VictorJuiz/thesis huggingface dataset:
Tracking chromatin dynamics and bimodal foxd3 mechanism on neural crest gene regulation in vivo

The neural crest (NC) is a transient embryonic stem cell-like population characterised by its multipotency and broad developmental potential. The core NC transcription factor foxd3, known to mediate late NC lineage decisions via transcriptional repression, is also pervasively expressed in the pre-migratory NC progenitors, where its putative role remains elusive.
To elucidate the mechanistic and temporal mode of foxd3 action, we analysed its genomewide binding profiles across multiple stages of zebrafish development. To this end, we have developed and used our novel biotin ChIP-seq approach allowing to specifically biotinylate factors of interest, such as foxd3 protein, in vivo. Foxd3 binding maps interpreted within the context of NC-specific transcriptional and epigenomic profiles of foxd3-mutant and control cells reveal that foxd3 acts bimodally throughout the NC ontogeny. We showed that first foxd3 functions globally as a pioneer factor to prime the onset of NC specification and migration genes by re-arranging their chromatin landscape. Strikingly, foxd3 then gradually switches from an activator to its well-described role as a transcriptional repressor and potentially uses different partners for each role.
By employing two enhancer reporter zebrafish lines, imaging and -omics tools, we have also shown that auto-regulation of foxd3 gene locus is involved during early cell-fate decisions and embryo patterning. In the cranial embryo regions, positive auto-regulatory foxd3 feedback is driving foxd3 expression that is needed for the NC and nervous system development. This auto-regulatory loop is ensured by a set of foxd3 cis-regulatory elements that exhibit NC-like regulatory signatures. Contrarily, foxd3 is auto-regulated by a different set of enhancers and, as a result, is expressed to lower levels during the apparent neuromesodermal progenitor specification in the caudal embryo regions.
Taken together, this thesis demonstrates that foxd3 needs to be tightly auto-regulated during early cell lineage decisions. Also, later in the NC development, foxd3 switches from a chromatin activator to a repressor in order to maintain NC multipotency and define its cell fates.

Keywords: gene regulation
-omics
Neural crest
embryogenesis
zebrafish
Advisor: Sauka-Spengler, T
The nature of the atonement in Athanasius

This research investigated Athanasius’ understanding of the atonement. It first orientated the reader by defending the category of ‘atonement’, briefly outlined Athanasius’ context, the goals of the study, and defended the use of a theological and textual approach rather than a historical and narrative methodology. It then proceeded by means of a sustained reading of substantial extracts from Athanasius to establish his understanding of the atonement. These explorations were organized topically, beginning with his views on creation and humanity, and then turning to his account of the fall and its progress and effects, before then examining his atonement views with regards to creation, the image, the law, and the demonic. The final chapter then summarized the main findings and explored the most important of these at some length.
There are three major findings from this research. The most evident, because it has informed the structure of the dissertation, is that Athanasius’ atonement thinking can only be understood against the backdrop of his exposition of creation, humanity, and the fall, rather than another theological topic such as the Trinity. The second is that Athanasius’ thinking on the atonement reflects fundamental principles and assumptions evident in some of his most significant topics, suggesting that this topic is also close to the heart of his theological vision. Finally, that his concept of the atonement is multivalent rather than monistic, with more than one mechanism, or ‘model’, on display. Three of these, creation, image, and law, can be compared to each other and their atoning mechanisms can be shown to operate by principles that vary along differing axis. The fourth, the demonic, is more radically different still, acting as an intensification and personification of the problem and solution matrix of the previous three categories. Athanasius’ atonement thought is irreducibly pluralistic.

Keywords: Athanasius
patristics
history of theology
atonement
Advisor: Edwards, M
Characterisation and modelling of the rate-dependent behaviour of adhesive bonded interfaces

This thesis develops a numerical and experimental framework to model and characterise the rate-dependent mechanical performance of adhesively bonded structures. Experimental methods suitable for various strain rates – including impact – enable direct measurement of mechanical properties to derive accurate adhesive interface models – such as the cohesive zone modelling approach. First, this thesis explores a newly developed experimental method. This was developed to enable the characterisation of adhesive joints for different loading rates. The method is then used to characterise the rate, fracture mode and thickness dependent behaviour of ductile adhesive inter- faces. Microstructural analysis is performed to prove the validity of the experimental measurements to calibrate cohesive zone models. These results are also used to rank two different types of adhesives: paste and film adhesive. Second, the experimental results are used to develop a cohesive zone model that captures all critical aspects of the observed phenomena. Third, fracture mechanics experiments are performed to understand the rate-dependent behaviour of similar and dissimilar material combinations. A new data acquisition method is developed for the high-rate mechanical response of the adhesive interface which relies entirely upon digital image correlation. Moreover, experiments with dissimilar material combinations provide information about the failure sequence which depends upon the loading rate regime. To the author best knowledge this is the first time that dynamic fracture mechanics experiments are performed in hybrid material adhesive structures. Finally, simulations of the experiments for both material combinations are used to validate the newly developed cohesive zone model. The ability of the model to predict cohesive failure under a wide range of strain rates and fracture modes is demonstrated. The simulations are then used to rationalise the failure performance of hybrid material adhesive joints.

Advisor: Petrinic, N
Characterisation of Hepatitis C Virus antiviral resistance in the era of direct acting antivirals

Hepatitis C Virus infects an estimated 71 million people world wide and accounts for approxi- mately 399,000 deaths per year from end stage liver failure due to cirrhosis or hepatocellular carcinoma. The development of direct acting antivirals (DAAs) has led to the elimination of the HCV infection, known as a sustained viral response (SVR) in >95% of patients who are treated. However, resistance associated substitutions (RAS) have been described for all DAAs and the presence of these RAS have been shown by multiple studies to reduce SVR rates. The aim of this work is to better characterise HCV RAS by studying the natural prevalence of RAS in a treatment naive cohort, to identify novel RAS and to study the prevalence of RAS in a cohort of patients who had not been successfully cured using first line DAA therapy and their effect on subsequent re-treatment. RAS to NS5A inhibitors in treatment naive genotype 3 (gt3) HCV infected patients are common with ∼12% of patients in a treatment naive cohort having detectable RAS. All gt3b and gt3g viruses had the A30K + L31M RAS combination, which was shown to dramatically increase the EC50 of NS5A inhibitors. Using viral genome wide association studies and whole genome HCV sequences the novel amino acid substitutions in NS2 I132V, NS2 119A NS3 67V and NS5B A150V were identified as being associated with sofosbuvir treatment failure in HCV gt3a infection. SVR rates for the retreatment of patients with prior failure to direct acting antiviral therapy are high (>89%), despite RAS being present in 71% of patients. However, the SVR rate for gt3 infected patients is significantly lower only 81%. This work demonstrates that despite SVR rates of >95% with DAA therapy, both innate resistance of understudied HCV subtypes and RAS present in treatment naive and experi- enced patients can effect treatment outcomes and should be viewed with concern particularly in patients who fail first-line therapy.

Advisor: Barnes, E
Ansari, A
Deformation and strain concentrations in coarse-grained alpha-uranium

This thesis presents an experimental characterisation of the deformation of coarse-grained cast alpha-uranium to assist the development of crystal plasticity finite element (CPFE) models.
Uranium exhibits elastic and plastic anisotropy and deforms heterogeneously via multiple slip and twinning modes. Strain concentrations that develop in the deforming grains may initiate fracture. There is an industrially-motivated drive to perform CPFE simulations that incorporate the unique properties of uranium to allow a better understanding of the conditions leading to fracture. Experiments have been performed by the author to provide data for calibration and validation of a CPFE model for cast α-uranium.
Time-of flight neutron diffraction was used to measure internal lattice strain development and texture changes during in-situ tension and compression. The coarse microstructure raises experimental challenges these are solved in a subsequent experiment. Deformation twinning causes a lattice reorientation that is detectable as a macroscopic texture change. A novel analysis was performed allowing active twinning modes to be identified from the texture changes. Twinning accounts for the observed tension-compression asymmetry in the material.
Digital image correlation (DIC) was used to measure the full-field surface strains during tensile deformation of cast uranium. The measured strains were highly heterogeneous the locations of strain concentrations were related to the crystallographic orientations measured with electron backscatter diffraction (EBSD).
The data generated in this thesis are found to be suitable to calibrate and validate a crystal plasticity model of cast α-uranium.

Keywords: neutron diffraction
mechanical testing
digital image correlation
uranium
strain concentration
Advisor: Marrow, J
Mathematical modelling of the Yeast Metabolic Cycle

The Yeast Metabolic Cycle (YMC) is an ultradian rhythm whose precise regulatory mechanism remains elusive. The YMC is a unique system that combines respiratory bursts with oscillations in both transcript levels and hundreds of metabolites in a tightly-controlled manner, creating an effective single-cell behavior that can be studied using sequencing techniques that require large quantities of cells. In this DPhil thesis I present a quantitative mathematical model of the YMC that is able to both describe the yeast synchronized metabolic activity and predict the outcome of several validating experiments.
Histone Modifications (HMs) are intimately related to gene activation and epigenetic changes regulated through chromatin organization. mRNA degradation is related to some HMs accumulation levels, and both are actively involved in the YMC regulatory mechanism. By comparing the RNA and HMs dynamics across the YMC, I have explored the functions of some HMs like H3K4me3 or H3 early-tail lysine acetylations in the yeast metabolism, discovering that H3K18ac abundance is incompatible with mRNA stability.
By clustering the yeast genome according to its expression dynamics during the YMC, I have revealed new insights into the way metabolic processes are compartmentalized at the different phases of the cycle and elucidated potential transcription factors like Met4p, Adr1p, or Thi2p, that may act as regulators of the different clusters, constituting a first attempt of unveiling the YMC regulatory mechanism.
I have employed these clusters as the cornerstone of a mathematical model describing RNA and protein dynamics at an isolated yeast cell using ordinary differential equations, concluding that a transcriptional oscillator guiding the yeast activity is more plausible that a fully metabolic oscillator.
Finally, I have combined a collection of three-component, robust, transcriptional oscillators entrained by a mean-field Hamiltonian to explain the coordination mechanisms underlying the origin and maintenance of the YMC. The resulting mathematical model is able to both replicate the YMC features described by the literature and predict the system behaviour when experimental conditions are changed or perturbations are introduced. In particular, our model explains the shape of the dissolved oxygen trace observed in the chemostat, replicates the spontaneous yeast synchronization obtained after a glucose starvation phase, and predicts the effect that carbon-source perturbations will have on the YMC.

Keywords: Computational Biochemistry
Yeast Metabolism
Data Analysis
Bioinformatics
Ultradian Rhythms
Advisor: Angel, A
Mellor, J
Nonlinear convection in sea ice and other mushy layers

The polar regions are changing dramatically. The Arctic ocean has seen an increasing fraction of young seasonal sea ice, which contains a relatively high fraction of liquid brine inclusions, and decreasing fraction of older multi-year ice. The binary mixture of solid ice crystals and liquid brine which forms sea ice is both porous and reactive, and can be classified as a mushy layer. Convection within porous sea ice rejects dense brine into the underlying ocean, where it provides an important buoyancy forcing, and circulates nutrients within the ice with consequences for the local biogeochemistry. In this thesis I aim to build understanding of convective processes within sea ice and other mushy layers. I develop a code for direct numerical simulations in two and three dimensions, which uses adaptive mesh refinement to efficiently resolve the key dynamical features across multiple scales by solving mesoscopic conservation equations. This code is then applied to a variety of settings, whilst focussing on the relatively unexplored far-from eutectic limit which is particularly relevant to sea ice. In this far-from eutectic limit the porosity is small except for a narrow porous layer near the mush-liquid boundary. New scaling laws are found for steady-state growth, where the convection is confined to this porous layer whilst the mush-liquid solute flux scales sublinearly with the Rayleigh number - a dimensionless parameter which characterises the ratio of buoyancy to dissipative forces. Simulations of transient growth from a fixed boundary provide new insights into the dynamics and spacing of brine channels, and I find that flow in 3-D is qualitatively similar to 2-D. Meanwhile, I find evidence that convection within warming sea ice may lead to periods of intense salt fluxes into the ocean. These results have important geophysical implications for the dynamics and biogeochemistry of the polar regions.

Keywords: fluid dynamics
adaptive mesh refinement
climate
sea ice
mushy layer
Advisor: Wells, A
Consequences of presynaptic dysfunction in Alzheimer’s Disease models

Soluble oligomeric assemblies of amyloid β (Aβo) drive much of Alzheimer’s disease (AD) pathology. Among these, changes in synaptic plasticity including attenuated long-term potentiation (LTP), and facilitated long-term depression (LTD), accompanied by postsynaptic weakening, are believed to be significant contributors to disease progression. Much work has been directed at characterising the postsynaptic effects of oligomers, with little or conflicting evidence of their impact at the presynaptic bouton. Some studies investigating presynaptic boutons directly, have suggested that Aβo elevate presynaptic transmitter release. Given that transmitter release precedes postsynaptic processes, an alteration in presynaptic biology could drive postsynaptic pathology. One important downstream process of AD pathology is tau hyperphosphorylation. The relationship between Aβo and tau phosphorylation is unknown. Recent evidence that tau plays a physiological role in AMPAR endocytosis as a result of LTD induction might provide a link between tau phosphorylation and Aβo-induced synaptic changes. Here I probe the presynaptic effects of Aβo and how they impact AD pathogenesis. I confirm that Aβo can enhance both evoked, and non-evoked spontaneous miniature presynaptic release using direct, optical techniques in rat hippocampal cultures. Furthermore, I show that partial reduction in presynaptic function can restore Aβo-induced plasticity deficits in adult mouse acute hippocampal slices. I also demonstrate that these plasticity deficits might underly tau pathology; In rat organotypic slices I show that chronic NMDAR-dependent LTD can cause pathological tau phosphorylation, mimicking the effects of chronic Aβo incubation, which also requires NMDARs. In addition, I show that reduction in presynaptic function prevents Aβo-induced pathological tau phosphorylation, suggesting that the pathological tau phosphorylation that occurs in AD could be a result of repeated LTD-inducing conditions driven by an enhancement of presynaptic release probability. Previously, little work has been done to establish a role for presynaptic changes in AD. I have developed this area within the thesis and have established a link between aberrant Aβo aggregation and pathological tau phosphorylation that could have an important impact on AD therapy.

Keywords: Alzheimer's Disease
Tau
Synaptic plasticity
Amyloid β
Advisor: Emptage, N
Galione, A
Theory of specialisations

This thesis aims to develop a theory of specialisations for Zariski structures. The main question this thesis is centred around is when is a specialisation is κ-universal?
In Chapter 3 we look at the case of algebraically closed fields and Zariski structures definable in these. We show that any specialisation of an algebraically closed field defines a residue map of a valuation ring, and moreover we show that any residue map induces a κ-universal specialisation whenever the algebraically closed field is κ-saturated over the residue field.
In Chapters 4 and 5 we look at the κ-universal specialisations of finite and infinite covers of Zariski structures. Under some natural assumptions we show that a specialisation of a cover of a Zariski structure is κ-universal if and only if it extends a κ-universal specialisation of a base Zariski structures and satisfies a simple axiom.

Keywords: Model Theroy
Valued fields
Specialisations
Zariski geometries
Zariski structures
Advisor: Zilber, B
Searching for Beyond the Standard Model resonances in the HH → bb̄bb̄ final state using the ATLAS detector

An ATLAS analysis searching for Beyond the Standard Model resonances, X, that are produced and decay through the pp → X → HH → bb̄bb̄ process is presented. These events are studied in the phase space region where the four b-quarks produce four well-separated jets.
A significantly stronger upper-limit is set on the pp → X → HH cross-section for these resonances than was set by the Early Run 2 ATLAS analysis. Above 350 GeV these limits are also stronger than those of the combination of all ATLAS di-Higgs searches with 27.5 fb-1 to 36.1 fb-1 of data. No statistically significant excesses are found, with the largest excess having a global significance of 1.2+0.4−0.3 σ. In particular, with an improved pairing algorithm and more sophisticated background modelling, the 2.8σ excess found at 280 GeV by the Early Run 2 analysis is not confirmed. The results of this analysis suggest the upcoming version, which uses an evolution of the same technique on the same data to look for Standard Model di-Higgs production, will be able to set stringent limits on that process.

Keywords: HH-&gt;4b
HH
HH4b
di-Higgs
ATLAS
Scalar resonance
Exotics
Higgs
Scalar
4b
HDBS
Advisor: Frost, J
Issever, C
Huffman, BT
Information theory and banking

This thesis uses information theory to study policy questions in banking, finance, and industrial organization. It consists of four independent papers.
The first paper, “Time Inconsistency in Stress Test Design”, shows that central banks face a time inconsistency problem when publishing bank stress test results. Before a stress test, they want to appear tough as the threat of letting banks fail the stress test incentivizes prudent behaviour. After the stress test, they want to act soft by releasing only partial information in order to reassure financial markets about bank health. The paper characterises an institutional design solution to this commitment problem: a social planner sets the framework within which the central bank communicates. We find that a hurdle rate framework, where all banks are judged to pass or fail relative to a common threshold, is optimal in many settings as it generates intermediate levels of both incentives and reassurance. We show that, in such a hurdle rate framework, stress tests become an informational contagion channel.
The second paper proposes a model of imperfect competition in markets with selection and investigates whether imperfect competition mitigates the inefficiency which, in these markets, arises under perfect competition. Focusing on markets with advantageous selection, such as consumer credit markets, we find that no degree of competition can restore the first best efficient allocation. We discuss policy alternatives.
The third paper shows that, in markets with adverse selection, tying contracts can prevent unravelling and thus have a substantial positive effect on welfare. We illustrate this effect for two insurance markets. When one characteristic (such as life-expectancy) is hidden information and causes agents to have high expected cost for one product (life insurance) but low expected cost for another (pension annuity), then for tying contracts cost differences partially cancel out. This can prevent unravelling.
In the fourth paper, which is joined work, we build on a field experiment, find that some agents increase effort when it becomes more costly, and rationalize this in a signalling model. In the field setting, agents also choose whether to truthfully disclose their effort. The data on this form of strategic communication adds further support to the interpretation that effort choices are driven by signalling motives.

Keywords: banking
imperfect competition
stress tests
strategic communication
insurance
tying contracts
selection markets
central bank design
Advisor: Vickers, J