VictorJuiz/thesis huggingface dataset:
A data-driven investigation into the behaviour and parameterisation of mesoscale eddies
Keywords: Turbulence
Gulf Stream
Parameterisation
Oceanography
Machine learning
Data driven
Ocean modelling
Mesoscale eddies

Mesoscale eddies, turbulent oceanic features of length-scales 10-100km, are an important component of the climate system. They impact the large-scale circulation of both the ocean and atmosphere, as well as the transport of tracers such as heat and carbon. Due to the computational costs of running ocean models at high-resolution, climate models generally do not fully resolve mesoscale eddies, and will not be able to for the foreseeable future. We, therefore, need to parameterise the effects of mesoscale eddies on the large-scale flow. Eddy parameterisations are typically derived from physical theories and mechanisms; this approach can sometimes over-simplify the underlying dynamical process. The primary aim of this thesis is to uncover new ways of capturing the complex non-linear behaviour of mesoscale eddies.
Using a hierarchy of numerical models, we take a data-driven approach to studying and parameterising mesoscale eddies. Using an observation-driven experiment, we investigate how the spatio-temporal variability of real mesoscale eddies affect tracer fluxes in the North Atlantic. In an idealised model, we demonstrate that modern machine learning algorithms, namely convolutional neural networks, can accurately represent eddy momentum fluxes. We also demonstrate that machine learning can construct expressions for eddy momentum and temperature fluxes while retaining interpretability. We find that, when implemented, data-driven parameterisations can emulate the scale-interaction between mesoscale eddies and the resolved flow, increasing the kinetic energy and improving the higher-order statistics of the velocity field.
Our results show that data-driven algorithms, while respecting physical principles, can be used to parameterise the effects of mesoscale eddies, with implementation in more realistic models now a possibility. The predictive skill of data-driven algorithms is not the only advantage: our use of interpretable machine learning opens up the door for more knowledge discovery studies about eddies and turbulence in general.
Exploiting pre-existing non-cognate T cell help to enhance humoral vaccine responses
Keywords: Liposome
Virus-like particle
Biotechnology
Immunology
Vaccine

Vaccination is one of the most powerful examples of scientific endeavour resulting in clear benefits for the population. Successes in vaccinology have largely been due to empirical approaches. However, the list of diseases for which there is still no effective vaccine remains long and it is likely that a more rational approach to vaccine design will be needed for these targets. Increasingly, this appears possible with technological advances and an improved understanding of the adaptive and innate immune systems. There is a pressing need for novel B cell vaccines to target pathogens such as malaria, influenza, and human immunodeficiency virus. Well-designed humoral vaccine approaches could also be valuable in the growing field of cancer immunotherapy.
This thesis describes a novel particle-based vaccine strategy designed to elicit rapid antibody responses by exploiting pre-existing non-cognate CD4+ T cell help. Vaccine particles were engineered to display target B cell antigens exclusively on the particle surface, while helper CD4+ T cell epitopes were contained in the particle core. In principle, corresponding vaccine particles could be produced by physical formulation (e.g. using a liposomal vector) or by genetic engineering (e.g. using a recombinant measles virus). Greater success was observed in this study using a liposomal platform that allows flexible particle engineering, avoids biological challenges such as achieving adequate viral titres, and is readily scalable.
Data generated with these liposomal nanoparticles show that pre-existing CD4+ T cell immunity induced by vaccination with ovalbumin (OVA) can enhance anti-circumsporozoite protein (CSP) antibody responses following the administration of CSP-coated liposomal particles that encapsulate OVA epitopes. Anti-CSP antibodies were produced faster, reached higher levels, were of a greater affinity, and contained more isotype-switched antibody in mice pre-vaccinated with OVA. The inclusion of TLR9 agonists to give ‘self-adjuvanting’ particles further increased the immunogenicity of the vaccine platform. Next, other sources of preexisting CD4+ T cells were examined. Many chronic viral infections induce dramatic T cell responses. Experiments using murine cytomegalovirus (MCMV) demonstrate that pre-existing anti-viral CD4+ T cells can also be re-purposed to provide non-cognate help to enhance antibody responses to CSP. Lastly, preliminary results show the utility of this approach in breaking tolerance to a cancer antigen.
The vaccine platform described in this thesis and the principles that it exploits could contribute to future rationally-designed vaccine strategies against infectious disease or cancer antigens.
Persons, populations, and value
Keywords: transitivity
personal identity
egalitarianism
population ethics
value theory

This thesis consists of six independent papers on personal identity, population ethics, and value theory. The central theme of this thesis is the unimportance of personal identity. I begin in Chapter 1 by developing new Parfitian arguments for the unimportance of personal identity in morality, paying special attention to their implications in population ethics. In Chapter 2 I analyse Mark Johnston’s similar metaphysics driven challenge to person based morality, but argue that it is less successful than my own. In Chapter 3 I lay out choices facing egalitarians in population ethics, arguing against some recently prominent forms of egalitarianism. In Chapter 4 I provide new decision theoretic arguments against deontic constraints on harming, suggesting that it is consequentialism rather than deontology that can better respect persons. In Chapter 5 I introduce transfinite extensions of the familiar value theoretic principles of transitivity and acyclicity. I use them to try to resolve some key issues in population ethics, concerning the value of creating new people and the procreative asymmetry. In Chapter 6 I aim to support these transfinite principles by analysing their role in the theory of rational choice.
Biophysical characterization of protein-protein interactions with mass photometry
Keywords: bioassay
protein interaction
antibody
binding affinity
kinetics
single-molecule microscopy

Interactions between biomolecules control the processes of life in health and their malfunction in disease, making their characterization and quantification essential. We first explore the capabilities of established methods for binding affinity measurements of protein-protein interactions and present mass photometry in this context. We explain that immobilization- and label-free analytical techniques are desirable because of their simplicity and minimal invasiveness, but that they struggle with quantifying tight interactions and resolving co-existing species.
After a bench-marking process we show that mass photometry can accurately count different unlabelled biomolecules at the single-molecule level, distinguishing them by molecular mass, thereby revealing the relative abundances of different oligomeric states and stoichiometries of complexes in vitro. We develop and characterize a single-shot measurement method to determine binding affinities over four orders of magnitude at equilibrium for both simple and complex stoichiometries, as well as the associated kinetics in experiments with minimal sample consumption (fmol) and efficient experimental procedures (< few minutes per sample).
We then present applications of this method for protein-protein interactions quantification of biotherapeutics and glycoproteins in the field of cancer, autoimmune disease, HIV and SARS-CoV-2 research.
These results introduce mass photometry as a rapid, simple and label-free method for studying sub-micro molar binding affinities, with potential to become a universal approach for characterizing wide range of biomolecular interactions.
External military assistance to civil wars: the unintended effects of intentional interference
Keywords: terrorism
military intervention
one-sided violence
civil war
civilian victimisation
coup d'état

Weary of the costs and condemnation associated with large-scale military intervention, countries increasingly rely on the provision of external military assistance to influence civil wars in their favour. The provision of weapons, matériel, and training with a military purpose aims to build local capacity to help partner militaries quell domestic insurgencies. Yet, such capacity building can potentially produce unintended consequences for regime stability and citizens’ safety. This thesis thus inquires how the provision of external military assistance affects actors’ incentives and strategies on the ground. By examining actors’ participation in three forms of political violence—coup d’état, one-sided violence, and domestic terrorism—it allows for a comprehensive examination of violent strategies during civil war. The first paper, ‘Building Capacity or Exacerbating Instability? US Military Training, External Military Assistance, and War-Time Coup Risk’ examines the effect of US military training on the risk of military coup during civil war and compares it to the effects of non-US support. The second paper, ‘‘Trained and Equipped’ to Kill Civilians? Quality of External Military Assistance and Government Forces’ Targeting Profiles in Civil Wars’ focuses on government forces’ use of violence against civilians depending on the military sophistication of the support provided. The third paper, ‘Trading One Problem for Another? External Military Assistance and Rebels’ Use of Terrorist Tactics in Civil Wars’ explores rebels’ reliance on terrorist tactics in response to externally-backed government forces and hypothesises the role of democratic external supporters in enticing terrorist backlash. Drawing upon original data on external support for the period 1975-2017, I assess these relationships empirically using large-N statistical analysis and a matching strategy to account for the non-random provision of external military assistance. Findings suggest that external military assistance can reduce coup risk in case of non-US support but is linked to higher levels of violence against civilians and terrorist violence depending on the type of supporter and support provided.
Cellular target engagement and selectivity profiling of small molecules for mechanism-of-action studies
Keywords: chemistry
chemoproteomics
biology
medicinal chemistry
molecular biology
chemical biology
proteomics

A high-quality chemical probe should possess the qualities of being highly specific, potent, and selective against off-target interactions, in order to enable target validation. By contrast, low-quality compounds, which display properties of promiscuity, reactivity and instability can in turn be misleading: such compounds, referred to as Pan-Assay Interference Compounds (PAINS) need to be removed from screening libraries. Target engagement and proteomic studies can often detect undesirable physicochemical properties or polypharmacology within small molecules, as well as help annotate and clean screening libraries and prevent compounds entering biology projects without precautions.
Herein are presented a number of target engagement techniques used to annotate compounds. The introduction summarises currently available techniques and provides a literature review pertaining to the Cellular Thermal Shift Assay (CETSA). The second chapter describes how the use of chemoproteomic techniques, including CETSA, has led to the discovery of a number of undesirable characteristics of a literature compound SJ-172550. The third chapter delves into mass spectrometry (MS)-based CETSA techniques, and describes the development of an algorithm to analyse MS-CETSA output data for target validation, using both open-access datasets as well as the dataset obtained from the analysis of a known protein arginine methyltransferase 5 (PRMT5) inhibitor. The fourth chapter describes the use of Immunoblot-CETSA to investigate cellular target engagement of peroxisome proliferator-activated receptor γ (PPARγ)-targeting compounds in the context of downstream induction of the uncoupling protein, UCP1. Subsequently, the fifth chapter concerns the development of an AlphaScreen-based target engagement assay with a high-throughput capacity, and the necessary optimisation steps, and provides the link between AlphaScreen-CETSA and MS-CETSA. The sixth chapter pertains to the proteomic analysis of PPARγ-expressing cells, including an MS-CETSA experiment involving a known PPARγ agonist, rosiglitazone, to investigate its off-target interactions. Chapters 5 and 6 together point to the combined use of AlphaScreen-CETSA for hit detection and MS-CETSA for hit follow-up.
Explaining black box algorithms: epistemological challenges and machine learning solutions
Keywords: Uncertainty
Explainability
Interpretability
Pragmatism
Machine learning
Causality
Artificial intelligence

This dissertation seeks to clarify and resolve a number of fundamental issues surrounding algorithmic explainability. What constitutes a satisfactory explanation of a supervised learning model or prediction? What are the basic units of explanation and how do they vary across agents and contexts? Can reliable methods be designed to generate model-agnostic algorithmic explanations? I tackle these questions over the course of eight chapters, examining existing work in interpretable machine learning (iML), developing a novel theoretical framework for comparing and developing iML solutions, and ultimately implementing a number of new algorithms that deliver global and local explanations with statistical guarantees. At each turn, I emphasise three crucial desiderata: algorithmic explanations must be causal, pragmatic, and severely tested.
In Chapter 1, I introduce the topic through real world examples that vividly demonstrate the ethical and epistemological imperative to better understand the behaviour of black box models. A literature review follows in Chapters 2 and 3, where I situate the project at the intersection of critical data studies, philosophy of information, and computational statistics. In Chapter 4, I examine conceptual challenges for iML that result in misleading, counterintuitive explanations. In Chapter 5, I propose a formal framework for iML – the explanation game – in which players collaborate to find the best solution(s) to explanatory questions through a gradual procedure of iterative refinements. In Chapter 6, I introduce a novel test of conditional independence that doubles as a flexible measure of global variable importance. In Chapter 7, I combine feature attributions and counterfactuals into a single method that retains and extends the axiomatic guarantees of Shapley values while rationalising results for agents with well-defined preferences and beliefs. I conclude in Chapter 8 with a review of my results and a discussion of their significance for data scientists, policymakers, and end users.
An exploration of student and teacher interpretations of individualised support within post-16 learning environments
Keywords: MLT 2020
MLT

This project viewed the social world as a linguistic construction. The National Curriculum and Standardised Assessment Tests, were seen to represent a subjective medicalised discourse, which may contribute to educational inequality. Individual student identities were conceived as fluid and unique. Students understood to have a variety of strengths, challenges and needs, each requiring individualised provision. This project sought to construct and review an intervention, designed to support the unique requirements of students, within the confines of current educational policy. An analysis of literature into Personalised Learning, led to the principles of one-to-one tuition and feedback being adopted as the fundamental elements of an intervention designed to better meet the individual needs of my students. This intervention was allocated the signifier FAT-CAT.
This action research project took place within one post-16 educational institution in England, where I am employed as a teacher. FAT-CAT was integrated into the learning environments of all my teaching groups for a period of 23 weeks. A continual collaborative cycle of review, reflection and implementation, involving students and colleagues, shaped the specific application of the process. The extent to which FAT-CAT was interpreted as valuable and practical, was explored through an ethnographic process, involving informal discussions, analysis of student work, attainment data, personal reflections, and surveys of student and teacher perceptions.
The findings suggest that the majority of teachers interpreted FAT-CAT as practicable. However, 30% were unsure and 15% did not believe that it could be implemented without creating excessive workload. The need to scaffold students towards independent learning, administration with larger groups, and pressure to deliver content; were identified as the most common challenges to practical implementation. Despite the identification of these challenges, the majority of students and teachers perceived FAT-CAT to be a valuable addition to teaching and learning environments. Over 87% of students and 83% of teachers, reported FAT-CAT to be either ‘very beneficial’ or ‘significantly beneficial’. I argue that the perceived value of FAT-CAT may be explained due to the facilitation of an environment, where teachers are able to better understand and cater to the variety of individual needs, within the confines of the current educational framework. This action research project has given me a better insight into the needs of my students and how I can shape the educational environment of my classroom to provide a better learning experience. I therefore encourage other teachers to consider implementing these principles into their teaching. However, further research is required to explore the impact of FAT-CAT on attainment, and the extent to which the potential challenges to practical implementation can be overcome.
The impact of the communicative classroom: communicative teaching methods and their impact on key stage 3 learners’ self-efficacy and motivation in the modern foreign language productive skills
Keywords: MLT 2020
MLT

In response to concerns around student engagement with productive tasks in Modern Foreign Languages (MFL), this investigation looks into the impact of three communicative teaching methods on the motivation and self-efficacy of Year 8 learners of French in an inner-city state school. The research aims to identify inclusive teaching methods to enhance engagement in the productive skills. Communicative Language Teaching (CLT) is identified as an approach to look into to achieve this (Mitchell, 1993). Literature reviewed from pedagogical and psychological domains demonstrated the positive impact of increased motivation and self-efficacy and how this might be achieved through a communicative classroom approach. The literature influenced the intervention choices with understandings around motivation and self-efficacy and their relationship with Communicative Language Teaching. The research questions focus on understanding the relationship between CLT, motivation and self-efficacy in language learning. A mixed-method approach is proposed. Student interviews, surveys, task results and classroom observations are planned to take place around a two-phase intervention. The proposed first phase employed three different communicative methods adapted from understandings taken from the literature reviewed: target language use (Christie, 2016), task-based learning (Mutton and Woore, 2014) and flipped learning (Bergmann and Sams, 2007). The two most positively impactful of these methods are then to be combined to create a fourth intervention. A baseline data collection was conducted with the research sample (N=12) through a Likert-scale questionnaire and an interview with participants. Statistical analysis is employed to analyse the motivation and self-efficacy levels of the students. An analysis of variance (ANOVA) was then used to note any significant difference between lower- and higher- attaining students. Research was interrupted by the COVID-19 pandemic. The investigation is therefore, in part, a proposal for future research. The evaluation criteria of post-intervention data taken from questionnaires, interviews, task data and observation notes are presented, but interventions and further data collection to the baseline did not take place. While data collection was interrupted, pedagogical reflections and implications for further research allow the project to remain valuable to professional development.
Minority politics by other means: Assyrian militias in Iraq 2014–2017
Keywords: Non-state armed groups
Assyrians
Minority politics
Civil war
Iraq
Militias

When the Islamic State in Iraq and Syria displaced Christian Assyrians from the Nineveh Plain in 2014, several militias were founded in response. These small groups aimed from the beginning to establish a presence on the ground after the defeat of their enemy, with the long-term goal to remain as security providers in their historical heartland. Lacking material resources or political power of their own, most militias tied themselves to a single ally affiliated with the Government of Iraq or the Kurdistan Regional Government — but others obtained support from several actors, or none. Considering the marginality of the political parties and political entrepreneurs behind the militias, those displaying loyalty to a single powerful ally could be expected to prevail against rival groups. Instead, a militia with weak ties to several actors established the strongest presence on the ground, and became the main security provider in the largest Assyrian town. To explain this puzzling outcome, the study provides a detailed account of how the militias formed, built their capacity, and deployed to the Nineveh Plain. The empirical data originates mainly from observations and interviews conducted in Iraq, as well as news and social media. With an inductive and iterative approach, the external relations of the militias emerged as the central explanation to address the research puzzle, but other factors are discussed as well. The study concludes that the most successful militia prevailed over its rivals by engaging multiple external actors with pragmatism and diplomatic skill, while tenaciously building a capable organisation. The findings demonstrate the potential of very small militias to exercise agency and assert themselves in an ongoing civil war.