VictorJuiz/thesis huggingface dataset:
Investing the role of FGF signaling in left-right determination

Left-right patterning is set up early in development, at embryonic day 8.5 in the mouse. Cilia are present on the cells of a transient structure, termed the node, the location where L/R symmetry is broken. In this pit-like structure, motile cilia generate a leftwards flow of extracellular fluid, which is translated into a left-specific signal by immotile cilia on crown cells at the edge of the node. How exactly this flow is translated remains unknown, with one hypothesis proposing that nodal vesicular parcels (NVPs) within the node transport signalling molecules to the left side. FGF signalling was first implicated in L/R patterning when an Fgf8 mutant mouse was shown to exhibit situs defects. The precise role of FGFs in L/R patterning is unclear, but they have been proposed to regulate NVP release. Other hypotheses include them functioning in the regulation of node cilia length, and in the formation and maintenance of the node structure. These hypotheses are explored in this thesis, through the re-assessment of the Fgf8 mouse mutant and through the use of FGF signalling receptor inhibitors in embryo culture. My findings confirm a role for FGF signalling in L/R determination, and support a role for FGF signalling in specifying, maintaining and/or patterning the cells that make up the embryonic node. My data also casts doubt on the evidence previously used to argue for the existence of NVPs. Analysis of the location of FGFRs in the embryo and within cells shows the presence of FGFR2 in the node cilia, but whether ciliary localisation of FGFRs is important in L/R patterning remains unclear. I present evidence that the major mechanism by which FGF signalling affects L/R determination is through the formation/patterning of the node. However, I also present evidence for a lesser role FGFs may play in controlling mammalian cilia length. Intriguingly, my data also indicates a strong influence of genetic background on the Fgf8 mutants.

Keywords: development
asymmetry
mouse
patterning
FGF
embryo
cilia
Advisor: Norris, D
Mommersteeg, M
Operator splitting methods for large convex conic programs

Convex optimisation is used to solve many problems of interest in optimal control, signal processing, finance, operations research, and machine learning.
While medium-size problems can be solved efficiently by interior-point methods, modern applications often yield problems with very large dimensions. Compared to interior-point methods, operator splitting methods are computationally inexpensive, which allows them to solve much larger problems. However, they tend to converge slowly to high accuracy solutions and their performance is sensitive to algorithm parameters and problem scaling.
This thesis investigates different acceleration and scaling techniques to both improve the convergence of operator splitting methods to achieve higher accuracy solutions and to reduce the per-iteration computation time of the methods. We consider general convex conic problems and focus especially on the subset of semidefinite programs (SDPs), for which finding a solution is particularly challenging at large dimensions. The first part of the thesis introduces COSMO, a novel general purpose solver for convex conic programs based on the alternating direction method of multipliers (ADMM). We demonstrate that our splitting, which combines a quadratic objective function with convex conic constraints, leads to competitive performance both for problems in the conventional conic problem form but also for quadratic programs and SDPs with norm constraints. We further show how the user can use custom convex constraints to allow more natural problem formulations.
The complexity of solving SDPs can be greatly reduced if the coefficient matrices that constrain the matrix variable are sparse. Chordal decomposition techniques then allow an equivalent problem formulation with multiple constraints only on the nonzero blocks of the matrix variable which often leads to orders of magnitude speed-up. In the second part of the thesis we develop a novel clique merging algorithm that combines some of the blocks after the initial decomposition to speed up the projection step of ADMM. We demonstrate that the method leads to significant performance improvements and avoids disadvantageous decompositions.
In the third part we demonstrate how to use repeated restarts and safeguarding checks to globalize Anderson acceleration for an ADMM solver. Comprehensive benchmark results show a significant reduction in both iterations and solve time to higher accuracy solution and a more robust algorithm.

Keywords: chordal decomposition
ADMM
clique merging
conic programming
semidefinite programming
Anderson acceleration
Advisor: Goulart, P
Cannon, M
The development of low-cost and non-invasive methods of preimplantation genetic testing

Over the past thirty years, numerous methods have been developed to assess genetic abnormalities in preimplantation embryos during IVF relevant to embryo health and viability, or that cause severe inherited disease (preimplantation genetic testing of aneuploidy; PGT-A or monogenic disease; PGT-M, respectively); however, these are often expensive, restricting patient access. Accordingly, this thesis aimed to develop low-cost methods of PGT. By applying long-read nanopore sequencing to parental gDNA samples, a novel low-cost means of identifying and phasing informative SNPs during the pre-clinical work-up phase of PGT-M was developed. Approaches based on long-range PCR amplicon sequencing and CRISPR- Cas9 enrichment are validated, with the potential to enhance patient access and improve test accuracy. Strategies based on the analysis of DNA within spent embryo culture media (SCM) during IVF (non-invasive PGT; niPGT) were also explored, with the potential to reduce costs and improve safety compared to traditional expensive and invasive embryo biopsy techniques. Specifically, a multiplex PCR-NGS protocol was developed for the non- invasive diagnosis of β-thalassaemia and sickle-cell anaemia, providing promising results during the optimisations. Moreover, niPGT-M assays for recessive X-linked disorders and sickle-cell anaemia were optimised, adopting an inexpensive recombinase polymerase amplification and lateral flow assay approach: although initial validations were promising, further optimisations are necessary to avoid misdiagnosis. To assess the potential for niPGT-A, a novel pipeline was developed utilising a whole genome amplification and next-generation sequencing approach. To date, the optimal method of amplifying DNA in SCM, which is of low quantity and likely somewhat degraded, has been unclear. After applying multiple methods to SCM, SurePlex achieved the highest levels of amplification and diagnostic concordance with paired trophectoderm biopsy specimens; however, rates were too low for clinical application. Therefore, analysis of the cumulus cell transcriptome was investigated as an alternative minimally-invasive and low-cost means of identifying oocyte-derived chromosomal abnormalities in the embryo. Transcriptome sequencing and qPCR analysis identified multiple novel candidate biomarkers, and most convincingly cytoskeletal protein PTSPIP1, with altered expression in cumulus cells associated with aneuploid embryos.

Keywords: transcriptomics
cell-free DNA
preimplantation genetic testing
preimplantation genetic diagnosis
spent culture media
preimplantation genetic testing of monogenic disease
non-invasive preimplantation genetic testing
next-generation sequencing
PGT
twistdx
embryo
nanopore
Advisor: Wells, D
The socio-demographic promise of expanded female education across sub-Saharan Africa

Sub-Saharan Africa (SSA) is highly vulnerable to both early childhood mortality and weather shocks as a cause of climate change. The region also exhibits very low levels of women’s status. The demographic literature suggests that maternal education could help reducing child mortality and increasing women’s status, as well as reducing vulnerability to the risks associated with climate change. This thesis contributes to this literature and expands it in several ways. The first essay demonstrates the causal role of maternal education in shaping under-five mortality in Malawi and Uganda. It finds a negative effect that operates through reduced financial barriers to medical care, increased attitudes towards modern health services, and rejection of domestic violence. Moreover, being more educated enhances proximity to a health facility and knowledge about the transmission of AIDS in Malawi, and wealth and improved personal illness control in Uganda. By providing a spatial portrait of male decision-making dominance across SSA, the second essay highlights considerable within and between country heterogeneity in women’s status. Using spatial panel data methods, it also finds evidence that diffusion of norms about family decision-making helps explain declining reports of male decision-making dominance over time and that women’s education and urbanisation are the main channels through which this diffusion occurs. The latter suggests that women’s education and urbanisation are important for the social interaction process leading to the diffusion of norms about family decision-making. The third paper focuses on the in-utero exposure to growing-season droughts and finds that it increases under-five mortality and that the lack of nutritious food among mothers during pregnancy could be driving this effect. It also provides evidence that maternal education may protect against drought-related fatality in early childhood.

Advisor: Monden, C
Learning and interpreting deep representations from multi-modal data

Deep learning has resulted in ground-breaking progress in a variety of domains, from core machine learning tasks such as image, language, and video understanding, to real-world industries such as medicine, autonomous driving, and agriculture. Its success has been driven by providing neural networks with manual supervision from large-scale labelled datasets such as ImageNet to automatically learn hierarchical data representations. However, obtaining large-scale labelled data is often a very time-consuming and expensive process. To address this challenge, we push the limits of self-supervision from multi-modal video data. Video data usually contain multiple modalities such as images, audio, transcribed speech and textual captions freely available. These modalities often share redundant semantic information and therefore can serve as pseudo-labels to supervise each other for representation learning without necessitating the use of manual human labels. Without the reliance on labelled data, we are able to train these deep representations on very large-scale video data of millions of video clips collected from the Internet. We show the scalability benefits of multi-modal self supervision by establishing a new state-of-the-art performance in a variety of domains: video action recognition, text-to-video retrieval, text-to-image retrieval and audio classification. We also introduce other technical innovations in terms of data transformations, model architecture and loss functions to further improve learning these deep video representations using multi-modal self-supervision. A secondary contribution of this thesis is new tools to improve the interpretability of deep representations, given that it is notoriously difficult to decipher the key features encoded in these deep representations. For images, we show how perturbation analysis can be used to analyze the intermediate representations of a network. For videos, we propose a novel clustering method using the Sinkhorn-Knopp algorithm to map deep video representations to human interpretable semantic pseudo-labels. The contributions in this thesis are steps to unlocking both the scalability and interpretability of deep video representation learning.

Keywords: multi-modal learning
deep representations
interpretability
video understanding
self-supervised learning
clustering
explainable AI
machine learning
representation learning
Advisor: Vedaldi, A
Henriques, J
Electronic quantum fluids in graphene and quantum Hall systems

This thesis focuses on several examples of strongly correlated electronic quantum fluids.
In chapter 2 we use a kinetic theory approach to describe the transport properties of bilayer graphene near charge neutrality. After solving the semiclassical Boltzmann equation, we find that the results are well approximated by a hydrodynamic two-fluid model. A fluid of electrons and a fluid of holes interact with each other via Coulomb drag.
Chapter 3 looks at quantum Hall edges. We consider a quantum Hall edge coupled to a driven quantum dot and compute the current on the edge downstream from the contact. We show that Coulomb interactions between the dot and the edge renormalize the charge in the current pulses.
Chapter 4 focuses on the bilayer quantum Hall system. Two layers of quantum Hall fluid are separated by a variable distance. At large interlayer separation, we have two well-separated composite Fermi liquids and we consider the pairing between the two layers as the interlayer separation is decreased. We propose a new trial state for this paired phase of matter and use exact diagonalization numerics to investigate this proposal.

Keywords: graphene
quantum Hall
Advisor: Simon, S
Which surgical treatment for Dupuytren’s Contracture is most cost-effective in England?

Objectives: To assess the cost-effectiveness of surgical interventions offered in the NHS for adults with Dupuytren’s contracture admitted into secondary care, when compared to the mainstay of surgical treatment (Limited Fasciectomy).
Perspective: From the healthcare payer’s perspective, which would be NHS England.
Setting: Inpatient admitted secondary care in the NHS in England.
Methods: A 34-year time horizon economic evaluation was conducted using individual patient data from Hospital Episode Statistics, the UK Hand Registry, and National Life Tables. A de novo cohort Markov model was developed to assess the cost-effectiveness of admitted patient Percutaneous Needle Fasciotomy (PNF), and Dermofasciectomy (DF) to Limited Fasciectomy (LF) as a comparator. This accounts for factors like life expectancy and further treatment for each year after the average age of treatment. Deterministic and probabilistic sensitivity analyses were undertaken to study model and parameter uncertainty.
Results: Using the incremental cost-effectiveness ratio, LF was the dominant procedure. For one less QALY, DF would cost an additional £1030.76 and admitted patient PNF would cost an additional £2207.96. Running one-way sensitivity analysis shows that modifying the cost and utility parameter values doesn’t result in a different outcome. Probabilistic sensitivity analysis suggests that there is a maximum probability of 55% that LF is the most cost-effective procedure.
Conclusions: This supports LF as the treatment of choice for first-line surgical treatment, compared to DF or admitted patient PNF administered through inpatient admitted care pathways. Constraints of the datasets, namely follow up as well as information on other settings, limited the relevance of this model to other settings. Further research might focus on differing severity of disease, and compare other pathways, such as outpatient PNF, which might be expected to have different costs. Randomised controlled trial data would be beneficial to extend this study and add granularity to the observational data available.

Keywords: Cost-effectiveness analysis
Dupuytren's
Advisor: Furniss, D
Rodrigues, JN
Pinedo-Villanueva, RA
Kolovos, S
The vital centre, the middle of nowhere, or something in-between: A study of political centrism in Western democracies

The nature of the centre is one of the most significant concepts in the study of comparative politics, due to its place at the fulcrum of the ideological spectrum. However, scholarly interest in the subject has not matched its importance, with a relative paucity of research leaving the idea of the centre often poorly defined, imprecise, and theoretically muddled.
The main contribution of this thesis lies in its response to this confusion. It advances a novel typology to streamline and clarify disparate conceptions of political centrism. It proposes a new theoretical framework of centrist parties and centrist voters, and contextually grounds it within the wider literature on ideology and its effects.
Guided by this typology and utilising several large-sample studies of ideology (expert surveys and manifesto content analysis for parties, and mass public opinion surveys for voters), the three empirical chapters explore several questions related to two fundamental themes – how centrist political actors differ from their counterparts on the left and right, and how centrist political actors differ among themselves.
Specifically, among other things, this thesis finds that subtle variations in centrist ideology can account for parties’ enthusiasm for European integration. It finds that many centrist voters are neither particularly moderate in their views nor are they as compromising and ideologically flexible as they are often presupposed. And it finds that the relationship between the intensity and extremity of preferences bears on electoral behaviour, as centrists are shown to be less sensitive to ideology than other voters when casting their ballots.
This research demonstrates the importance of a more nuanced and comprehensive conception of the centre, and the crucial implications it has for the wide range of subjects in the social sciences relating to political ideology, including party competition, voter behaviour, political psychology, and democratic theory.

Keywords: political ideology
left-right
party competition
centrism
centre
voter behaviour
Advisor: Green, J
Utilisation of enzymes as powerful tools towards fluorinated biomolecules

Incorporation of fluorine into biomolecules provides versatile opportunities for clinical and pre-clinical imaging, with 18F-PET and 19F-MRI and as reporter tags for “zero-background” 19F-NMR. Considerable effort has been made towards achieving direct fluorination of biomolecules, however nucleophilic fluorination methods typically require anhydrous conditions and organic solvents, while electrophilic methods suffer from high reactivity of fluorine gas and low specific activity, conditions which are protein incompatible. There are currently no known methods for direct C-F bond formation on large biomolecules, however the fluorinase enzyme has been shown to allow for direct fluorination of peptides in aqueous media using inorganic fluoride. Enzymatic catalysis provides an alternative to standard chemical methods, allowing for reactivity under mild conditions.
Herein, a method for direct nucleophilic site-selective incorporation of fluoride into a protein containing an engineered recognition motif in aqueous media is described. Initial work was performed on a small-molecule model to allow investigation of critical parameters pertaining to the reactivity of this enzyme. Substrate promiscuity of the enzyme was evaluated alongside alterations to the co-factor/additive of the enzyme to improve reactivity. In addition, a side-product of the enzymatic reaction was observed and its role was investigated.
Optimised conditions from the small-molecule reactions were applied for on-protein work and allowed for the first example of direct C-F bond formation on a protein in aqueous media. The compatibility of this methodology was assessed with a range of different proteins and further assessed for the 18F-fluorination of a protein.
An alternative approach to 18F-labeling of biomolecules was also explored in this work, where three enzymes were combined in a reactor to allow for transformation of the radiotracer, [18F]FDG to another radiotracer of interest, [18F]FDT. The enzymes were immobilized and introduced into a cartridge, and flow-chemistry was adopted to allow for easy purification, facile handling, removal of endotoxins, and possible automation of this process in the future.
We anticipate that the methodologies described in this work will contribute towards ready labelling of complex biomolecules under diverse mild conditions for potential clinical applications.

Advisor: Davis, B
Gouverneur, V
Protecting the right to leave in an era of externalised migration control

This thesis explores the right to leave any country, including one’s own, in international law and its applicability to externalised migration control. Destination states and the European Union are employing a range of practices designed to prevent certain migrants leaving the state they are in and their irregular arrival, typically in cooperation with other states, private actors, and international organisations. Motivated by this phenomenon, this thesis focuses on the right to leave for migrants (including nationals seeking to leave their own state), which is fundamental on its own terms and in securing liberty and equality. It assesses the compatibility of key externalisation measures with the right and considers which actors bear responsibility for ensuing violations. Part I develops a general framework for determining whether restrictions conform with the right to leave, analysing the right’s scope and requirements and outlining corresponding obligations and duty-bearers. This shifts the focus onto challenging the traditional view that states have an almost unfettered right to exclude non-nationals, illustrating obligations to admit before demonstrating that the right to leave is exercisable irrespective of any right of entry. It then reveals the practical and legal necessity of the right for asylum seekers, appropriately formulated as a ‘right to leave to seek asylum’ and accompanied by several duties. Part II examines the law on jurisdiction and international responsibility. Applying the previous findings, Part III turns to externalisation, analysing the compatibility of visas, carrier sanctions, pushbacks, and pullbacks with the right to leave. It concludes that in most circumstances, such practices violate the right, with each actor responsible for their respective role. Overall, this thesis highlights the need for the primary contours of the right to be integrated into migration control policies and practices, compelling the dismantlement of many externalisation strategies and a re-imagining of the global (im)mobility infrastructure.

Keywords: Externalised Migration Control
Right to Leave
Migration
Refugee Law
International Human Rights Law
Advisor: Costello, C
Jackson, M