VictorJuiz/thesis huggingface dataset:
Ancestry, blood, and heredity. Attitudes towards biological descent in late medieval Tuscany, c.1250-1400

This thesis examines intellectual and social attitudes to biological descent in late medieval Tuscany. In recent decades, historians have paid increasing attention to the body as a locus of experience, individuality, and identity. Yet bodies, like individuals, always have a genealogy. Thus, in this thesis, I set out to explore how ideas of biological descent shaped medieval understandings of the body and the significance of biological ties. First, I argue that medieval society developed a proto-materialistic approach to human personality that highlighted the role of hereditary physiological principles in the interpretation of character and behaviour. As a result, biological ancestry and blood emerged at the centre of individual and group identities. Subsequent chapters explore thinking about biological descent in the family, social units like the nobility, and political communities. A final chapter explores the diffusion of theories of natural love and demonstrates how similar patterns of thinking about biological descent can be identified across different dimensions of social life. In this thesis, intellectual and literary sources delineate the framework of ideas, beliefs, and values which informed attitudes to biological descent. On the other hand, normative and documentary sources illustrate how ideas of biological descent informed, and were informed by, social, legal, and political practices and structures. In this manner, biological descent emerges as a valuable category for the analysis of social relationships, offering fresh insights into a number of intertwined historiographical areas of concern. My study reveals that against dualist conceptions of human personhood, late medieval society held that human beings ‘were’ rather than ‘possessed’ bodies. As a result, the body and descent were perceived to be imbued with meaning and a source of normative values. Ultimately, this thesis lends support to the idea that late medieval society recovered nature as an ordering principle of society.

Keywords: biological descent
naturalisation
medieval
blood
natural love
natural nobility
heredity
Tuscany
adoption
ancestry
myths of origin
Advisor: Skoda, H
A stranger priority? Topics as the outer reaches of effective altruism

This thesis examines three philosophical topics relevant to the project of identifying and acting on the most effective ways of doing good: anthropic reasoning, simulation arguments, and infinite ethics. These topics are unified in their potential to disrupt the empirical and normative assumptions underlying the most straightforward case for “strong longtermism” (that is, the view that positively influencing the long-term future is the key moral priority of our time). The first chapter examines the debate between the Self-Indication Assumption (“SIA”) and the Self-Sampling Assumption (“SSA”) in the context of anthropic reasoning – a debate with important implications for the size of humanity’s future (and, plausibly, of the universe itself). I argue that SIA is the superior view, and that the most prominent objection to SIA – the so-called “Presumptuous Philosopher” – is a bullet that we should consider biting. The second chapter formulates what I see as the strongest version of a “simulation argument” – that is, an argument that we should be highly confident that at least one of the following is true: either the ratio of simulated beings (“sims”) to non-simulated beings (“non-sims”) of certain types is not high, or we are sims. I distinguish between ways of making this argument that rely on empirical assumptions (for example, about the computational power available to advanced civilizations) and those that do not; I suggest that the latter are superior and independently forceful; and I explore some of the complications and uncertainties that the latter lead to. The third chapter surveys a variety of problems that infinities create for ethics, and it reflects on the implications of those problems. In particular, I argue that these problems puncture the dream of a simple, bullet- biting utilitarianism, and that they put pressure on some of the broader intuitions underlying common arguments for strong longtermism as well.

Keywords: simulation argument
effective altruism
longtermism
anthropic reasoning
infinite ethics
Advisor: Greaves, H
McMahan, J
Engineering a modular virus-like particle platform for enhanced vaccine assembly

Virus-like particles (VLPs) are assemblies that resemble viruses in their size, shape, and multivalent display of protein subunits, but lack the genetic material to infect cells. VLP-displayed antigens are more immunogenic than in their uncoupled form. SpyCatcher003 is a protein engineered from a fibronectin-binding protein of Streptococcus pyogenes that rapidly forms an irreversible isopeptide bond with its peptide partner, SpyTag. This thesis presents SpyCatcher003-mi3 VLPs, which I generated by fusing SpyCatcher003 to the mi3 scaffold, a modified version of the computationally-designed i301 nanocage. I demonstrate that SpyCatcher003-mi3 can be solubly expressed in Escherichia coli, can be purified via ammonium sulfate precipitation to high yields, and remains stable at temperatures between 25 °C and 95 °C. This VLP can accommodate antigens of diverse sizes and symmetries. Assembly on SpyCatcher003-mi3 elicits high levels of neutralizing antibodies against influenza haemagglutinin and neuraminidase, as well as the receptor-binding domain (RBD) of SARS-CoV-2 and select betacoronavirus variants. I demonstrated that SpyCatcher003-mi3 can be expressed solubly in a mammalian cell-line. Then I engineered N-linked glycosylation sequons on flexible hydrophilic loops on the VLP with the goal of shielding antibody binding to the mi3 scaffold and SpyCatcher003, to focus antibody responses on the displayed antigen. I found no significant change in the level of antibody titers that bound specifically to the mi3 scaffold and the SpyCatcher003:SpyTag003 moiety, relative to that of the displayed antigen (SARS-CoV-2 RBD). Fusion of SpyCatcher003-mi3 with the albumin-binding sequence, ABD035, was also insufficient to change the relative induction of antibodies specific to SARS-CoV-2 RBD, the SpyCatcher003:SpyTag003 moiety and the mi3 scaffold. Further analysis and combination of blocking components will be required to maximize glycan and albumin-dependent antibody shielding. Nonetheless, the high stability, simple purification, and easy functionalization of the existing SpyCatcher003-mi3 platform can potentially accelerate the vaccine development process against many infectious diseases.

Keywords: VLP
SpyCatcher003-mi3
Advisor: Howarth, M
Townsend, A
Enhancing oncolytic virotherapy of glioblastoma by targeting innate immune ligands with a bispecific T cell engager

Glioblastoma (GBM) is a highly aggressive brain tumour in adults, often becoming resistant towards conventional therapy of radiotherapy and temozolomide (TMZ) chemotherapy. The oncolytic herpes simplex virus-1 (oHSV- 1) G207 is a promising approach for GBM immunotherapy, capable of selective infection, replication and causing cell lysis within GBM but not healthy cells. However, G207 has demonstrated only limited efficacy in GBM clinical trials.
The Natural Killer Group 2 Member D (NKG2D) receptor plays a key role in the innate immune control of cancers. The ligands for this receptor (NKG2DLs) are minimally expressed or absent on healthy cells, while stressed or malignant cells upregulate NKG2DLs, resulting in innate immune activation. We have developed a strategy targeting upregulated NKG2DLs on GBM cells with a bispecific T cell engager (BiTE) consisting of a recombinant NKG2D receptor linked to an anti-CD3 domain. Simultaneous binding of the NKG2D BiTE to NKG2DLs on GBM cells and CD3 on T cells causes antigen-independent T cell activation, pro-inflammatory cytokine release, and tumour cell death.
Here, we engineer G207 to express the NKG2D BiTE from infected GBM cells, allowing the G207-NKG2DBiTE virus to combine direct viral oncolysis and BiTE- mediated cytotoxicity via activation of local T cells. NKG2DL expression was elevated on GBM cells following pre-treatment with sublethal doses of TMZ and radiation, sensitising them to NKG2D BiTE activity and achieving synergistic cytotoxicity with G207-NKG2DBiTE virus.
We also demonstrate a novel strategy for targeting glioma stem-like cells (GSCs), which are a source of resistance to conventional therapies. In contrast to differentiated GBM cells, GSCs are non-permissive to G207 infection, but they remain sensitive to NKG2D BiTE. Therefore, we propose a potential model for targeting GSCs in heterogeneous tumours, whereby differentiated GBM cells infected with G207-NKG2DBiTE virus produce NKG2D BiTE locally, directing T cell cytotoxicity towards the GSC sub-populations in the tumour microenvironment.

Keywords: immunotherapy
oncolytic virotherapy
bispecific T cell engagers
glioblastoma
Advisor: Seymour, L
Khalique, H
Jeyaretna, S
Narratives, identity, and cases of non-recent child sexual abuse in football


In 2016, Child Sexual Abuse (CSA) in football was brought into public consciousness when ex-professional footballer Andy Woodward waived his right to anonymity by speaking out about the abuse he suffered as a child at Crewe Alexandra Football Club. Woodward broke the silence that had long plagued the sport, resulting in a surge of disclosures of non-recent CSA across numerous grass-roots and professional football teams across the UK. Through drawing upon twenty-one interviews with victims, victim advocates, practitioners, and criminal justice professionals, as well as a victim questionnaire and victim autobiographies, this thesis explores the narratives of the victims of non-recent CSA in football who disclosed their abuse either privately or in the public domain. Victim questionnaire participants identified as male, White, over forty years old, and as coming from a working-class or lower middle-class background. This thesis, therefore, focuses on how their identity, including their gender, class, and age, and their own self-perception, has been impacted by, or impacted on, their experiences from abuse to the pursuit of justice. Although certain identities are more fixed, many are tied to societal constructions and expectations, with the role of the audience influencing an individual’s self-perception and experiences. Through using the theoretical tools of agency and communion (Bakan, 1966; Abele and Wojciszke, 2013; Pemberton et al., 2019a), I explore how the victim’s sense of self can be rebuilt by speaking out, either individually or collectively, about the abuse they suffered. I also introduce a third concept of ‘action’ to explore the crucial impact of victim-led advocacy and activism on victims’ narratives and identify how their intersectional identities impacted on their status in this space. Doing so highlights the significance of identity on every facet of the victims’ experiences.

Keywords: narrative victimology
football abuse
victims
hegemonic masculinity
intersectionality
non-recent child sexual abuse
criminal justice system
CSA
white working-class boys
Advisor: Condry, R
The mechanistic modelling and simulation of vaccine-adjuvant induced immune responses

Vaccination is one of the most successful public health interventions in human history. A key component of subunit-vaccines are adjuvants; immunostimulants that shape and enhance the immune response to antigens. Despite the importance of adjuvants, the mechanisms of how adjuvants promote immune responses are not fully understood, limiting detailed appli- cation of modelling and simulation to determine optimal vaccine formulations, dosing and timings of prime and boost. To rationally accelerate next-generation vaccines while promot- ing transparency, it is critical to foster a detailed understanding of the mechanism of action of efficacious adjuvants. AS01 is a patented adjuvant used in clinically approved Malaria (RTS,S/AS01) and Herpes-Zoster vaccines (Shingrix). In this thesis, the first detailed the- oretical model of AS01’s mechanism of action from injection site to generation of antibody response is presented. From this non-executable description of AS01 biology, mathematical models were developed. These mathematical models permitted analysis of the interplay of cytokines (IFNγ, IL12 and IL18) and cells (macrophages, dendritic cells and monocytes) in early events based on data from a murine iliac draining lymph node. Model analysis led to the novel hypothesis that dendritic cells are the predominate cell type responsible for early IL12 production. IL12 is known to synergise with macrophage-derived IL18 to initiate early IFNγ. We provide evidence that AS01-mediated loss of subcapsular macrophages has a role in regulating the duration of IFNγ production acting as an endogenous inhibitory mechanism. Model analysis suggests that this cell loss affects the minimal temporal spacing of AS01-based vaccination required to obtain canonical IFN responses. This mathematical model was extended to capture CD4+ T cell priming dynamics. By analysing two simula- tions that permit exploring different hypotheses of AS01-mediated CD4+ T cell priming, we observed that our hypothesis of how IFN regulates CD4+ T cell priming was likely to be incomplete, which led to a refined hypothesis for IFNγ’s role in this process. We observed that ‘inflammation-induced’ na ̈ıve CD4+ T cell recruitment may be a key factor regulating the magnitude of CD4+ T cell priming. Thus, physiological factors including time of the day and spacing of consecutive jabs may have a key role in AS01 vaccine efficacy.

Keywords: vaccine
adjuvants
modelling
vaccination
mathematical
mechanistic
AS01
simulation
Advisor: Coles, M
Timmis, J
The international movement of financial assets: a liberal egalitarian perspective

This thesis discusses how a liberal egalitarian society should respond to the international movement of financial assets. Specifically, it addresses what constraints can be legitimately imposed on the freedom of individuals and corporations to transfer their financial assets, which include cash, bonds, and other types of liquid assets, out of the country. The thesis consists of two parts. The first part lays out the theoretical framework. It argues that there are three liberal egalitarian justifications for constraining an agent’s claim and exercise of private property rights: the priority of the disadvantaged, the demand for fair contribution, and the requirement of membership. After that, it defends an internationalist interpretation of these constraints by defending a culturalist conception of justice under which two distinctive sets of principles of justice should apply to domestic liberal egalitarian societies and the international arena respectively. The justification for this two-tiered account of justice is that the public political culture that mediates the relation between the citizens of a liberal egalitarian society is fundamentally different from the one that mediates the relation between societies in the international arena. The second part of the thesis applies the theoretical framework developed in the first part to three different cases of international movement of financial assets: capital relocation, profit shifting, and personal asset migration. It argues that in each case a liberal egalitarian society has good reasons to impose constraints on the outflow of financial assets. The restrictions on capital outflow are justified because they prevent the interests of disadvantaged citizens from being sacrificed for the gains of the already advantaged. The ban on profit shifting is legitimate because it helps secure a fair financial contribution from the rich and multinationals. The constraints on emigrants’ freedom to leave the country with their personal property are justified because a society has the right to impose financial conditions on emigration. Together, the thesis offers a critique of a pillar of global capitalism as it is known today—the international free movement of financial assets.

Keywords: culturalist theory of justice
John Rawls
anti-cosmopolitanism
cross-border movement of assets
tax avoidance
global justice
immigration
justice of international trade
internationalist conception of justice
international justice
public political culture
Advisor: Laborde, C
MSH3 promotes back-up DNA end-joining pathways that sustain the survival of BRCA2- deficient cells

DNA repair pathways that maintain genomic stability are essential in avoiding carcinogenesis. However, inactivation of these repair pathways frequently occurs during tumorigenesis and cancer cells become dependent on alternative mechanisms for DNA repair. Cancer cells with heterozygous germline mutations in BRCA1 and BRCA2 have abrogated HR function, hence they rely on alternative DSB repair pathways known to promote genomic instability, one of which is alternative non-homologous end-joining (A- NHEJ). This pathway requires the activity of error-prone DNA polymerase θ (Polθ) to anneal sequences with microhomology and utilise them as primers for DNA synthesis. Previous studies have shown that Polθ activity is critical for the survival of BRCA2- deficient cells and A-NHEJ has also been implicated in the resistance of BRCA2-deficient tumours to chemotherapy. Hence, factors of A-NHEJ represent potential targets for the elimination of BRCA-deficient tumours. The MSH2/MSH3 heterodimer has been canonically characterised in mismatch repair (MMR) in recognising long distortions in DNA structure. Notably, yeast and hamster MSH2/MSH3 displayed MMR-independent activity in repairing DNA lesions by joining DNA breaks with microhomologies, similar to A-NHEJ. The aim of this thesis was to investigate the potential role of MSH3 in the A- NHEJ pathway in BRCA2-deficient cells. We discovered that concurrent loss of MSH3 and BRCA2 reduced cell viability, thus indicating a role for MSH3 in the survival of BRCA2-deficient cells. Subsequently, we performed epistatic experiments with MSH3 and Polθ which indicated that MSH3 likely has a role in A-NHEJ. PARP-inhibitors are known to eliminate BRCA2-deficient cells. Interestingly, we observed that MSH3 loss in BRCA2-deficient cells led to their increased sensitivity to PARP inhibitor (PARPi) treatment. Thus, we have identified novel functions of MSH3 in the survival and response to treatment of human BRCA2-deficient cells.

Keywords: Polθ
cancer
MSH3
alternative non-homologous end-joining
DSB repair
PARPi
BRCA2
Advisor: Tarsounas, M
Dagg, R
Scaling-up of the electrochemical leaf system

This thesis presents an exploration of the Electrochemical Leaf (e-Leaf) with a novel application-oriented direction. The e-Leaf, a recent breakthrough made in the Armstrong group in the area of bio-electrochemical catalysis, is inspired by the natural leaf: enzyme cascade is immobilised in the nanopores of the electrode, allowing multi-step biotransformations to be energised, controlled, and monitored in real time. Ferredoxin NADP+ reductase (FNR) is the key enzyme in the e-Leaf, catalysing the interconversion of NADP+/NADP(H). Other co-entrapped NADP(H)-dependent enzyme(s) catalyse reactions coupled to this regeneration, achieving a fast conversion due to the very high effective concentration of enzymes and short distances for cofactor and reactants to diffuse between the enzymes in the nanopores. The e-Leaf is a powerful tool for the investigation of biocatalytic processes and potentially for the production of valuable chemicals.
In this work, the e-Leaf has been exploited for its versatility in application. First, the e-Leaf has been scaled up from a 4 mL lab-scale cell to a 500 mL pilot level reactor with new reactor designs, optimisations of the electrode construction and optimisation of reaction conditions. The productivity scales up linearly with the size of the reactor, showing the feasibility and potential of scaling up an electrochemical system.
The e-Leaf has also been explored to function as a biphasic reactor. The introduction of an organic layer containing substrate and(or) solvent has provided the electrochemical system with a sustainable substrate supply with simultaneous relief of product-inhibition. The final step in engineering the e-Leaf has been its transformation from an original batch design into a flow reactor in which the electrochemical reactions have been performed under flow as a proof of concept. The e-Leaf therefore has the potential to work in series continuously with high space-time-yield to accommodate complex requirements for industry-level syntheses.
In a separate branch of work, the e-Leaf has been exploited to achieve the deracemisation and stereoinversion of a secondary alcohol in a dually-controlled method, with the ability to switch the direction of the redox reaction and to change the enantioselectivity of the electrode. The reaction process is monitored in real-time to complete a one-pot, one-step deracemisation (or stereoinversion).

Keywords: electrochemical leaf
Advisor: Armstrong, F
Vincent, K
In situ diagnostics of damage accumulation in Ni-based superalloy

There has been a significant interest in capturing how the damage is initiated and accumulated in polycrystalline Ni-based superalloys while applying thermal and mechanical impact – tensile and creep loading at 800◦C. This is because the turbine component in jet propulsion or power generation these materials applied can experience such environments while in service and need to avoid unexpected degradation and failure causing severe accidents. In situ damage observation techniques required to be developed to understand the sequential mechanisms of damage growth even in such complicated environment.
In this work, for the first time in this field, a design and operation of laboratory-scale X-ray computed tomography (XCT) arrangement is developed for the purpose of in situ damage observation. The in situ XCT technique covers high-temperature mechanical testing and improvements of tomography image processing for high resolution enables to capture the sequential damage growth during tensile or creep loading at 800◦C, in examples of polycrystalline Ni-based superalloys, Inconel 718 and Nimonic 80A. Furthermore, laser-based Acoustic Emission (AE) techniques are combined with the system to determine whether the object is damaged to be captured by XCT.
The developed in situ observation technique was applied to high-temperature tensile and creep testing. Our results indicated that the damage growth could be captured with the resolution of 30 µm at 800◦C, and can be compared not only with strain rate and loading condition but with the stress state of the deformed testpiece, and that AE the technique can be the damage indicator of the object by observing the change in AE energy and frequency.

Keywords: creep
in situ X-ray computed tomography
void growth
acoustic emission
high temperature testing
superalloy
Advisor: Reed, R
Korsunsky, A