VictorJuiz/thesis huggingface dataset:
Improved methods for serial femtosecond crystallography reduction

X-ray free electron lasers (XFELs) are a young technology which alleviates a number of issues, including radiation damage, which remain problematic in conventional macromolecular X-ray crystallography. As it turned out, existing methods had been optimised for synchrotron-based rotation data and coped poorly with snapshot XFEL diffraction images. In the first four results chapters, I present algorithms developed in my efforts to contribute to improved data reduction for XFEL analysis. In order of execution, these are: detector geometry refinement, indexing, initial orientation matrix refinement and post-refinement. Geometry refinement has been a field plagued with the problem of correlated parameters. I introduce the "slip-and-slide" algorithm to solve this by reparameterising detector movements based on their effect on diffraction. I developed an indexing algorithm, TakeTwo, to reduce diffraction pattern wastage by maximising information content on a single image. Initial orientation matrix refinement aims to reduce, without any prior reference, errors of a crystal model from its own information content. When an approximate solution is available, one may implement post-refinement, which, in combination with a model describing the partial illumination of each reflection, drives the model parameters towards a self-consistent data set. In the final results chapter, I present an example of how the combination of all of these algorithms can push the information quality to new levels, illustrated by merging XFEL diffraction collected from scarce quantities of bovine enterovirus type 2 crystals and demonstrating the power of the amplitudes to drive phase extension. I end the thesis with a discussion of the realistic impact of these algorithms, the directions that methods developer communities could take from here onwards, and my personal scientific direction for the future.

Advisor: Stuart, D
Evans, G
The relationship between DNA modifications and mutations in cancer

Somatic mutations are the main triggers that initiate the formation of cancer. Large sequencing data sets in recent years revealed a substantial number of mutational processes, many of which are poorly understood or of completely unknown aetiology. These mutational processes leave characteristic sequence patterns, often called "signatures", in the DNA. Characterisation of the mutational patterns observed in cancer patients with respect to different genomic features and processes can help to unravel the aetiology and mechanisms of mutagenesis. Here, we explored the effects of DNA modifications and DNA replication on mutagenesis.
The most common mutation type, C&GT;T mutations in a CpG context, is thought to result from spontaneous deamination of 5-methylcytosine (5mC), the major DNA modification. Much less is known about the mutational properties of the second most frequent modification, 5-hydroxymethylcytosine (5hmC). Integrating multiple genomic data sets, we demonstrate a twofold lower mutagenicity of 5hmC compared to 5mC, present across multiple tissues.
Subsequently, we show how DNA modifications may modulate various mutational processes. In addition to spontaneous deamination of 5mC, our analysis suggests a key role of replication in CpG>TpG mutagenesis in patients deficient in post-replicative proofreading or repair, and possibly also in other cancer patients. Together with an analysis of mutation patterns observed in cancers exposed to UV light, tobacco smoke, or editing by APOBEC enzymes, the results show that the role of DNA modifications goes beyond the well-known spontaneous deamination of 5mC.
Finally, we explored which of the known mutational processes might be modulated by DNA replication. We developed a novel method to quantify the magnitude of strand asymmetry of different mutational signatures in individual patients followed by evaluation of these exposures in early and late replicating regions. More than 75 % of mutational signatures exhibited a significant replication strand asymmetry or correlation with replication timing. The analysis gives new insights into mechanisms of mutagenicity in multiple signatures, particularly the so far enigmatic signature 17, where we suggest an involvement of oxidative damage in its aetiology. In conclusion, our results suggest that DNA replication or replication-associated DNA repair interacts with most mutagenic processes.

Keywords: 5-hydroxymethylcytosine
5-methylcytosine
mutation
mutational signature
Advisor: Schuster-Boeckler, B
Kriaucionis, S
Colour word and colour category learning in infants and toddlers

This thesis examines how and when infants learn colour words, and how the knowledge of colour words affects their comprehension of colour categories. Over the course of seven experimental chapters, the ability of infants and toddlers to learn colour words, use colour words to process colours, and the role that colour words play in learning to perceive colour are all assessed. Chapters 2 and 3 assess claims that colour words are learned late using parental report and eye-tracking methods, finding that colour words are learned as early as 19 months. In contrast to this, Chapter 4 demonstrates that toddlers do not learn to modify colour words as dark or light until much later. Chapter 5 demonstrates that colour words are a crucial component for processing the colours of objects, showing that infants do not look to a colour-matched object unless they comprehend the colour word. Chapters 6 and 7 employ novel paradigms to explore categorical processing of colour, finding that infants have a preference for within-category colours, but that this has no effect on their attention to dynamic coloured stimuli. In Chapter 8, a prototype for an infant colour vision test is shown, demonstrating that the second year of life is crucial for development of visual closure. The generalisability of these results to infant perception and word learning is also discussed.

Advisor: Plunkett, K
Husband, E
A grammar of Wano

This thesis is a descriptive analysis of Wano, a Trans-New Guinea language found in West Papua which is spoken by approximately 7,000 native speakers. The thesis includes: (i) an introduction of Wano topography and demography; a brief ethnographic sketch; some sociolinguistic issues such as name taboo, counting system and kinship terms; and typological profile of the language in chapter 1; (ii) morphophonological properties in chapter 2; (iii) forms and functions of nouns in chapter 3; (iv) verbs in chapter 4; (v) deixis in chapter 5; (vi) clause elements in chapter 6; and (vii) intransitive/transitive non-verbal predication in chapter 7; (viii) clause combination is consecutively observed in terms of coordination and subordination in chapter 8; serial verb constructions in chapter 9; clause linking in chapter 10; and bridging linkage in chapter 11. Chapter 12 sums-up the overall thesis.
Wano has 11 consonantal and 5 vocalic phonemes expressed through their allophonic variations, consonantal assimilation and vocalic diphthongs. The only fricative phoneme attested is bilabial fricative /β/. There are two open and two closed syllable patterns where all consonants are syllable-onset, while approximants can also be syllable-coda. Vowels are syllable-nucleus. Stress is syllable-final which will be penultimate in cliticization. The phonology-morphology interface provides a significant contribution to the shaping of conjugational verbs, which, in turn, plays an essential role to an understanding of Wano verbal system where distinction between roots, stems, citation forms, sequential forms and tense-aspect-mood is defined.
Wano is a polysynthetic language that displays an agglutinative-fusional morphology. Although the alienable-inalienable noun distinction is essentially simple in its morphology, the sex-distinction of the possessor between kin terms allows room for semantic-pragmatic complexity in the interpretation of their various uses. Wano has four non-verbal predications, consists of experiential event, nominal, adjectival, and deictic predicates. Wano is a verb-final language that allows pronominal pro-drop and has no rigid word order for arguments. A clause may consist only of (i) a single verb, (ii) a single inalienable noun, (iii) a serial verb construction, (iv) a combination of an inalienable noun with a verb, and or (v) a combination of an inalienable noun with a serial verb construction. To maintain discourse coherency, Wano makes use of tail-head linkage construction. The thesis consists of: pre-sections (i-xxxiii), contents (1-478), bibliography (479-498), and appendices (499-594) that include verb paradigms, noun paradigms, some oral texts and dialectal wordlist.

Keywords: Wano
Descriptive
Willem Burung
Grammar
Papuan language
Trans-New Guinea languages
Advisor: Dalrymple, M
The regulation of Mps1 kinase during mitosis

The spindle assembly checkpoint (SAC), a conserved surveillance system, ensures genomic stability by delaying anaphase entry until all sister chromatids are attached to the mitotic spindle. The SAC network is active at unattached kinetochores and a complex signalling cascade culminates in the production of a diffusible ‘wait anaphase’ signal. Regulation of protein:protein interactions by reversible phosphorylation is critical in this signalling pathway. The checkpoint kinase Mps1, a central regulator of the SAC, plays a positive role in enabling protein interactions. Mps1 builds the SAC network by phosphorylating multiple kinetochore targets and in doing so it coordinates mitotic exit with microtubule binding. Given the critical role Mps1 plays in SAC activation, precise regulation of the activity and localisation of Mps1 must be key in controlling the activation status of the SAC.
Mps1 binds to unattached kinetochores and is activated by autophosphorylation of its T-loop. However, once chromosomes are attached to the spindle and the SAC is satisfied Mps1 is switched off. The mechanisms controlling the inactivation of Mps1 were unknown. Here, it is shown that phosphorylation of T676, located on the activation loop of Mps1, is important in controlling Mps1 activity and SAC signalling. A PP2A-B56 phosphatase complex opposes Mps1 activation by directly dephosphorylating its activation loop both in vitro and in vivo. The interaction of PP2A-B56 with BubR1 is essential for this dephosphorylation event. Moreover, preliminary results from experiments combining Mps1 immunoprecipitations with mass spectrometry indicate that phosphate groups are globally lost from Mps1 when the SAC is inactive. The binding of interaction partners is a common mechanism used by kinases to regulate their function. Knl1 is present in Mps1 complexes by immunoprecipitation and mass spectrometry. While these results are still preliminary it is clear from siRNA depletion that Knl1 plays a previously unidentified role in regulating the localisation of Mps1. Together, these results signify an important advance in our knowledge of how the function of Mps1 is controlled.

Advisor: Gruneberg, U
Neural mechanisms underlying advanced cognition in humans

Humans have a remarkable capacity for generalizing experiences to novel situations. In a brain network that has expanded the most during mammalian evolution, known as the default mode network, grid cells and place cells organize spatial representations into mental maps. The aim of this thesis is to use non-invasive functional magnetic resonance imaging and computational analyses to test how well-understood codes at the single-cell level in animals also generalize to complex human behaviours.
We first asked how brain mechanisms used for spatial navigation help us understand non- spatial cognition. We designed an equivalent computer task to the one used for real spatial navigation, but in an abstract space. Next, we tested for hexagonal signals using the same analyses as those developed for navigation in physical space. We found hexagonal grid- like signals in the same brain network for navigating in conceptual space and in physical space. This suggests that the brain organizes concepts into a mental map, allowing conceptual relationships to be navigated in a manner similar to that of space.
Next, we aimed to develop a new analysis method that is closer to electrophysiology, and thus could detect gradients in place and grid-cell coding of physical space with neuroimaging. We show that our analysis can detect such gradients in simulated data. Moreover, using a big data approach, we found behavioural evidence that humans form precise maps of our environment. We also show preliminary evidence of neural patterns at submillimeter resolution, suggestive of place and grid-cell coding. Such analyses open the possibility to investigate functional gradients in place and grid-cell coding during novel behaviours that are more easily accessible in humans, such as non-spatial memory, abstract reasoning and imagination.
Together, these studies illustrate the potential power of functional magnetic resonance imaging techniques to investigate precise computations in humans.

Advisor: Behrens, T
O'Reilly, J
Brokerage as an institutional strategy in fragmented fields: the crafting of social entrepreneurship

Although the scholarship on organizational fields has prevalently focused on emerging, mature and disrupted fields, some social arenas cannot be classified in any of these categories. One such field is that of social entrepreneurship. Despite its progressive establishment and the development of shared norms, understandings, regulations and values governing all of its players, this field still presents unclear boundaries, multiple conceptions, and a high ambiguity in terms of legitimate roles, practices and organizational forms. How can this be the case? The work of some scholars shows that meso-level factors are required to explain the peculiarity of this field. This study builds on their findings and uses the social entrepreneurship field in England as setting to explore how institutional agents can favour the creation of a fragmented field and successfully operate in it. Influencing a fragmented field requires both the creation and the maintenance of a coalition of key stakeholders supporting the enactment of the desired institutional architecture over time. Therefore, this research explores what organizations do to maintain the support of multiple stakeholders in competitive settings and to use the advantages that this creates for sustaining the co-existence of their desired field’s conception and institutional architecture with competing ones. Given the advantages that brokers have in such settings and in pursuing such a strategy, this work makes use of the well-developed literature on brokerage strategies, which focuses on tertius gaudens and tertius iungens strategic orientations, and connects it with that on institutional agency. By using as case studies four brokering agencies active in the social entrepreneurship field in England, this study discovers that combinations of gaudens and iungens strategic orientations, when used by institutional agents, can help them create and sustain over time their sub-field in face of competition. Furthermore, it explores how the co-existence of multiple organizations adopting complementary brokerage strategies as institutional ones, can lead to the creation of a permanently fragmented field. Together, these findings contribute to develop the literature on brokerage, on institutional agency — especially in relation to fragmented fields —, and that on social entrepreneurship.

Keywords: social entrepreneurship
fragmented fields
brokerage
tertius gaudens
tertius iungens
institutional strategy
Advisor: Nicholls, A
Ventresca, M
A study of the effects of iron deficiency on cardiac function

The research presented in this thesis is an interdisciplinary study of the effects of iron deficiency on cardiac physiology. The aim of the study was to gain insight into the mechanism by which cardiac function is affected by iron deficiency, induced through the administration of an iron-deficient diet, on a murine model.
Chapter 3 of this thesis introduces the mouse model, demonstrating that the administration of an iron-deficient diet does lead to iron deficiency, and in some animals, anaemia. It also provides in vivo evidence of impairment of heart function in iron-deficient animals. Alterations in cardiac function could be rescued by correction of the iron deficiency by intravenous iron supplementation.
Chapter 4 describes the study which investigated the effects of iron deficiency on the cardiac gene expression profile using RNA-sequencing technology. This study revealed that the administration of an iron-deficient diet leads to many genome-wide changes, some of which are likely to be related to the cell’s stress response.
Chapter 5 presents the study into cardiac metabolism. Iron-deficient hearts were found to have increased glycolytic flux and lactate production. Alterations in metabolism occurred in the absence of changes in mitochondrial numbers or morphology. Instead, the proposed mechanism for changes in cardiac energetics is hypoxia of the cardiac tissue.
Chapter 6 reports the findings of the study which explored the effects of an iron-deficient diet on the cardiac calcium signaling pathway. Iron deficiency was associated with higher diastolic calcium levels and decreased calcium transient amplitude, which could be prevented by reversal of iron deficiency by intravenous supplementation of iron.
Overall, this thesis provides evidence that severe iron-deficiency anaemia is sufficient to cause modest impairment of cardiac function and that this functional impairment is the result of complex alterations that occur at the genetic, metabolic and signaling level.

Advisor: Robbins, P
Swietach, P
A theory of early classical Ḥanafism

Fiqh, literally 'deep understanding', is the science of religious law in Islam. What does it mean for an Islamic jurist to 'do fiqh'? And how does an engagement with fiqh guide a jurist to produce statements of law for particular social contexts? These are perennial questions in the field of Islamic legal studies. The current thesis offers an answer to these questions from the viewpoint of jurists from the early classical Ḥanafī tradition of Central Asia. The thesis starts with an examination of Central-Asian Ḥanafī works of legal theory to extract the underlying epistemological foundations of this legal tradition. The remainder of the thesis presents a series of investigations into a leading work of legal commentary – the Hidāyah of Burhān al-Dīn 'Alī ibn Abī Bakr al-Marghīnānī (d. 593/1197) – to assess how these epistemological foundations inform the work. These investigations range from a study of the processes by which the legal cases commented on in the work were seen to be authoritative, to a study of the use of rational arguments, dialectical sequences and juristic disagreement in exploring and expositing cases of the law. The thesis also studies points of theory employed in the commentary that reveal how social context was seen to impact on the production of law. The study concludes by suggesting a general theory of Ḥanafī jurisprudence, explaining what it means to 'do fiqh' – presented as a particular form of engagement with the legal cases transmitted from the teaching circle of Abū Ḥanīfah (d. 150/767), the school's eponym – and how this fiqh engagement with Ḥanafī precedent informed the production of legal statements tailored to specific contexts – by the application of a particular filter of legal mechanisms, each of which reflects an understanding of the overarching principle of 'necessity' (ḍarūrah). The study presents a uniquely Ḥanafī legal epistemology which is underpinned by particular notions of authority, rationality and tradition.

Keywords: The Hidāyah
Islamic legal epistemology
al-Marghīnānī
Hanafi law
Advisor: Melchert, C
Inference on Markov random fields: methods and applications

This thesis considers the problem of performing inference on undirected graphical models with continuous state spaces. These models represent conditional independence structures that can appear in the context of Bayesian Machine Learning. In the thesis, we focus on computational methods and applications. The aim of the thesis is to demonstrate that the factorisation structure corresponding to the conditional independence structure present in high-dimensional models can be exploited to decrease the computational complexity of inference algorithms. First, we consider the smoothing problem on Hidden Markov Models (HMMs) and discuss novel algorithms that have sub-quadratic computational complexity in the number of particles used. We show they perform on par with existing state-of-the-art algorithms with a quadratic complexity. Further, a novel class of rejection free samplers for graphical models known as the Local Bouncy Particle Sampler (LBPS) is explored and applied on a very large instance of the Probabilistic Matrix Factorisation (PMF) problem. We show the method performs slightly better than Hamiltonian Monte Carlo methods (HMC). It is also the first such practical application of the method to a statistical model with hundreds of thousands of dimensions. In a second part of the thesis, we consider approximate Bayesian inference methods and in particular the Expectation Propagation (EP) algorithm. We show it can be applied as the backbone of a novel distributed Bayesian inference mechanism. Further, we discuss novel variants of the EP algorithms and show that a specific type of update mechanism, analogous to the mirror descent algorithm outperforms all existing variants and is robust to Monte Carlo noise. Lastly, we show that EP can be used to help the Particle Belief Propagation (PBP) algorithm in order to form cheap and adaptive proposals and significantly outperform classical PBP.

Keywords: Variational Inference
Computational Bayesian Statistics
Expectation Propagation
Bayesian Machine Learning
Sampling Methods
Bouncy Particle Sampler
Markov Random Fields
Advisor: Doucet, A
Teh, Y
Childhood trauma and executive functioning in violent and criminal samples

Violent and criminal behaviours have significant economic and psychological costs to society that contribute to substantial pain and suffering. It is important to understand the processes involved in such behaviours in order to implement preventative strategies and interventions.
The first paper is a meta-analytic review exploring the association between childhood trauma and violent outcomes in prospective studies. A systematic search yielded 18 eligible papers, all of which defined childhood trauma in terms of child maltreatment and witnessing domestic violence. Overall, childhood trauma was found to increase the risk of violent outcomes with a random-effects odds ratio of 1.8 (95% CI 1.4-2.4) and substantial heterogeneity ( I2 = 92%). It is concluded that childhood trauma is associated with violent outcomes, and the clinical and forensic implications are discussed together with recommendations for future research.
The second paper presents a quantitative study investigating aspects of executive functioning in older probationers. Executive dysfunction is considered to have a role in offending behaviour but to date no studies have specifically examined the executive functioning of older probationers. Thirty-two males aged fifty years and over were recruited and completed the Verbal Fluency and Stroop tests to assess mental flexibility and response inhibition. They also completed measures of mental health, substance use and cognitive impairment. In comparison to normative data older probationers did not present with deficits in executive functioning although they did display high rates of mental health and substance use difficulties. These preliminary findings can be used to guide future research with older probationers. The study strengths and limitations, service implications, and suggestions for future research are discussed.

Advisor: Fazel, S