we may effectively interface molecular materials with nanoscopic quantum devices and control them. My aim in this thesis is to start exploring these issues, combining numerical and analytical theoretical methods to allow researchers to explore the properties of various molecular magnets, and predict and understand their behaviour when they are integrated into nanoscopic quantum devices. Maintaining a strong connection to real examples by considering specific molecular magnets, I cross-check the results with various characterisation techniques. I also consider commercially available molecular compounds and their possible practical use in actual quantum devices. In doing so, I also present and develop new methods of data analysis, to extend the information that can be extracted from experiments; throughout, I compare theory and experiments, corroborating the results. First, I mostly consider various compounds based on rare-earth metals, and deal with the challenges linked to numerically modelling the spin anisotropy of these systems. I demonstrate how careful treatment of the data can find the molecular anisotropy axes even in systems with high crystal symmetry. Moreover, I show how various methods allow us to predict the behaviour of single-molecule spin devices. Second, to investigate how the second-quantisation formalism impinges on the magnetisation’s macroscopic dynamics, I consider a wellknown, model spin system, Mn12-acetate, and then explore in theory how we might expect a strongly coupled system to behave. Third and finally, I consider the theory of strongly coupled gadolinium-based systems, finding good agreement between experimental results and first-principles calculations, and explore what such systems could make possible for the future of quantum devices.

Keywords: torque magnetometry
rare-earth magnet
MOLCAS
strong coupling
RASSCF
ab initio
single-molecule magnet
Advisor: Bogani, L
Molecular determinants of immune receptor signalling

Immunoreceptors play a key role in leukocyte function. Despite the important role of these receptors, the mechanisms by which non-catalytic tyrosine-based receptor signalling is initiated in response to their ligands is still controversial. To fully understand the molecular mechanisms driving receptor signalling, previous work has focused on determining the structure of these receptors prior to and following ligand binding, as well as the organisation of the receptors on resting cells, often with contradictory conclusions. Among these, the B-cell receptor (BCR) plays a central role in the activation of antigen-specific B cells and the production of targeted antibody responses. In this study, a new super-resolution imaging technique is used to characterise the three-dimensional distribution of the BCR in resting B cells, in the context of the often-overlooked complex architecture of the cell membrane. B-cell responsiveness to membrane antigens was also tested for antigens on supported lipid bilayers (SLBs), and the impact of antigen molecular height in BCR signalling was assessed. Moreover, purification of fully assembled BCR complexes in the presence or absence of antigen molecules ligated in situ provided material for preliminary cryo-electron microscopy (cryo-EM) analysis of individual BCR molecules. Similarly, complexes of the high-affinity IgE immune receptor, FcεRI, were also purified in the presence or absence of their ligand for future structure determination using cryo-EM. Together, these results provided initial observations that seek to define the molecular mechanisms driving both immunoreceptor assembly and signalling.

Keywords: FcεRI
immunology
BCR
B cell
receptor signalling
Advisor: Davis, S
Cornall, R
Efficient explanations: a powers hypothesis for how the mental causes

This thesis attempts to offer a powers causation solution to the difficulties posed by mental causation. I do so by arguing against what I call “events-pair” analyses of causation. As is known, mental causation seems to raise the problems of overdetermination and the possible exclusion of the mental cause. Jaegwon Kim presents one possible answer by using his Supervenience Argument to urge reduction, whereas Thomas Kroedel presents another by defending a Lewisian counterfactual condition for causation. I argue that both these views use a common view of causation that depends on the assumption that causation is the relationship between a pair of temporally separated events. Against this assumption, I present and defend a powers view of causation, which can account for both the simultaneity and interruptibility of a causal process. I then apply the powers perspective to mental causation, with the beneficial results that overdetermination no longer poses a threat, double-prevention can be re-analyzed into constituent causal stages, and mental causes can be, without contradiction, one part of the sufficient cause of intentional bodily movement. Overall, I thus present a new powers solution to the difficulties of mental causation.

Keywords: philosophy of Mind
mental causation
powers causation
counterfactuals
overdetermination
Advisor: Williamson, T
Understanding and preventing surgical site infection in hand trauma surgery

Hand and wrist injuries, known as hand trauma, are a common occurrence and account for a significant number of Emergency Department (ED) visits and operations in the UK each year. Surgical site infections (SSIs) in hand trauma surgery can lead to additional morbidity, prolonged hospital stays, and even amputation. Antimicrobial sutures have been found to prevent SSIs in other surgical fields, but their effectiveness in hand trauma surgery is unknown. The aim of this thesis was to estimate the risk of SSI in hand trauma surgery and to establish the feasibility of conducting interventional trials to moderate it. The thesis comprises a systematic review, meta-analysis and meta-regression of data from 315,618 patients, an innovative national cohort analysis of primary and secondary care real world data and a multi-centre, randomised, controlled, feasibility trial of antimicrobial sutures in hand trauma surgery. Through my systematic review and meta-analysis, novel summary statistics for overall SSI in hand trauma have been generated, indicating an overall risk of 5% but in the context of substantial variation in SSI reporting. National cohort analyses have added granularity to this summary statistic, demonstrating a risk of superficial SSI of 6.2% by 30 days and 14.4% at 90 days; the deep/organ space SSI risk is 1.4% by 30 days and 2.0% at 90 days. Following this, a feasibility trial of antimicrobial interventions in hand trauma surgery was designed and executed. In seven months, 116 participants were randomised across three sites, demonstrating solid recruitment, randomisation, and adherence. Difficulty was encountered in retention. Comprehensive retention strategies are necessary for future definitive trials in this population. This thesis supports the need for evidence-based prevention of SSI in hand trauma surgery, informed by clinical trials of antimicrobial interventions.

Keywords: clinical trials
infection
hand surgery
plastic surgery
trauma
Advisor: Prieto-Alhambra, D
Costa, M
Cook, J
Rodrigues, J
Characterising the immune response to combined skin and solid organ transplants

Transplantation offers a life-saving solution for patients with end-stage organ failure. Despite advances in recent years, managing acute rejection episodes remains challenging. This is partly due to difficulties in recognising when acute rejection is taking place. The concept of a sentinel skin flap for monitoring of organ transplantation has recently been introduced as a potential solution for this. The advent of abdominal wall transplants for the reconstruction of large defects in patients undergoing small bowel transplantation has further highlighted the usefulness of skin for monitoring, particularly in differentiating organ rejection from infections. Sentinel skin flaps also provide a site that is easy to biopsy, and which patients can be trained to review.
There are limited data in the literature on the alloresponse to a combined skin and solid organ transplant. The aim of this thesis is to characterise in depth this immune response. In chapter 3 the systemic immune response is examined using a combination of flow cytometry and gene expression analysis to analyse blood samples. Chapters 4 and 5 investigate the local immune response in small bowel and skin samples respectively, using the multiplexed gene expression and spatial proteomic techniques. Finally in Chapter 6 a human transgenic mouse model is used to explore the role of Langerhans cell related pathways in skin transplant rejection.
This is the first study to characterise both the systemic and local immune response in a combined skin and solid organ transplant, offering unique insights into the dynamic changes in immune phenotype post-transplantation and during rejection. The data provide support for the use of a sentinel skin flap for immune monitoring in solid organ transplantation and will be used to guide future clinical trials.

Keywords: organ rejection
abdominal wall transplant
sentinel skin flap
immune monitoring
Advisor: Friend, P
Giele, H
Hester, J
Issa, F
Genomic analyses of the immune system

Project 1. Genetic variation in key immune system components
Genes underpinning the diversity and plasticity of the human adaptive immune system, such as the HLA and immunoglobulins, are known for their complex structures and polymorphism. The emergence of long-read sequencing technologies has revolutionised genomics research, in particular the characterisation of segmental duplications and structural variation. Here, using long-read sequencing and additional genomics data from a healthy donor identified as HV31, I built two iterations of de novo personal genome assemblies for HV31 as a foundation to study the genetic variation of the immune system. I analysed complex structural variants found in genomic regions encoding key immune system components, and validated them against sequencing data. I also evaluated long-read sequencing accuracy and developed a tool for genomic data visualisation. Collectively, these efforts demonstrate the applications of personal genome assemblies in studying the immune system.

Project 2. Effects of low-dose IL-2 immunotherapy in T and NK cells
Low-dose interleukin-2 (IL-2) immunotherapy is a promising treatment for type 1 diabetes (T1D). IL-2 supresses autoimmune reactions by increasing the number of regulatory T cells (Tregs). To better understand the mechanism of action of low- dose IL-2 immunotherapy, I analysed single-cell multiomics data of T and NK cells collected from T1D patients before and after low-dose IL-2 treatment. I confirmed that low-dose IL-2 selectively expanded thymic-derived FOXP3+ HELIOS+ regulatory T cells and CD56br NK cells, and showed that the treatment reduced the frequency of IL-21-producing CD4+ T cells. In addition, I identified a long-lived gene expression signature induced by IL-2, which featured the upregulation of CISH and downregulation of AREG. Notably, I found that the signature remained detectable one month after the treatment. Further analyses of publicly available COVID-19 cohort data revealed that SARS-CoV-2 infection induced opposite changes that persisted for several months after recovery. These findings suggested potential mechanisms of long COVID and longer-term benefits of IL-2 immunotherapy.

Keywords: type 1 diabetes
regulatory T Cells
long-read sequencing
interleukin-2
structural variation
human leukocyte antigens
immunoglobulins
Advisor: Todd, J
Band, G
Ferreira, R
Crouch, D
Bashford-Rogers, R
Is the UK tax system effective in supporting disabled people?

In 2020-21, some 22% of people in the UK reported a disability. The impacts of different impairments are hugely variable but for many disabled people – and their families – they may be profound, including limitations on the ability to work; and the need to meet considerable additional costs.
The UK benefits system is the most substantial source of public financial support for disabled people and their carers - alongside a range of public services. Separately, UK tax legislation contains nearly 40 reliefs spanning multiple taxes for eligible disabled taxpayers. The rationales for these reliefs vary: for example, some mitigate tax costs to assist with meeting ‘costs of disability’; others seek to eliminate discrimination; or facilitate an intended ‘after-tax’ result from a compensation claim or benefit payment.
Against this backcloth, this thesis seeks to answer the question ‘Is the UK tax system effective in supporting disabled people?’. In answering this question, the thesis does not seek to evaluate the nature and extent of general redistribution to disabled people: its focus is on the effectiveness of the existing range of tax reliefs, together with ease of tax compliance and administration for disabled people and those who support them. It draws upon comparative analysis with four other countries to identify areas where alternative – or additional reliefs – may be effective in achieving policy intent.
This thesis finds that the position is variable: many tax reliefs work smoothly and deliver meaningful results; others have limited effects, suffer from implementation issues, or are overly-complex. Whilst taxing authorities have made considerable progress in improving system access and compliance for disabled people, it seems that more can be done. The thesis makes a number of recommendations for modifications, further research, or the consideration of alternative reliefs to achieve overall policy intents.

Keywords: tax disability
Advisor: Loutzenhiser, G