VictorJuiz/thesis huggingface dataset:
Molecular mechanisms of recombination hotspots in humans

Meiotic recombination involves the exchange of DNA between two homologous chromosomes, forming cross-overs and gene conversion events. The cross-over process is important for the proper segregation of chromosomes during meiosis, and drives genetic diversity. Human hotspots are enriched for a 13-bp motif, CCNCCNTNNCCNC; a close match to this motif occurs in about 40% of our cross-over hotspots. A DNA binding protein called PRDM9, having histone trimethyltransferase (H3K4me3) activity, binds the motif and is becoming established as a major determinant of recombination hotspots (narrow regions with high cross-over activity). This research aimed to understand the mechanisms involved in promoting PRDM9 binding to its target sites, and subsequently, initiating cross-over hotspot activity.
We first explored the relationship between PRDM9 binding and DNA sequence, to directly confirm whether PRDM9 binds to the 13-bp hotspot motif using in-vitro gel-shift assays, and found that it does bind sequence specifically to the canonical 13-mer motif. PRDM9 is able to bind the motif in a highly selective manner, with certain single base pair changes abolishing binding. However, we observe that it is also able to tolerate degeneracy in its binding sites, as demonstrated by strong in-vitro binding to degenerate versions of the 13-bp motif. Hence, these results confirmed that PRDM9 is able to directly bind to the 13-bp hotspot motifs, and given that it can also tolerate degeneracy, this raised the question of why PRDM9 is able to bind only a subset of all such potential binding sites in the genome.
To address this, a ChIP-seq analysis was performed to identify genome wide binding sites for PRDM9. This information also helped us to characterise binding sites and investigate if factors such as the local chromatin environment play a role in specifying PRDM9 binding tar- gets and hotspot formation. We were able to identify over 170,000 PRDM9 binding sites in the genome. Surprisingly, these binding sites were also enriched in promoter regions, however, bound sites in these regulatory regions showed low recombination activity. We found that PRDM9 is able to confer the H3K4me3 mark on all bound sites, even those without a pre-existing H3K4me2 mark. We also investigated the role of other chromatin related marks on PRDM9 binding and found that binding occurs in chromatin accessible, but nucleosome rich regions, whereas heterochromatin regions tend to inhibit binding. Further, for hotspot formation, it was seen that less chromatin accessible, nucleosome dense regions away from transcribed sites, are preferred. Hotspots tend to avoid regions marked by transcription activating histone modifications, however, these regions do not appear to inhibit PRDM9 binding itself. These results show how PRDM9 binding in the genome is dependent on both primary DNA sequence and the surrounding epigenetic factors. Together these factors promote binding and, with additional downstream factors, positioning of hotspot locations in the human genome.

Keywords: meiotic recombination hotspots
PRDM9
Advisor: Myers, S
Knight, J
McVean, G
Food for thought: genetic, historical and ethnobotanical studies of taro Colocasia esculenta (L.) Schott in Africa

The presence of exotic plants both in Africa and in Asia has long attracted the attention of scholars who have attempted to understand the human activities linked to them. Archaeological and ethnographic evidence for the reconstruction of these activities is often very limited, but indirect methods such as the study of DNA have become useful tools in building models of early human dispersal. Among the plants that were carried across the Indian Ocean, sometimes known as the “tropical food kit”, the staple crop taro (Colocasia esculenta (L.) Schott) has continued to be the subject of ongoing research. The use of this crop in antiquity is well documented by discoveries of ancient taro starch granules found on archaeological artefacts from sites in Southeast Asia and the Pacific islands, making it one of the oldest plants consumed by people. However, less is known about the use of taro in Africa and the Mediterranean region, where it is found both in the wild and under cultivation - often representing a staple crop in Sub-Saharan Africa. In this doctoral thesis, genetic analysis was performed on modern samples of taro collected from Africa and other regions of the Indian Ocean, using four molecular markers. Two main clusters have been identified, and within this main sub-division four populations of taro have been detected in Africa. By integrating the genetic results with historical and linguistic research, and extensive ethnobotanical fieldwork in Africa, two of these populations are proposed to represent early translocations, with modern distribution patterns suggesting diverse dispersal routes at different times. These results open up a new scenario in which the “tropical food kit” is finally unpacked, with important historical implications for each of the crops contained within it.

Keywords: arum
ouingon
taro
Africa
Colocasia esculenta
Asian crop
Advisor: Boivin, N
Quasi-phase-matching of high-harmonic generation

This thesis describes the use of counterpropagating pulse trains to quasi-phase-match high-harmonic generation (HHG).
Two novel techniques for generating trains of ultrafast pulses are described and demonstrated. The first method makes use of a birefringent crystal array to split a single pulse into a sequence of pulses. The second method makes use of the time-varying polarisation of a chirped pulse passed through a multiple-order wave plate to generate a train of pulses by the addition of a polariser. It is demonstrated that this second technique can be used to make pulse trains with non-uniform pulse separation by using an acousto-optic programmable dispersive filter to manipulate the higher-order dispersion encountered by the chirped pulse.
The crystal array method is used to demonstrate quasi-phase-matching of HHG in a gas-filled capillary, using one and two counterpropagating pulses. Enhancements of up to 60% of the intensity of the 27th harmonic of the 800,nm driving laser light are observed. Information on the spatial and dynamic properties of the HHG process is obtained from measurements of the coherence length in the capillary.
Simulations of HHG in a capillary waveguide have been performed. These agree well with the results of the quasi-phase-matching experiments. The effect of mode-beating on the generation process in a capillary and its use as a quasi-phase-matching mechanism are investigated.

Keywords: waveguides
high harmonic generation
mode beating
femtosecond
ultrafast optics
quasi phase matching
pulse shaping
Advisor: Hooker, S
High dimensional American options

Pricing single asset American options is a hard problem in mathematical finance. There are no closed form solutions available (apart from in the case of the perpetual option), so many approximations and numerical techniques have been developed. Pricing multi–asset (high dimensional) American options is still more difficult. We extend the method proposed theoretically by Glasserman and Yu (2004) by employing regression basis functions that are martingales under geometric Brownian motion. This results in more accurate Monte Carlo simulations, and computationally cheap lower and upper bounds to the American option price. We have implemented these models in QuantLib, the open–source derivatives pricing library. The code for many of the models discussed in this thesis can be downloaded from quantlib.org as part of a practical pricing and risk management library. We propose a new type of multi–asset option, the “Radial Barrier Option” for which we find analytic solutions. This is a barrier style option that pays out when a barrier, which is a function of the assets and their correlations, is hit. This is a useful benchmark test case for Monte Carlo simulations and may be of use in approximating multi–asset American options. We use Laplace transforms in this analysis which can be applied to give analytic results for the hitting times of Bessel processes. We investigate the asymptotic solution of the single asset Black–Scholes–Merton equation in the case of low volatility. This analysis explains the success of some American option approximations, and has the potential to be extended to basket options.
Cooperative, range-based localization for mobile sensors

This thesis describes the development of an offline, cooperative, range-based localization algorithm for use in settings where there is limited or no access to a positioning infrastructure. Motivating applications include underground animal tracking and indoor pedestrian localization. It is assumed that each sensor performs dead reckoning to estimate its current position, relative to a starting point. Each measurement adds error, causing the position estimate to drift further from the truth with time. The key idea behind the proposed algorithm is to use opportunistic radio contacts to mitigate this drift, and hence localize with greater accuracy.
The proposed algorithm first fuses radio and motion measurements into a compact graph. This graph encodes key positions along sensor trajectories as vertices, and distance measurements as edges. In so doing, localization is cast as the graph realization problem: assigning coordinates to vertices, in such a way that satisfies the observed distance measurements. The graph is first analysed to certify whether it defines a localization problem with a unique solution. Then, several algorithms are used to estimate the vertex coordinates. These vertex coordinates are then used to apply piecewise corrections to each sensor's dead reckoning trajectory to mitigate drift. Finally, if sufficient anchors are available, the corrected trajectories are then projected into a global coordinate frame.
The proposed algorithm is evaluated in simulation for the problem of indoor pedestrian tracking, using realistic error models. The results show firstly that 2D and 3D problems become provably more localizable as more anchors are used, and as the experiment duration increases. Secondly, it is shown that widely-used graph realization algorithms cannot be used for localization, as the complexity of these algorithms scales polynomially or greater with graph vertex count. Thirdly, it is shown a novel piecewise drift correction algorithm typically works well compared to a competing approach from the literature, but rare and identifiable graph configurations may cause the method to underperform.

Keywords: mobile
cooperative
tracking
localization
sensor
Advisor: Trigoni, N
Investigating the role of ADAM10 and ADAM17 in cetuximab resistance in head and neck squamous cell carcinoma

Epithermal Growth Factor Receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC). Cetuximab is the first and the only anti-EGFR monoclonal antibody which received approval from FDA for the treatment of HNSCC. However, most patients either do not respond to cetuximab or develop acquired resistance. The aim of my D.Phil. study was to investigate the role of ADAM10 and 17 in resistance mechanisms of cetuximab in HNSCC. Chronic exposure to cetuximab led to an activation of HER receptors and downstream signalling pathways in HNSCC cell lines. Higher levels of ADAM10 and 17 and their substrates, BTC and NRG-1 were found in cetuximab resistant cells compared to their parental cells, suggesting the involvement of ADAM-mediated ligands’ release in reactivation of HER receptors. Inhibition or knockdown of ADAM10 and 17 enhanced cetuximab response and reversed cetuximab resistance in HNSCC cells. In addition, results from this study showed that the combination of cetuximab with EGFR-TKIs had greater effect in parental cells and reversed cetuximab resistance in HNSCC cells. Upregulation of ADAM10 and 17 also was observed in HNSCC TMAs compared to normal head and neck TMAs. High nuclear ADAM10 and cytoplasmic ADAM17 expression levels were associated with shorter DFS. By evaluating tumour excision samples from HNSCC patients who underwent a cetuximab window study high ADAM10 and 17 expression levels were found to be associated with poor response to cetuximab. In conclusion cetuximab-induced ADAM-mediated ligands’ release is a potential mechanism of resistance to cetuximab in HNSCC. Thus, targeting ADAM10/17 or subsequent HER activations may represent an important strategy in overcoming resistance to cetuximab in HNSCC. Results from this study also suggest the implication of ADAM10 and 17 as potential prognostic and predictive biomarkers in HNSCC although further validation is required.

Keywords: ADAM10
resistance
ADAM17
cetuximab
Advisor: Seymour, L
Kong, A
Roxanis, I
The growth of fringe benefit provision

Social scientists interested in labour costs, the labour market, the distribution of income, class structure, social policy, the sociology of work and organisations have all had some view of fringe benefits. This is the first attempt to offer a sociological study of the causes of the growth and distribution of benefits, and their role in the labour market, the employing organisation and the class structure. It offers (a) a systematic - and so far as the available data permit - comprehensive, survey of the fringe benefits provided to employees at all levels of the enterprise in the private sector since 1945 (b) a sociological interpretation of these provisions and of such changes as are overtaking, them, (c) consideration of what wider significance, if any, the inquiry has for an advanced industrial society like our own.
In Chapter 1 approaches by social scientists to fringe benefit provision are considered and a definition of benefits developed. Chapter 2 develops a theoretical framework stressing the importance of both structure and action. Chapter 3 links the ideas of Chapter 2 with the empirical material in the main body of the thesis.
Chapter 4 describes the growth of benefits in Britain since the war, while Chapters 5, 6 and 7 consider their distribution by occupation, size of company and industry.
In Chapter 8 the ideologies and practices of employers regarding benefit provision are examined. Chapter 9 considers ideologies and practices of trade unions and the TUG while Chapter 10 investigates how Government action has affected benefit provision, Chapter 11 analyses the responses of employees to benefits.
The main conclusions are:
(i) benefit provision has grown differentially since the war mainly because of different benefit policies adopted by employers towards manual workers, routine white collar workers and managers. In this employers have been influenced by a number of factors including Government, and less so trade unions, size of company and industry.
(ii) on the basis of inadequate data it is hypothesised that benefits rarely increase the integration of the manual worker, are not very important to the routine white collar worker, but are often financially valuable to the senior manager.
(iii) It is hypothesised that benefits have had little effect on freedom of choice, done little to increase social order and integration in the firm, but have undermined redistributional measures taken by Governments, and influenced the principles on which social policy is based.
The metabolic context for virulence in Pseudomonas syringae

The apoplast is the site of infection for many important bacterial crop pathogens, including the model pathogen Pseudomonas syringae pv. tomato DC3000 (Pst DC3000). The chemical environment within the plant apoplast can determine the outcome of bacterial infection and the composition of this compartment is known to change in response to the presence of invading organisms. However, this metabolically dynamic environment has received little attention in the literature, and even less is known about how metabolites in the apoplast influence the expression of virulence genes.
In this study, several aspects of the metabolic context of virulence were assessed. First, a broad-scale analysis of the tomato apoplast was undertaken, which identified metal ions, sugars, organic acids and amino acids, the most abundant of which was the non-protein amino acid gamma-aminobutyric acid (GABA). The impact these components had on the expression of virulence genes and metabolism in Pst DC3000 were then tested. Components such as fructose and aspartate caused high levels of virulence gene expression which correlated with the accumulation of intracellular glutamate, whereas repressive components, such as GABA and threonine, resulted in lower glutamate levels. Second, metabolic flux analysis showed that Pst DC3000 underwent major changes in central carbon metabolism in response to virulence gene inducing conditions. The identification of altered internal metabolism in Pst DC3000 cells expressing virulence genes led to the conclusion that Pst DC3000 may understand its external environment by sensing intracellular metabolites or metabolic fluxes. Third, the role of GABA assimilation in virulence was explored, and it was found that high internal GABA levels resulted in virulence gene repression. In addition, previously unidentified mechanisms for GABA uptake and transport were detected by the use of a novel ‘unlabelling’ experiment.

Keywords: Pseudomonas syringae
Plant pathology
GABA
bacterial metabolism
Advisor: Preston, G
Śaṅkara's soteriological tradition

This study attempts to show that an appeal to the 'perspective of the witness' is essential to better understand the way Sankara makes sense of the richly diverse Vedanta material. It goes beyond the general understanding that Sankara 'conveniently' arranges such material into the categories of the conventional and the absolute placing texts speaking of the Absolute (Brahman) with properties in the conventional/relative category. It suggests that the fundamental properties associated with a theistic conceptualisation of the Absolute, which all authoritative texts attest to, need not be seen as dogmatic tenets that Sankara has to contend with while expounding his non-dual system of thought. Instead, it argues that they should be regarded as meaningful devices that have for their sole purpose to lead the spiritual seeker to the realization of the absolute unity of being, a result that the Advaita tradition holds as the highest goal of life. Three key conceptions of Brahman are explored: Brahman as the cause of the world, as an entity who is gracious towards his devotees, and as an object of devotion. It is argued that all three can be better understood and appreciated when considered in their proper and larger pedagogical context, whose climax is 'the perspective of the witness.' The first three chapters of this thesis are mainly concerned with epistemological and didactic means that are associated with demonstrating the 'perspective of the witness.' The fourth and fifth chapters evaluate how much help such a standpoint can provide us in our appraisal of these three aspects of the Absolute in the context of Sarikara's writings.

Advisor: Clooney, F
Cosmological tests of general relativity

Understanding the apparent accelerating expansion rate of the universe is a challenge for modern cosmology. One category of explanations is that we are using the wrong gravitational physics to study the observations. Our paradigmatic theory of gravity – Einstein’s theory of General Relativity – may be subsumed by a larger theory.
This thesis develops a selection of tools for testing General Relativity and the numerous alternative theories of gravity that have been put forward. I advocate that an elegant and efficient way to test this space of theories is through the use of parameterized frameworks. Inspired by the Parameterized Post-Newtonian framework I develop a new formalism, the Parameterized Post-Friedmann formalism, that aims to unify the linear cosmological perturbation theory of many alternatives to General Relativity.
Having introduced the Parameterized Post-Friedmann formalism and demonstrated its application via a suite of examples, I examine several issues surrounding parameterized tests of gravity. I first consider how the structure of a parameterization can influence the constraints obtainable from a given set of data. I then consider how to describe the growth of the large-scale structure of the universe in a parameterized manner. This leads to a convenient tool for calculating corrections to the growth rate of structure in modified theories, which can be used both with the Parameterized Post-Friedmann formalism or independently of it. I present forecasts for how well generalized deviations from General Relativity will be constrained by the next generation of galaxy surveys.
Throughout, this thesis aims to take a synoptic approach to theories of modified gravity, rather than focussing on specific models. A question yet to be answered is whether this approach is realistic in practical terms. The final part of this thesis takes the first steps towards an answer.

Keywords: gravity
cosmology
general relativity
Advisor: Ferreira, P
Prediction of extreme wave-structure interactions for multi-columned structures in deep water

With a continuing and rising demand for hydrocarbons, the energy companies are installing infrastructure ever further offshore, where such infrastructure is often exposed to extreme waves. This thesis explores some aspects of wave-structure interaction, particularly the maximum water surface elevation increase in severe storms due to these local interactions.
The effects on wave-structure interactions of column cross-sectional shape are investigated using linear and second-order wave diffraction theory. For multi-column structures, the excitation of locally resonant wave modes (near-trapping) is studied for several column cross-sectional shapes, and a simple method for estimating the surface elevation mode shape is given. The structure of the quadratic transfer functions for second-order sum wave elevation is investigated and an approximation assuming these QTFs are flat perpendicular to the leading diagonal is shown to be adequate for the first few lowest frequency modes.
NewWave-type focused wave groups can be used as a more realistic model of extreme ocean waves. A Net Amplification Factor based on the NewWave model is given as an efficient tool for finding the incident frequencies most likely to cause a violent wave-structure interaction and where these violent responses are likely to occur. Statistics are collected from Monte Carlo type simulations of random waves to verify the use of the Net Amplification Factor. Going beyond linear calculations, surface elevation statistics are collected to second-order and a desig≠r′waveisfound→modelthemostextremesurfacee≤vationresponses.Adesigner' wave can be identified at required levels of return period to help to understand the relative size of harmonic components in extreme waves.
The methods developed with a fixed body are then applied to an identical hull which is freely floating, and the responses between the fixed and moving cases are compared. The vertical heave motion of a semi-submersible in-phase with the incident wave crests is shown to lead to a much lower probability of water-deck impact for the same hull shape restrained vertically. The signal processing methods developed are also applied to a single column to allow comparison with experimental results. Individual harmonic components of the hydrodynamic force are identified up to at least the fifth harmonic. Stokes scaling is shown to hold even for the most violent interactions. It is also shown that the higher harmonic components of the hydrodynamic force can be reconstructed from just the fundamental force time history, and a transfer function in the form of a single phase and an amplitude for each harmonic. The force is also reconstructed well to second-order from the surface elevation time history using diffraction transfer functions. Finally, possible causes of damage to a platform high above mean water level in the North Sea are investigated.

Keywords: NewWave
ocean waves
offshore engineering
second-order
diffraction
Advisor: Taylor, P
Eatock Taylor, R