VictorJuiz/thesis huggingface dataset:
SeroTracker: synthesising seroprevalence data to map the true extent of COVID-19 infection and immunity

Effective decision-making during pandemics requires understanding the true extent of infection and immunity. Seroprevalence studies measure the population prevalence of antibodies, providing key insight into these quantities. However, the results from these studies are dispersed, hindering their use. We developed SeroTracker, a dashboard and data platform for SARS-CoV-2 seroprevalence studies. Through its ongoing systematic review, SeroTracker identified over 3,800 seroprevalence studies and made their data available to global health, government, and academic stakeholders. Meta-analysing these studies, we show that global SARS-CoV-2 seroprevalence was 59.2% in September 2021 (95% confidence interval 56.1 − 62.2%), and rose steeply during 2021 due to infection in some regions and vaccination in others. We also identify limitations of seroprevalence studies: their timeliness, where the median study is published 154 days after being conducted; measurement bias, where assay manufacturers systematically overestimate sensitivity by 5.4% and specificity by 2.8%; and coverage, where seroprevalence studies are sparse in time and space. To address these challenges, we develop a Bayesian modelling framework that synthesises information from case and seroprevalence data to provide up- to-date estimates of true infections. We validate this model on simulated data and apply it to Canadian data, showing that only approximately 20% of infections were detected as cases at the start of the pandemic, and revealing substantial geographical heterogeneity in infection dynamics. Returning to SeroTracker’s evidence synthesis process, we develop an automated tool for risk of bias assessment with excellent reliability compared to manual review (intraclass correlation 0.77), and implement a natural language processing-based process to screen abstracts for our systematic review that reduces screening time by approximately 70%. Finally, we reflect on the increased risk posed by pandemics and discuss future work applying engineering to public health to reduce these risks, including the development of a central data repository for respiratory virus surveillance data.

Keywords: antibodies
seroprevalence
biostatistics
dashboard
COVID-19
global health
statistical modelling
Advisor: Clifton, D
New methods to study macrophage biology in vitro and in vivo

Macrophages are heterogeneous and plastic cells, which populate almost every organ in the body and migrate towards sites of inflammation. However, tools designed for studying macrophage biology, particularly genetic models and chemotaxis assays, are standardised to investigate a broad range of leukocyte populations. They fail to capture the unique properties of macrophages and distinguish them from other ontologically related populations. In this thesis, I set out to create novel in vitro and in vivo tools that are adjusted for studying macrophage biology. To address the in vivo arm of this project, I phenotyped a novel tamoxifen-inducible hCD68-CreERT2 mouse line. Having established an optimal protocol for tamoxifen dosing, I detected robust expression of Cre recombinase activity in tissue-resident macrophage populations in peritoneum, spleen and liver. Importantly, the expression was restricted to tissue-resident macrophages with marginal effects in blood leukocyte populations and splenic non-macrophage populations. When compared to other ‘macrophage-specific’ lines, hCD68-CreERT2 mice had fewer ‘off-target’ effects. Additionally, I was able to successfully use hCD68-CreERT2 mice to target macrophages present in atherosclerotic lesions. To address the in vitro arm of this project, I used the Freestyle Fluidics (FF) platform to design and optimise circuits that can be used to study macrophage migration. I created a passive diffusion-based system and an active pumping system that created stable controllable gradients. I showed that both chemotaxis and chemokinesis can be readily detected and quantified in both systems. Using the FF chemotaxis assay, I observed novel properties of macrophage behaviour such as population-level coordination of chemotaxis and the ability to sense the gradients both spatially and temporally. In summary, this project advanced the macrophage-specific technology platforms available to researchers.

Keywords: cre recombinase
microfluidics
macrophage
mouse model
chemotaxis
Advisor: Greaves, D
Raff, J
Design and modular self-assembly of nanostructures

As nucleic acid nanostructures grow larger and more complex, new tools and methods are needed to facilitate their design. DNA origami structures, for example, are limited by the lengths of their scaffolds but larger assemblies can be bound together by interactions between multiple components. This thesis presents two projects, each approaching the design of such modular structures at a different level of abstraction.
Project 1 presents the polycube self-assembly model, where building blocks assemble stochastically using bindings between complementary patches. The assembly of both 2D polyominoes, as well as 3D polycubes, is considered. First, the mapping between input rules (defining the set of available species) and output shapes is investigated, revealing a clear bias toward low--complexity structures. Frequent shapes also tend to be highly modular and symmetric. Secondly, the reversed mapping is explored, presenting a method to find the minimal rule that assembles a specified output shape. Differences in assembly kinetics between possible solutions are investigated using patchy particle simulations, showing that minimal rules can assemble as well as fully addressable rules.
Project 2 presents a more detailed approach to the design of modular structures and individual modules: the oxView toolkit for the design, analysis, and visualisation of DNA, RNA and protein nanostructures. While many other design tools exist, oxView makes it easy to import and connect their designs into complete assemblies. Furthermore, oxView allows for free-form editing and rigid-body manipulation. Designs can then be interactively simulated using the oxDNA model, providing a more intuitive understanding of the resulting dynamics.
In conclusion, the design of self-assembling nucleic acid nanostructures has been investigated on both an abstract and a more detailed level. The presented projects have resulted in tools and methods for creating, simulating and analysing modular structures with minimal complexity, potentially containing building blocks created in multiple design software.

Keywords: self-assembly
nanotechnology
DNA origami
polycube
Advisor: Turberfield, A
Louis, A
CRISPR/Cas9-mediated engineering of subtype-specific cell lines for iPSC-derived cardiomyocyte phenotyping

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) represent a useful tool for cardiovascular research. However, the mixed subtypes, including atrial-like, ventricular-like and nodal-like, that result from differentiation protocols present a challenge for selective studies. This thesis exploited the emerging genome engineering technology “CRISPR/Cas9” to generate subtype-specific fluorescent reporter systems to label specific CM subtypes, facilitating subsequent isolation for use in subtype-specific disease modelling.
Atrial-specific myosin light chain 7 (MYL7)-mClover and pituitary homeobox 2 (PITX2)-mClover, ventricular-specific myosin light chain 2 (MYL2)-mClover and nodal-specific hyperpolarisation activated cyclic nucleotide-gated potassium channel 4 (HCN4)-mScarlet iPSCs were established by targeted insertion of the fluorophores at the stop codons of the target genes. Each fluorophore was preceded by a P2A linker, allowing bicistronic expression. Unfortunately, the PITX2-mClover and MYL2-mClover lines failed quality control and could not be used for fluorescent reporter iPSC-CM derivation. The MYL7-mClover and HCN4-mScarlet lines, however, exhibited faithful reporter systems where the expression of the fluorophores mirrored that of their respective target genes.
Heterozygous TTN c.59926+1 G>A, a truncating mutation of the titin gene, is associated with atrial fibrillation and dilated cardiomyopathy. This mutation was introduced into parental iPSCs for preliminary characterisations. Subsequently, the mutation was engineered in the MYL7-mClover iPSCs for exploring the application of subtype-specific reporter systems in disease studies. The fluorescent sorting of the cells could not be optimised in the available time, however, the engineered mutant MYL7-mClover line was differentiated towards the atrial and the ventricular lineages.
No prominent consequences in heart failure-associated foetal gene reprogramming, overall TTN expression, myofibrillar protein isoform switching, sarcomere organisation, sarcomeric protein localisation were identified in the heterozygous mutant model. Interestingly, the Ca2+ transients were altered specifically in the atrial-like heterozygous model. This alteration may underlie irregular, fast atrial rhythm in atrial fibrillation. The atrial-specific phenotype of TTN c.59926+1 G>A may be further clarified when using purer atrial-like iPSC-CMs obtainable by fluorescence-activated cell sorting of the differentiated MYL7-mClover iPSC-CMs.

Keywords: selective disease modelling
iPSC-CM subtype purification
iPSC-CM population's heterogeneity
TTNtv
CRISPR/Cas9-assisted genome editing
fluorescent reporter line generation
Advisor: Davies, B
Redwood, C
Gehmlich, K
Vernacular queer and shifting power in Russia: from the late Imperial era up to the 1930s

This thesis explores the development and complexities of queer existence shown ‘from below’, that is to say, focusing on the direct speech of non-elite homosexual men and sexual and gender non-conformists from the late imperial era up to the 1930s. The current historiography of homosexuality provides a somewhat limited view, emphasizing the importance and overarching influence of medical and legal discourses on queer subjects. The thesis offers a different perspective, shifting the analysis of hegemonic discourses of experts to the self-expression of homosexuals and gender and sexual non-conformists in the tumultuous time of the 1920s. More broadly, the thesis seeks to answer the question of when a modern homosexual identity emerges not as a scientifically constructed type but as a self-accepted category. The thesis attempts to reorient our understanding of the difference between the sodomite and the homosexual, demonstrating the process of self-fashioning as a crucial element of modern sexuality. It has been previously acknowledged that the Russian Revolution of 1917 and the abrogation of the anti-sodomy article greatly influenced the understanding of homosexuality by medical professionals and triggered the proliferation of new approaches to it.
Following this assessment, the thesis demonstrates how homosexuals and gender and sexual non-conformists inventively absorbed new knowledge to fashion themselves and made sense of their ‘abnormal’ sexuality. Even those who continued self-pathologizing were not passive objects of expert indoctrination. They conflicted with the doctors and sought new options to be cured. Others overcame the limited frame of ‘deviant sexuality’, insisting on their inclusion in the new society on their terms (‘no conventions will convince us that our actions are criminal and abnormal’). Being primarily focused on self-identified homosexuals and those males who experienced same-sex relations, this thesis also recognizes that emancipatory impulses were not restricted to them and greatly influenced a gamut of sexual and gender non-conformists who cannot be easily defined in modern terms of LGBTQ nomenclature.

Keywords: gender
Soviet history
queer
Russia
homosexuality
Advisor: Healey, D
Investigating the function of coding polymorphisms within the TBX15-WARS2 locus associated with waist-hip ratio as a risk factor for metabolic syndrome

As prevalence of obesity and metabolic disorders increase, it is necessary to elucidate mechanisms driving body mass, body composition and energy homeostasis. Elevated waist-hip ratio (WHR) increases type 2 diabetes and cardiovascular disease risk. The TBX15-WARS2 locus contains several independent association signals for WHR adjusted for BMI (WHRadjBMI). However, whether these risk variants are functional remains to be determined. The aim of my DPhil was to characterise two potentially functional TBX15-coding polymorphisms, rs10494217 (p.H156N) and rs61730011 (p.M566R), at a cellular and organismal level to investigate their impact on TBX15 function in adipose tissue biology.
Firstly, I prioritised the mechanism-of-action of these two polymorphisms at either a DNA-regulatory or protein-coding level in silico. I showed the most likely mode-of-action was at the protein-coding level with p.H156N predicted to alter a loop structure in the T-box of TBX15, further implicated in altered protein-protein dimerisation. However, this was not recapitulated in vitro (within assay sensitivity limits).
TBX15-WARS2 signals were associated with differential TBX15 and WARS2 expression, and several Tbx15 and Wars2 mouse models had altered body composition phenotypes. I metabolically characterised heterozygous knock-out (Tbx15+/-) mice and mice carrying orthologous human polymorphisms p.H156N (Tbx15H156N) or p.M566R (Tbx15M566R) and showed all three alleles conferred resistance to fat mass gain.
Finally, to evaluate the effect of TBX15 on gene expression, I generated a TBX15 regulatory network using ChIP-sequencing of preadipocyte cell lines, and RNA-sequencing of adipose tissues from homozygous knock-out (Tbx15-/-) and Tbx15H156N mice. Functional enrichment of differentially expressed genes implicated TBX15 in regulating lineage determination, adipogenesis of committed preadipocyte cells and immune response. In summary, these results suggest TBX15 regulates adipose tissue biology and body composition and shows a novel functional role for two human WHRadjBMI risk variants. Further work is needed to elucidate underlying mechanisms of action that can be targeted therapeutically.

Keywords: GWAS
in vivo models
adipose biology
Advisor: Cox, R
Wilson, C
Bentley, L
Dumbell, R
On the projective normality of an embedding of the moduli space of stable marked rational curves into projective space

We study an embedding of the fine moduli space of stable rational curves with n marked points into projective space for each n > 4. This embedding is developed from work of A. Gibney and D. Maclagan. It is related to the embedding given by the log canonical system, which is shown to be projectively normal in a paper by S. Keel and J. Tevelev using methods in sheaf cohomology. In this thesis, we prove the projective normality of our embedding for n = 5 and n = 6 using combinatorial methods. From this we can give, in a new way, a description of equations defining
¯
M
0,6 as a projective variety. We begin work on extending these ideas to obtain analogous results for each n > 6, as well as give conjectures on equations defining
¯
M
0,n as a projective variety in this general case.

Keywords: projective normality
moduli space
log canonical
rational curves
moduli
stable rational curves
Advisor: Szendroi, B
Ethics and humanity in (post-)Kantian philosophy

Bringing together work in ethics, political philosophy, and history of philosophy, the thesis examines the normative implications of the concept of humanity, arguing for a critical, egalitarian humanism that opposes hierarchies of moral standing among human beings while acknowledging our obligations to non-human animals. In the Introduction, I argue for a broad understanding of ‘humanism’ that captures a variety of different views, each with a different conception of the normative relevance of the notion of the human being. I then elucidate two problems for historically influential forms of humanism, namely that they have instituted unacceptable hierarchies among human beings and perpetuated a damaging anthropocentrism. I argue that instead of embracing anti-humanism, we should reform or rethink humanism in such a way that it avoids these difficulties. I then critically examine ethical conceptions of ‘the human’ in the work of four philosophers from apparently disparate traditions – Immanuel Kant, Martin Heidegger, Judith Butler, and Ludwig Wittgenstein. I argue that while neither Kantian humanism nor Heidegger’s anti-humanism can convincingly overcome the two problems explained in the Introduction, resources from Butler and Wittgenstein’s work can provide a new basis for a more attractive form of humanism that gives central place to the notion of bodily vulnerability and the need to acknowledge it.

Keywords: anti-humanism
ethics
Judith Butler
Martin Heidegger
Post-Kantian Philosophy
political philosophy
humanism
human being
Ludwig Wittgenstein
humanity
Immanuel Kant
Advisor: Moore, A
Srinivasan, A
The role and impact of Knowledge Organisers in the classroom: how can history teachers best make use of Knowledge Organisers at GCSE to facilitate meaningful retrieval practice?

This project explored the usage and impact of Knowledge Organisers (KOs) in the history classroom, to support the retrieval of substantive knowledge for GCSE. The secondary history department in question had concerns that knowledge retrieved in classroom quizzes was not being effectively utilised in an applied exam setting. The study aimed to make retrieval practice using KOs more meaningful for students, in order to support them to use substantive knowledge in an exam setting and to ensure their motivation for the subject was not negatively impacted by the continued focus on substantive knowledge. Participants in the study were a mixed ability Year 10 cohort studying GCSE history, working remotely using a virtual learning platform due to school closures in March 2020. The study used a combination of online survey, task choice and teacher assessment to draw conclusions about student attitudes and preferences towards retrieval and KOs, as well as performance in exam style questions. Results showed that students found the more varied KO retrieval activities engaging and more useful for answering exam-style questions. Overall, this suggests that students would benefit from engaging in retrieval practice, using knowledge organisers, that is more varied than short-answer quizzes. Therefore, the department should instead include retrieval activities that rely not merely on the recalling of factual information, but also provide students with an opportunity to use substantive factual knowledge alongside other historical knowledge, for example to reach judgements about causation or to consider context and period.

Keywords: MLT
MLT 2020
How to engage parents in language learning in order to motivate young linguists without causing undue
workload to practitioners

The aim of this action research project was to build upon the success of a pilot study using star of the week letters sent out on a weekly basis to students. The intention was also to gain a greater understanding of the impact parental/carer1 interventions and increased engagement can have in education, and to potentially decrease disillusion with language learning in the British MFL (modern foreign languages). Whilst some may find the thought of collaborating with and pushing to further engage parents somewhat daunting, it is nonetheless an often underused, ignored or underestimated strategy in fostering and nurturing student motivation on a Secondary school level in language teaching. A language feedback diary was issued in class to two different groups, a control group and an experimental group. The diary contained sections to allow the teacher to give students feedback on a specific task, spoken or written, and for the student to make a note of the verbal feedback and to write their reflections. The experimental group had an extra section where parents would write a message to their child based on their performance, and would write related comment or question to the subject teacher such as “I see my son/daughter is struggling with present tense verbs, what websites do you recommend for further practice?.” At the end of the study, students were asked via a questionnaire if the element of parental engagement had increased their motivation as a young linguist or not to measure the impact of the intervention.

Keywords: MLT
MLT 2020
Towards the development of a departmental target language culture: what classroom-based strategies are most effective in promoting spoken target language use in an English all-boys selective secondary school 
context?

Research has established that strategies can be a useful tool for foreign/second language (L2) learners. Speaking skills of Modern Foreign Languages (MFL) pupils in England are known to be poor when compared internationally. Explicit strategy-based instruction (SBI) has been successful in enhancing language skills, but less research has been conducted into its effect on speaking skills. From the limited body of SBI investigation into schoolchildren whose first language (L1) is English, there is some evidence of success among boys in particular. Addressing these gaps in the literature, the current two-cycle action research and development study, with a quasi-experimental design, investigates the impact of 12 hours of strategy intervention training on target language (TL) speaking skills in an all-boys selective secondary school in England. Participants are beginner (Y7) and intermediate (Y10) learners of French (L2) (N=268). The impact of the intervention is assessed using mixed methods through questionnaires, lesson observations, interviews and informal discussions, and analysis of pupil outcomes. In Cycle 2, pupils navigate the Strategy Island Map, an innovative tool to track their strategy use when speaking TL. Intervention is shown to have a positive impact on quantity and quality of spoken TL, confidence, and engagement among both beginner and intermediate learners. Noteworthy implications for collaborative departmental practice are discussed.

Keywords: MLT 2022
MLT