VictorJuiz/thesis huggingface dataset:
Follow the leader: collective cell migration in cancer and developmental biology

Collective cell migration is an essential phenomenon in biology, occurring in diverse processes such as neural crest stem cell migration and angiogenesis (the formation of new blood vessels from pre-existing ones). One particular mode of collective cell migration involves two distinct phenotypes: leader cells, which migrate towards external biophysical signals, and follower cells, which move in response to leader-created cues. Mechanisms underpinning leader-follower migration remain poorly characterised in general, partly because they occur over multiple spatial and temporal scales. Mathematical modelling can address such issues, as it can be used to tractably evaluate different biological hypotheses, connect individual cell interactions to the behaviour of collectives, and guide the design of in vivo experiments. Open questions remain, however, regarding the validity of certain mathematical models and the conditions for which they accurately capture data from biological experiments.
In this thesis, we address different questions relating to leader-follower migration within the contexts of angiogenesis and neural crest cell migration. By comparing agent-based model simulations for angiogenesis to solutions from both a classical phenomenological framework and an alternative coarse-grained model, we identify parameter regimes for which the phenomenological framework accurately describes results of the other two systems. In doing so, we uncover implicit physical assumptions that underpin the continuum models. We also collaborate with experimental colleagues to develop a new agent-based model for cranial neural crest cell migration that incorporates cell remodelling of, and movement through, a naive extracellular matrix. We perform a global sensitivity analysis on the model and rank the mechanisms that most dominate collective cell behaviour. Further tests of this model suggest that migration is most efficient when leader and follower cell phenotypes are not identical. We conclude by providing, to our knowledge, the first detailed investigation of mechanisms that ensure robust neural crest cell migration.

Keywords: asymptotic analysis
sensitivity analysis
neural crest cell
angiogenesis
contact guidance
collective cell migration
extracellular matrix remodelling
coarse graining
agent based model
multiscale modelling
Advisor: Maini, P
Byrne, H
The molecular epidemiology of bloodstream infections caused by non-Salmonella Gram-negative bacteria in a tertiary hospital in Nepal with focus on neonatal sepsis and Enterobacter species

Bloodstream infections (BSIs) are common cause of morbidity and mortality among patients of all age groups. Of particular concern is the increasing emergence and spread of antimicrobial resistance (AMR) in many Gram-negative bacteria (GNB) that cause BSIs. The aim of this thesis was to determine some of the epidemiological features of BSIs in a tertiary hospital in Nepal providing a specific focus on the molecular aspects of AMR, virulence, and variations in Enterobacter spp., a clinically important GNB associated with BSIs.
To better understand BSIs-causing non-Salmonella GNB and their AMR determinants in this setting, I conducted a retrospective surveillance study, accessing data from 2012 to 2018. I identified a high prevalence of multi-drug resistance (MDR) and several key AMR genes associated with predominant GNB pathogens. The neonatal intensive care unit (NICU) and the emergency room (ER) were the most prevalent hospital departments for BSIs. To gain an insight into the epidemiology of hospital-acquired (HA) BSIs and identify potential preventive measures, I conducted a further prospective study in the NICU. An increased isolation of Enterobacter spp. in the NICU during the study period suggested an outbreak, prompting an outbreak investigation of Enterobacter spp. isolates using whole genome sequencing (WGS). Identification of ER to having the highest burden of BSIs due to Enterobacter spp. demanded for an epidemiological research to understand the genomic determinants of virulence, AMR, and variations of Enterobacter spp.. To address this, I performed a comprehensive WGS analysis of Enterobacter spp. isolated in the ER.
The conclusion of my work is that BSIs due to antimicrobial resistant non-Salmonella GNB is an expanding problem in our hospital, highlighting the need for a continued AMR surveillance. I found that Enterobacter spp. was an emerging MDR pathogen causing BSIs in this hospital. The complex transmission dynamics of Enterobacter spp. observed in ER warranted for a more comprehensive genomic investigation complemented with demographic and clinical data of patients to better disaggregate the epidemiology of BSIs in ER.

Keywords: bloodstream infections
whole genome sequencing
epidemiology
antimicrobial resistance
Nepal
Enterobacter
Gram-negative bacteria
neonatal sepsis
Advisor: Karkey, A
Baker , S
Dixit, SM
The four elements of nature and narrative: from antiquity to neo-mythological Russian drama

The present thesis examines Russian twentieth-century drama composed by Innokenty Annensky, Valery Bryusov, Fyodor Sologub in the context of Classical, Medieval and contemporary philosophical and literary works, as well as in the context of visual art (archaeological, sculptural and numismatic evidence: Greek pottery and vase-painting, Greek and Roman coinage, Etruscan mirrors, Roman sarcophagi). In my thesis I adopt an intertextual approach to Russian drama in relation to Ancient Greek and Roman epic, dramatic, elegiac and mythographic traditions, which are represented as a single mythological hypertext. I attempt to show the applicability of a narratological approach to a manifestly non-narrative, i.e. performative genre, which inherits a narrative structure from the mythological plotline underlying it, and argue that a parallel system of four closely interconnected narrative elements underlies the hypertext of Annensky’s tragedies.
My thesis explores the main variants of artistic myth-making in Silver Age drama based on traditional mythological plots, projected onto contemporary life, the creation of individual systems of mythologemes and motifs, the use of temporal-chronological planes and causal-consecutive connections, and the functions of archetypal themes, images and characters (cosmos vs. chaos, hero vs. anti-hero, love vs. strife).
My thesis offers a basis for understanding Annensky’s mythological tetralogy as a cosmogonical universe based on the reception of Empedoclean principles, which accounts for the choice of mythological plots based on the four Classical elements of nature (earth, fire, water and air). Each of the four mythological dramas composed by Innokenty Annensky is conceptualised through an element, enabling the poet to explore problems of psychology and ethics by fusing the natural world with the human soul.

Keywords: Drama
Mythology
Innokenty Annensky
Narratology
Intertextuality
Advisor: Kelly, C
An exploration of regulatory T cells in transplantation: cell therapy development and immune monitoring

Regulatory T cells (Tregs) are powerful modulators of immune function, and are of increasing interest as an adoptive cellular therapy for the treatment of transplant rejection. In a number of early clinical trials, polyclonal Treg therapy has demonstrated efficacy in maintaining graft function. However, optimal Treg immunotherapy should employ alloantigen-reactive, rather than polyclonally-reactive Tregs to ensure specificity against transplant alloresponses. In the first part of this study, a method was developed to expand functional human alloantigen-reactive Tregs (arTregs). These arTregs have enhanced in vitro suppressive function and harbour more potent allospecific inhibition in comparison to polyclonally-expanded Tregs. An in-depth characterisation of arTregs is presented, providing a detailed immunophenotypic analysis. In the second part of this study, the phenotypical changes in peripheral immune cells in renal transplant patients receiving Treg therapy were assessed over time using standardised flow and mass cytometry panels. Immunophenotyping provided insights into the immune status of transplant recipients after Treg infusion. In the Treg therapy group, a distinct B cell signature of elevated transitional B cell numbers was identified. Mass cytometric characterisation of the peripheral Treg compartment in patients receiving Tregs identified an enrichment of Treg functional markers with notable changes in the expression of chemokine receptors on peripheral Tregs. In the final part of this study, cellular infiltrates in protocol renal biopsies of recipients who received Treg therapy were examined by spatial profiling and compared to rejection biopsies. This identified a unique signature of B cells, Tregs, and apoptotic regulators in the biopsies from Treg-treated patients. Further analysis revealed interesting differences between the cellular infiltrates in FOXP3hi segments from cells therapy compared with rejection such as enrichment in regulatory molecules and anti-inflammatory proteins. The findings presented in this thesis demonstrate the phenotypical and molecular processes associated with stable renal allograft in patients receiving Treg therapy, which in turn may assist in understanding the mechanisms of therapeutic immune regulation and the optimal timing for immunosuppression minimisation.

Advisor: Hester, J
Issa, F
The comparative ecology of eleven species of wheatear (genus oenanthe) in S. W. Iran 

Wheatears, genus Oenanthe, are small chat—like thrushes (family Muscicapidae, sub—family Turdinae). Eighteen species have been recognised of which four are confined to Africa while the remaining 14 have largely Palaearctic breeding distributions. They are all similar in size and morphology and some are alike in plumage. Their behaviour and ecology are also, broadly speaking, similar. They typically inhabit open, barren plains and hillsides which are often stony and boulderstrewn. They feed chiefly on insects and other small invertebrates which they catch largely on bare ground, mainly by making rapid pursuits on foot or by pouncing from elevated watch—posts. Most nest in rock crevices, under boulders or in holes in the ground. Suitable habitat is found particularly in the arid zone to which 11 of the 14 Palaearctic species are largely confined. Some species differ in their altitudinal ranges, geographical distributions and/Or habitats but the majority have contiguous or overlapping ranges so that in many areas, particularly in North Africa and the Middle East, several species occur. Indeed different species of wheatear have often been reported side by side in the same habitat.
[abstract continued in thesis]

Advisor: Lack, D
Using an aerosol human BCG infection model to define the early immune response in the lung and systemic circulation

There remains much that we do not understand about the interaction between Mycobacterium tuberculosis (M.tb) and the host immune response. Development of an effective vaccine is hampered by an incomplete understanding of the immunoprotective mechanisms, no biomarker of infection and no validated correlate of protection. Initial immune events driven by the innate system play an important role in the development of adaptive immunity and protection. This thesis describes the development of an aerosol BCG human infection challenge and demonstrates that this model is safe and well tolerated in BCG and M.tb naïve UK adults. This novel challenge model is then used to describe the initial innate and adaptive immune events at the site of infection, the airway parenchymal interface. The response is characterised by a local innate and adaptive lymphocytosis by day 7, and rapid upregulation of MHC-II antigen presentation differential gene expression pathways and Th1 effector function. There is a corresponding peak in antigen-specific IFN-y production at day 7 in the peripheral circulation, and improved mycobacterial growth control by peripheral blood mononuclear cells at day 14 on an ex-vivo functional assay. By describing underlying early immune responses to a mycobacterial airway infection in humans, this thesis provides an invaluable contribution to the field. This body of work has created a rich resource of early immune variables from which new hypotheses can be drawn for further investigation. Novel immune mechanisms, if correlated with growth control, could be used for rational tuberculosis vaccine design, to help tackle this pervasive disease.

Keywords: BCG
CHIM
Aerosol
Tuberculosis
Mucosal immunology
Innate immunology
Advisor: McShane, H
Satti, I
Some social and economic aspects of country house building in England, 1500-1640

Country houses have long been subject to the attentions of architectural historians. As a result of their labours a considerable amount of information is known about the architectural and functional developments of the period with which this study is concerned, and a beginning has been made on the biographical investigation of some of the principal craftsmen involved. But the history of the country house cannot be written solely in terms of its architecture. This is especially true of the sixteenth and early seventeenth centuries when country houses were built in such large numbers that even today there is hardly a rural parish in England which does not exhibit some evidence for a manor building of the period. The building of a country house was not just an important stage in the creation of the man-made landscape. It was equally important as a social and economic activity whose influences cannot simply be confined to the man who commissioned it, but must be extended to the artisans who built it, and indeed, to the community in which it was built.
Continued in thesis ...

Keywords: England
manors
Renaissance architecture
country house
country house building
country houses
country homes
domestic architecture
Renaissance
house building
Inferring the transmission intensity of malaria using genetic data

Despite a recent decline in prevalence, malaria still incurs a substantial burden on global health. Further progress towards elimination will require developing control strategies that are guided by detailed epidemiological surveillance. Yet, many existing surveillance approaches – including estimating parasite prevalence with community-level surveys, or tracking resistance with therapeutic efficacy studies -- are time consuming and labour intensive. There is an interest in harnessing the increasing availability of P. falciparum genetic data for surveillance, but several challenges remain outstanding. First, the relationships between genetic and epidemiological processes are poorly understood, hindering epidemiological inference from genetic data. Second, the ubiquity of mixed infections complicates analysis of malaria genetic data. Third, how the collection of genetic data can be efficiently integrated into malaria control is still being resolved.
In this thesis, we first elucidate relationships between genetic diversity statistics and epidemiological parameters affecting parasite prevalence, by developing an agent-based simulation that includes a model of parasite DNA. We find many genetic diversity statistics are correlated with parasite prevalence, but that the strength and timelines of these relationships varies. In particular, statistics related to mixed infections are strongly correlated with, and rapidly responsive to, changes in parasite prevalence.
Second, we leverage identity-by-descent patterns present within mixed infections to make inferences about the microepidemiology of malaria. We separate mixed infections comprised of two strains into those generated by a single mosquito bite (co-infection) and those generated by two mosquito bites (super-infection). Applying our approach to the Pf3k data resource, we find evidence for serial co-infection across several hosts, and show that the regional rate of serial co-infection is related to parasite prevalence.
Finally, we develop an approach to genetic data collection that can be deployed in malaria-endemic countries. Using nanopore sequencing and working with local scientists, we infer the drug resistance status of ten samples from Zambia, in-country and in two days. In addition, we present evidence suggesting the approach could be used to identify mixed infections and infer their complexity.
We end by discussing what statistical modelling approaches are most likely to permit parasite prevalence inference in the future, and outline some of the challenges associated with sequencing in the malaria-endemic world.
The n-queens problem

The famous n-queens problem asks how many ways there are to place n queens on an n × n chessboard so that no two queens can attack one another. The toroidal n-queens problem asks the same question where the board is considered on the surface of the torus and was first studied by P´olya in 1918. Let Q(n) denote the number of n-queens configurations on the classical board and T(n) the number of toroidal n-queens configurations. P´olya showed that T(n) > 0 if and only if n ≡ 1, 5 mod 6 and much more recently, in 2017, Luria showed that T(n) ≤ ((1 + o(1))ne−3)n and conjectured equality when n ≡ 1, 5 mod 6. Our main result is a proof of this conjecture, prior to which no non-trivial lower bounds were known to hold for all (sufficiently large) n ≡ 1, 5 mod 6. Furthermore, we also show that Q(n) ≥ ((1 + o(1))ne−3)n for all n ∈ N which was independently proved by Luria and Simkin. Our result counts only those configurations with at most 12 queens attacking toroidally. Combined with our main result, this completely settles a conjecture of Rivin, Vardi and Zimmerman regarding both Q(n) and T(n). Our proof combines a random greedy algorithm to count ‘almost’ configurations with a complex absorbing strategy that uses ideas from the recently developed methods of randomised algebraic construction and iterative absorption.
This is joint work with Peter Keevash.

Advisor: Keevash, P
Constitutional rights and private law: foundations

Constitutional rights and private law are on a collision course. Constitutional rights have many consequentialist aspects, grounded in collective responsibilities to bring about states of affairs amounting to social justice. Because social justice is affected by the actions and activities of private agents, constitutional rights often intrude into areas of law regulating private relations, such as tort law or contract law. The problem is that private law rights have many deontological aspects: they are grounded in personal responsibilities to treat others in certain ways regardless of considerations external to our direct relations with them.
This thesis makes the first steps in mediating these conflicting legal clusters. It sees both right-types as important parts in legal systems that try to preserve their integrity and legitimacy in conditions of moral pluralism. A delicate balance must therefore be found be-tween subordinating private law to constitutional rights and immunizing it from their scrutiny. As a first step, most constitutional rights should not entail duties for private agents, as this would risk the politicization of private relations. However, they can burden private agents indirectly, by creating state duties about the regulation of private relations.
To discharge these constitutional duties without ignoring, distorting, or eroding the relational normativity of private law rights, state agents must carefully locate public in-roads into private law in contexts in which private agents are responsible to attain or sustain social justice: sometimes personally and sometimes as part of the political collective. Such bridges from large-scale consequentialist prescriptions to small-scale interactions are not foreign to private law. But they are often undertheorized and underdeveloped. For constitutional rights to realize social justice through private law effectively, they must be broadened and placed on solid foundations. This requires connecting them to the normative features of each right-type and the conflicting moral paradigms underlying them.

Keywords: constitutional rights
responsibility
rights
private law
Defining antibiotic treatment duration and its impact on antimicrobial resistance

Reducing antibiotic treatment duration is a key stewardship intervention to mitigate antimicrobial resistance. In this thesis, I first address methodological issues introduced by non-adherence in non-inferiority trials, the commonest design for antibiotic duration randomised controlled trials. I conducted a simulation study and found that the probability of concluding non-inferiority when the treatment efficacy is actually inferior can be increased to as high as 0.1 from the acceptable 0.05 when adherence is relatively high at 90%. The simulations also highlighted the importance of anticipating patterns of non-adherence and accounting for this in power calculations. These findings were incorporated in the design of the "Reducing antibiotic treatment duration for ventilator-associated pneumonia (REGARD-VAP)" trial. The REGARD-VAP trial randomised patients with VAP to either a short (three to seven days) or a standard-of-care duration (eight days or more). The primary outcome was mortality or pneumonia recurrence by day 60. From May 2018 to July 2021, 340 patients were enrolled from seven hospitals in Nepal, Thailand, and Singapore. The second interim analysis, which included the first 231 patients, showed non-inferiority of the short duration arm based on a pre-defined Fleming-Harrington-O’Brien boundary. Adjusted analysis with inverse probability weighting suggested that a short duration was potentially superior to long duration. Lastly to examine shortened antibiotic duration as a strategy to reduce antimicrobial resistance in the hospital setting, I constructed agent-based models that incorporated within- and between-host dynamics of susceptible and resistant bacterial carriage in response to clinically-indicated antibiotic treatment. I found that shortening antibiotic duration is most effective at reducing resistance carriage in high transmission settings, and when resistant bacteria rapidly increase in abundance under antibiotic selection pressure and rapidly decrease when treatments are stopped amongst the treated individuals. A meta-analysis of antibiotic duration randomised trials showed an estimated odds ratio of 1.05 (80% credible interval 0.90 to 1.23%) with one additional day of antibiotic treatment. I conclude by discussing the future directions of the above work and the REGARD-VAP trial network.

Advisor: Cooper, B
Limmathurotsakul, D