VictorJuiz/thesis huggingface dataset:
Towards local property assessment of advanced manufactured microstructures: a case study in linear friction welded titanium
Keywords: aerospace
fatigue
bayesian optimisation
advanced manufacturing
micromechanics
materials
titanium
mechanical
additive manufacturing

Recent developments in manufacturing technology have enabled a wealth of designs to be created and implemented in engineered products. These methods, empowered in part through data-driven approaches to materials processing, have optimised the structure of additive products and refined the processes for complex joining technologies. However, in doing so they radically change the material structure, often introducing strong local heterogeneity either by design or by consequence. A commensurate local understanding of the material and its behaviour at relevant length scales is necessary in order to ensure these parts live up to the stringent requirements in demanding or safety critical applications. Two methods are developed to contribute to this effort, with data-driven approaches to similarly accelerate the development cycles described above.
The effect of microstructure on the mechanical behaviour is investigated with these methods using a Ti-64 linear friction welded (LFW) joint as a case study. The LFW joint contains a highly varied microstructure, from the globular alpha and bimodal structures in the parent material on either side to the Widmänstatten structure found near the weld-line. The weld-line itself is known to be highly crystallographically textured, with a preference for the c axis to align with the transverse direction. The local static and dynamic material properties from the bulk microstructures to the refined and textured weld-line have been explored through nanoindentation and a novel mesoscale fatigue method. Local static properties are determined through correlated nano-indentation mapping and Electron Back Scatter Diffraction (EBSD), providing rapid structure property assessments.
Local fatigue properties are explored with a Bayesian Optimised data collection protocol and novel meso-scale ultrasonic fatigue test, permitting the efficient sampling of fatigue behaviour of weld-line material. These two methods provide new methods and datasets for assessing the properties of advanced manufactured materials, reflecting established knowledge and novel quantitative comparisons in the case study described.
Essays on competitive and strategic bidding in multi-object auctions
Keywords: auctions with budget constraints
Fisher markets
multi-unit auctions
strategic bidding
competitive equilibrium
experiment

This thesis addresses four important issues in multi-object auction markets, focusing on a theory of strategic bidding and corresponding empirical evidence, on questions of equilibrium existence with distributional preferences, and on the equivalence of market objectives.
The product-mix auction (PMA) designed by Paul Klemperer is used by the Bank of England to allocate loans to commercial banks at least monthly. If only a few bidders were thought to be participating, strategic behaviour may harm efficiency. I develop a theoretical model of strategic bidding in the PMA that enables the comparison with other auction formats commonly used for the sale of differentiated substitutes. While the theory predicts that the considered auctions perform (nearly) identically in bidder surplus, revenue, and efficiency, I also show contrasting empirical evidence. In a virtual lab experiment, the PMA achieves highest bidder surplus and efficiency. When bidders are symmetric, payoffs in the PMA are even between 90% and 156% higher and efficiency is 12% higher than in other auctions.
The product-mix auction was developed for substitute preferences, but similar concepts may be useful in markets with substitutes and complements. Extending the product-mix preferences and bidding language, I consider an even richer market with substitutes, complements, and distributional preferences. In this market, the seller can favour, e.g., a more concentrated allocation of products among buyers, or an even distribution of products. This type of preference, while common in many real world applications, is novel in the literature. I develop a graph-based bidding language and derive new results on the existence of competitive (Walrasian) equilibria, which can be computed via linear programming. The auction design I develop guarantees fair and transparent pricing.
In the context of substitutes, it is often practical for buyers to state their preferences with a budget. This may be spent on several products, while trade-offs between those products are stated as prices. Without budget constraints, it is known that revenue and welfare optimum may not coincide. We show, however, that with budget constraints, the market objectives of maximising revenue and maximising welfare result in the same, unique, market clearing prices and the same allocation. Our proof of this result also constructs an algorithm to identify these prices.
Optimal control and reinforcement learning for formula one lap simulation
Keywords: autonomous vehicles
ppo
formula one
gpu compute
self driving
optimal control
reinforcement learning
torch
lap simulation

Lap simulation in a Formula One context is a subclass of optimal control problems and describes the computation of optimal trajectories around racing circuits. The results of lap simulation are primarily used for vehicle setup and strategic racing decisions. The optimal lap problem is solved using two classes of algorithms. The first algorithm uses direct collocation to compute optimal trajectories and the second algorithm uses specially constructed reinforcement learning environments and generalised function approximation to compute desirable system inputs. Historically direct collocation methods were considered impractical for minimum lap time simulations, due to their high computational costs. The exponential increase in computational performance has enabled the practical application of these algorithms. These lap time simulations require a vehicle model, as well as a track discretisation. As an example for this, the classical bicycle model along with a curvilinear track model are introduced. To solve the resulting direct collocation problems, algorithms for non-linear optimisation problems are presented and performance critical aspects are discussed. The optimisation algorithm is accelerated by utilising highly parallel computer architectures, such as graphics processing units (GPUs). An analytical gradient approximation is presented to achieve approximations of projection systems which constitute one most performance critical components of the solution process. Mesh refinement algorithms are discussed and a novel mesh refinement heuristic based on optimal polynomial approximation in an L1 sense is discussed. The L1 approximation is improved by detecting singularities and using Clenshaw--Curtis quadrature on intermediary intervals. In Chapter 4 of this work, the lap time optimisation problem is reformulated as a reinforcement learning environments. For this, the relevant background literature on reinforcement learning is discussed and a translation of a training optimisation environment is constructed. Details of this environment are discussed in the form of reward signals, terminal conditions, and observation features. A series of learning models is discussed with increasing feature fidelity leading to an algorithm that can generalise well across representations of circuits from the 2022 Formula One calendar. This work expands on the current literature by providing novel, physically motivated, reinforcement learning environments for lap time optimisation tasks. The results of both approaches are combined by using strategy extraction to initialise the collocation optimisation algorithm and optimise the underlying mesh.
Defending Henry VIII's royal supremacy in England and Ireland
Keywords: Religio-political history
Royal supremacy
Thomas Cromwell
ecclesiastical authority
ecclesiastical history
English history
Irish history
Tudor history
Irish Reformation
ecclesiastical government
history of ideas
Christopher St German

This thesis offers new perspectives on the intellectual rationales employed to defend Henry VIII’s royal supremacy. It affirms that, far from being explicable merely by reference to the exigencies of politics, the supremacy was shaped by ideas about the nature of temporal authority over the Church, and it demonstrates the importance of securing ideological commitment to the supremacy.
The thesis addresses the intellectual case for the supremacy advanced by the English government, and especially by Thomas Cromwell, in the formative years of the 1530s, and the relationship between ideology and the institutional structures and functioning of the supremacy. The thesis also considers the application of the intellectual case for the supremacy to Ireland, although there the issues of Henry’s supremacy played out over a longer period, and are therefore pursued to the end of Edward VI’s reign.
There are three principal elements to the thesis.
The first concerns the role played by Cromwell in shaping the supremacy. It is argued that he initially promoted a parliamentary supremacy in accordance with his political philosophy, and manifested this by exercising the supremacy through statute. However, when Cromwell, as vicegerent, was endowed with extraordinary ecclesiastical powers, both the way in which the supremacy functioned, and the model of supremacy which he sanctioned in polemic, changed.
The second revises previous scholarly interpretations of Christopher St German’s proposals for the resolution of doctrinal issues by the king-in-Parliament, and argues that, ultimately, he repudiated his own theories.
The third proposes that the intellectual case for the supremacy was compromised in Ireland by political circumstances there and by policy decisions taken by the English government, and argues that a failure to convey an adequate intellectual justification for the supremacy to the people of Ireland is a factor helping to explain the Reformation’s rejection there.
Computational studies of lipopolysaccharide interactions with membrane transporters
Keywords: LPS
Lpt complex
LptB2FGC
lipopolysaccharide
Native Mass spectrometry
molecular dynamics
HDX

Lipopolysaccharide (LPS) lipids compose the outer leaflet of the outer membrane in pathogenic Gram-negative bacteria and are chiefly responsible for host-immune responses. Therefore, the membrane proteins which interact with LPS as well as the transport system for LPS, the Lpt system, represents a class of extremely important drug targets. The focus of this thesis is to employ molecular dynamics studies to examine the effects of LPS binding upon the Lpt complex at every stage of the transportation process, validating and conferring recent mass spectrometry and cryo-electron microscopy (Cryo-EM) studies.
Molecular dynamics (MD) studies in this thesis reveal that LPS binds to other proteins found in the inner membrane in a similar manner to the transporter subcomplex LptB2FGC. Within the transporter itself, simulations of recently resolved Cryo-EM structure reveal that LPS shifts position to facilitate transportation across the periplasmic protein bridging complex. Binding energy calculations between the acyl chains of LPS and the bridging complex reveal a generally flat energetic landscape before reaching the terminal outer membrane subcomplex of the Lpt system, LptDE. Here, MD studies validate and explain hydrogen-deuterium exchange mass spectrometry results which capture the conformational changes required for LPS insertion into the outer membrane. With an increasing prevalence of antibiotic resistant pathogens, this thesis concerns characterising LPS interactions with its transport machinery suggesting means for developing antimicrobial therapeutics which target this essential system.
Dissecting the impact of chimeric antigen receptor expression levels on T cell behaviour and response
Keywords: scRNA-seq
T cells
microRNA
synthetic biology
immunotherapy
CAR T cells
immunogenomics
tumour immunology

Chimeric antigen receptor (CAR) T cells have heralded in a new age in cancer treatment. CAR T therapy has demonstrated remarkable responses in cancer patients of blood cancers. The therapy's success lies in the expression of a chimeric antigen receptor (CAR) that reprograms and redirects T cells to specifically target and attack cancer cells. However, CAR T therapy has faced numerous challenges with attempts to translate this success into solid cancers. Issues related to on-target, off-tumour toxicity, tonic signalling, and T cell dysfunction have limited numerous efforts. However, recent evidence demonstrated that CAR expression levels are a critical determinant in T cell activity and therapeutic efficacy – even more so in mediating T cell exhaustion. While insightful, this work assesses only two levels of CAR expression. Thus, there is a notable, outstanding gap in thoroughly understanding how CAR expression levels impact T cell function and response. In this thesis, I report the effects of extensive fine-tuning of CAR expression levels on the T cell transcriptome. First, I adapt microRNA silencing-mediated fine-tuners (miSFITs) technology to tune CAR expression levels in a T cell model. I leverage this model to show that tuning CAR expression correspondingly tunes CAR T cell activation. Next, I translate this technology into primary, human T cells, showing that miSFITs robustly and precisely tune CAR expression. I then demonstrate how tuned CAR expressions controls the expression of CD69 to stepwise levels. Finally, I use single-cell RNA-sequencing to comprehensively dissect the effects of tuning CAR expression in T cell responses, generating a transcriptomic atlas against step-wise levels of CAR expression. I use this atlas to first demonstrate how tuning CAR expression impacts several genes related to T cell activation, dysfunction, and memory. Using gene signatures, I demonstrate how CAR expression can be optimised to mitigate T cell dysfunction yet spare T cell activation and memory. Embarking on an unbiased discovery analysis, I identify genes, regulons, and signaling pathways that are influenced by CAR expression, providing a novel view on T cell dysfunction. My findings underscore the important role CAR expression levels have on T cell response and provide a promising avenue to address pressing, longstanding challenges hindering the success of CAR-T therapies.
Neural mechanisms underlying memory in drosophila melanogaster
Keywords: mushroom body
dopamine
retrieval
differential associative learning

In a complex and constantly changing environment, animals are required to guide behaviour in a dynamic way to adapt to the current environment as well as the organism’s needs. Although the ability to remember past events allows animals to predict future outcomes and thereby guide behaviour, an input does not always produce stereotypical behaviours. Factors such as conflicting information from parallel memories, cue specificity and context will impact the predictability of an outcome across time. Similarly, the animal’s internal state influences whether the predicted outcome should be pursued at a given moment. Moreover, biological relevance of the memory, such as nutrient-reinforced associations, are thought to affect the lability of the memory and therefore how accessible it will be. Integration of predictability, motivation and memory stability allows a dynamic retrieval of appropriate memories to guide behaviour to properly balance their internal state.
Previous research in Drosophila has yielded detailed mechanisms describing the neural circuitry and molecular correlates involved in memory processing, but we lack a full understanding of how factors affecting memory retrieval become integrated to produce changes in behaviour. The work presented throughout this thesis uses Drosophila melanogaster to investigate the neuronal and behavioural mechanisms and how these factors regulate behavioural outcomes across time. In this work, repeated stimulus presentations were used to address how stimulus exposure prior to learning affects the formation and expression of new memories across time. Our results show that odour pre-exposure leads to an aversive memory which competes with subsequently acquired memories, leading to latent inhibition of memory expression. Changes in context between pre-exposure and testing allow conflict resolution, retrieval of the appropriate trained memory and inhibition of pre-exposure memory.
The second experimental chapter examines nutrient-reinforced long-term memory and the dynamics of its retrieval across time. Interestingly, neuronal stimulation studies have suggested that emergence of long-term nutrient-reinforced memory is independent of short-term memory, suggesting a delayed association between stimuli and nutrient-reward. However, the results presented here suggest that this apparent emergent memory results from an inhibition of short-term memory, potentially due to a motivational switch produced by co-activation of retrieval-inhibiting neurons. Taken together, the work presented throughout this thesis delves into how different mechanisms, from memory integration to motivational suppression and context, lead to a temporal inhibition of memory retrieval to shape a changing behaviour across time.
Exploring mammalian chromatin architecture and its impact on gene regulation
Keywords: TADs
Hi-C

Mammalian chromatin architecture appears hierarchically organised and is composed of chromosome territories, compartments, topologically associating domains (TADs), loops and nucleosomes. The study of chromatin architecture has recently become prevalent due to the advancement of chromosome conformation capture (3C) and microscopy-based techniques. Many studies have predicted that TADs display important functional characteristics such as forming tissue and species-invariant regulatory domains, promoting co-regulation and insulating genes from aberrant regulation. Even with the increasing availability of data, the relationship between chromatin structures such as TADs, gene expression and function is still not fully understood. In this thesis, I use publicly available Hi-C data to rigorously assess this relationship.
To further investigate the characteristics of TADs I compiled a re-annotated TAD dataset consisting of 13 human and 20 mouse genomes, covering 8 broad tissue/cell type groups. Using this TAD dataset as a foundation, I investigated the functional features of TADs in three main areas: tissue and species specificity, functional annotations, and phenotypic characteristics. Comparative analyses between TADs and randomly placed TADs revealed that there is some evidence that TADs are both tissue- and species-specific, genes which singly occupy a TAD are highly constrained and enriched for developmental functions, and genes sharing a CTCF TAD are not more functionally similar than can be explained by their linear proximity alone. Lastly, using adipose TADs as well as chromatin loops, I investigate the aetiology of genetic variants associated with fat distribution.
The comprehensive analyses outlined suggest that contrary to common claims in the literature, TADs display a significant degree of both tissue and species specificity and play a limited role in promoting gene co-expression. These results contribute to understanding the relationship between 3D mammalian chromatin structure and gene regulation which is crucial for dissecting gene regulatory programs.
Globular multicategories with homomorphism types
Keywords: higher category theory
homomorphism types
directed identity types
globular operads
iterated enrichment
globular multicategories
homotopy type theory

We introduce various notions of globular multicategory with homomorphism types. We develop a higher dimensional modules construction that constructs globular multicategories with strict homomorphism types. We illustrate how this construction is related to iterated enrichment. We show how various collections of “higher category-like”objects give rise to globular multicategories with homomorphism types. We show how these structures suggest a new globular approach to the semantics of (directed) homotopy type theory.
The generation of Paneth-like cells in colorectal cancer to alter T-cell responses
Keywords: immune response
colorectal cancer
paneth cells

Immunotherapy in colorectal cancer (CRC), the third most diagnosed cancer worldwide, results in limited and unpredictable responses. There are two main molecular subtypes of CRC: microsatellite unstable and the more common microsatellite stable type. Microsatellite unstable CRC develops as a result of somatic or germline, genetic or epigenetic perturbations to DNA mismatch repair genes. Importantly, microsatellite stable cancers mostly respond poorly to immunotherapies due to their apparent lack of neoantigen presentation and immune infiltration. The main curative treatment of these cancers thus remains surgical resection of the tumour and adjacent lymph nodes with some patients then offered conventional chemotherapy. Traditional views propose the benefit of lymphadenectomy is to either prevent further spread of the disease from involved lymph nodes or to improve staging. However, a recent transcriptomic analysis from the Buczacki Group demonstrated a strong enrichment in adaptive immune response related gene sets associated with high lymph node (LN) yields. Given more immunogenic tumours are associated with better outcomes, these data suggest a tumour-intrinsic reason for the enhanced survival seen. Interestingly, our analysis also found signatures for Paneth cells were enriched in this high LN yield group. Paneth cells are a cell type found in the small intestine and only rarely in the large intestine, where colon cancer develops. In the small intestine they secrete antimicrobial peptides and regulate the inflammatory response. I hypothesise that the presence of Paneth-like cells in colon cancer enhances the host immune response against the tumour. In this study, in-silico analysis revealed heterogeneity within Paneth cell populations in CRC, separating LYZ- and DEFA5-specific clusters. ATOH1 plasmid overexpression and SATB2 CRISPR-cas9-knockout induced Paneth cell-specific DEFA5 gene and protein expression in CRC cell lines and spheroids. Paneth cell differentiated models were co-cultured with Jurkat cells to test for immune effects. Co-culturing with ATOH1-overexpressing and SATB2- knockout cells caused an increase in spheroid infiltration and IL2 secretion of Jurkat cells. Therefore, I propose that differentiation therapy could potentially augment current immuno-oncology approaches by enhancing the host immune response against CRC.