VictorJuiz/thesis huggingface dataset:
Theory of defect interactions in metals

The static relaxation program DEVIL has been updated to use N-body Finnis-Sinclair potentials. Initial calculations of self-interstitial and monovacancy formation energies confirm that the modified program is working correctly.
An extra repulsive pair potential (constructed to leave the original fitting unaltered) overcomes some deficiencies in the published Finnis-Sinclair potentials. The modified potentials are used to calculate interstitial energies and relaxations in the b.c.c. transition metals vanadium, niobium, tantalum, molybdenum and tungsten.
A study of migration of point defects in the perfect lattice provides information on the mobility of interstitials and vacancies. The possible reorientation of split dumbbell interstitials in a migration step comes under scrutiny. The total energy needed to form and migrate an interstitial is compared with that required for a vacancy.
The interaction between point defects and dislocations is studied in detail. Binding energies for both sclf-intcrstitials and monovacancies at edge dislocations are calculated for the five metals mentioned above. Formation energies of the point defects in the neighbourhood of the edge dislocation are calculated for niobium, and the extent of the regions from which the defects are spontaneously absorbed are found. For split dumbbell interstilials, the size and shape of the absorption region depends on the orientation of the dumbbell. Migration of both interstitials and vacancies into the absorption zone is studied; the presence of the dislocation has a particularly dramatic effect on vacancy migration. The results on absorption zones are related to the dislocation sink strengths vital in radiation damage theory.

Advisor: Matthews, J
In silico modelling of tumour-induced angiogenesis

Angiogenesis, the process by which new vessels form from existing ones, is a key event in the development of a large and malignant vascularised tumour. A rapid expansion in in vivo and in vitro angiogenesis research in recent years has led to increased knowledge about the processes underlying angiogenesis and to promising steps forward in the development of anti-angiogenic therapies for the treatment of various cancers. However, substantial gaps in knowledge persist and the development of effective treatments remains a major challenge.
In this thesis we study tumour-induced angiogenesis within the context of a highly controllable experimental environment: the cornea micropocket assay. Using a multidisciplinary approach that combines experiments, image processing and analysis, and mathematical and computational modelling, we aim to provide mechanistic insight into the action of two angiogenic factors which are known to play central roles during tumour-induced angiogenesis: vascular endothelial growth factor A (VEGF-A) and basic fibroblast growth factor (bFGF). Image analysis techniques are used to extract quantitative data, which are both spatially and temporally resolved, from experimental images. These data are then used to develop and parametrise mathematical models describing the evolution of the corneal vasculature in response to both VEGF-A and bFGF.
The first models developed in this thesis are one-dimensional continuum models of angiogenesis in which VEGF-A and/or bFGF are released from a pellet implanted into a mouse cornea. We also use an object-oriented framework, designed to facilitate the re-use and extensibility of hybrid multiscale models of angiogenesis and vascular tumour growth, to develop a complementary three-dimensional hybrid model of the same system. The hybrid model incorporates a new non-local cell sensing model which facilitates the formation of well-perfused and functional vascular networks in three dimensions.
The continuum models are used to assess the utility of the cornea micropocket assay as a quantitative assay for angiogenesis, to characterise proposed synergies between VEGF-A and bFGF, and to generate experimentally testable predictions regarding the effect of anti-VEGF-A therapies on bFGF-induced angiogenesis. Meanwhile, the hybrid model is used to provide context for the comparison that is drawn between the continuum models and the data, to study the relative distributions of perfused and unperfused vessels in the evolving neovasculature, and to investigate the impact of tip cell sensing dysregulation on the angiogenic response in the cornea.
We have found that by exploiting a close link with quantitative data we have been able to extend the predictive and hypothesis-testing capabilities of our models. As such, this thesis demonstrates the potential for integrating mathematical modelling with image analysis techniques to increase insight into the mechanisms underlying angiogenesis.

Keywords: Angiogenesis
Cancer
Mathematical modelling
Computational modelling
Advisor: Maini, P
Byrne, H
Cooper, J
Quaiser, T
Shochat, E
Differential involvement of glutamate receptors in neuronal responses of the cerebral cortex

I studied how glutamate receptor-mediated responses, spatial arrangements, intrinsic properties and molecular specificity of cells serve cortical functions. I tested whether two somatosensory submodalities in the primary somatosensory (SI) cortex can be distinguished by glutamate receptor involvement in vivo. Low-threshold responses evoked by innocuous stimuli had a short-duration and long-duration component. The short-duration responses were mostly mediated by AMPA/kainate receptors and the long-duration responses involved the additional recruitment of NMDA receptors. High-threshold responses evoked by noxious stimuli were unimodal and mediated by both AMPA/kainate and NMDA receptors throughout the entire response. During noxious stimulus trials, an increase in baseline activity in SI cortical cells was observed. I attribute the changes in baseline activity to cells in the medial thalamic nuclei, which project to the SI cortex and are involved in the affective-motivational aspects of nociceptive signalling.
To gain insight into the influence of synaptic organisation of a well-defined cortical area, I studied in vitro whether the intrinsic properties of two anatomically well-defined nonpyramidal cells in the hippocampus can provide clues into the modulation of neuronal signalling. During a depolarising current pulse, O-LM and O-Bi cells were distinguished by their accommodation of action potentials depending on the early or late part of the response. Also, during a hyperpolarising current pulse, O-LM cells displayed a prominent voltage 'sag' as compared to O-Bi cells. Both cell types contain somatostatin and I showed that O-LM cells express the metabotropic glutamate receptor type 1α. Although O-LM and O-Bi cells have a similar somatodendritic position their different axonal arbours imply that they are involved in the feedback modulation of the entorhinal and CA3 glutamatergic influences, respectively. I also found that contrary to previous reports not only somatostatin but also vasoactive intestinal polypeptide containing cells express mGluR1α, which might facilitate their oscillatory responses.
To relate the action potential discharge of specific cortical cell classes to behaviourally relevant network activity, I also sought to identify hippocampal cells following in vivo recording. Novel information was provided for both the temporal and anatomical properties of cells not recorded previously. In particular, a putative interneuron targeting nonpyramidal cell and backprojection cell was recorded in relation to theta field events. A novel nonpyramidal projection cell was recorded in relation to sharp wave field events. A remarkable specificity was found in the dendritic and axonal patterns of these cells.
The results show that distinct types of glutamate receptors are differentially involved in cortical function. The intrinsic properties and expression of mGluR1α in particular is highly specific in distinct nonpyramidal cell classes.

Advisor: Somogyi, P
Prelude to decolonisation in West Africa

This study sets out to examine the development of British colonial policy towards West Africa between the years 1938 and 1947. It is primarily a study of the so-called 'official mind' of British colonialism because, as the sources indicate, the nationalists were mainly excluded from the review process. It has been decided to begin the thesis with the Colonial Secretaryship of Malcolm MacDonald. With the assistance of the West Indian Crisis, which propelled the colonial issue into the political arena in Britain, and Hailey's African Survey, which set out the deficiencies of British rule in Africa, MacDonald was supplied with the political lever and the requisite guidelines for him to successfully initiate a review of colonial policy in 1938. In particular MacDonald wished to see resolved the potential contradictions which existed in Britain's colonial policy. As he put it, "Important decisions may have to be taken in order to prevent Native Authorities on the one hand and Legislative Councils on the other from developing along divergent lines with undesirable results". This theme dominated the British West African policy review until 1947, by which time constitutions designed to effect such a harmony had either been implemented or announced.
[Please see pdf. for full abstract.]
Geometric context from single and multiple views

In order for computers to interact with and understand the visual world, they must be equipped with reasoning systems that include high–level quantities such as objects, actions, and scenes. This thesis is concerned with extracting such representations of the world from visual input. The first part of this thesis describes an approach to scene understanding in which texture characteristics of the visual world are used to infer scene categories. We show that in the context of a moving camera, it is common to observe images containing very few individually salient image regions, yet overall texture structure often allows our system to derive powerful contextual cues about the environment. Our approach builds on ideas from texture recognition, and we show that our algorithm out–performs the well–known Gist descriptor on several classification tasks.
In the second part of this thesis we we are interested in scene understanding in the context of multiple calibrated views of a scene, as might be obtained from a Structure–from–Motion or Simultaneous Localization and Mapping (SLAM) system. Though such systems are capable of localizing the camera robustly and efficiently, the maps produced are typically sparse point-clouds that are difficult to interpret and of little use for higher–level reasoning tasks such as scene understanding or human-machine interaction. In this thesis we begin to address this deficiency, presenting progress towards modeling scenes using semantically meaningful primitives such as floor, wall, and ceiling planes.
To this end we adopt the indoor Manhattan representation, which was recently proposed for single–view reconstruction. This thesis presents the first in–depth description and analysis of this model in the literature. We describe a probabilistic model relating photometric features, stereo photo–consistencies, and 3D point clouds to Manhattan scene structure in a Bayesian framework. We then present a fast dynamic programming algorithm that solves exact MAP inference in this model in time linear in image size. We show detailed comparisons with the state–of–the art in both the single– and multiple–view contexts.
Finally, we present a framework for learning within the indoor Manhattan hypothesis class. Our system is capable of extrapolating from labelled training examples to predict scene structure for unseen images. We cast learning as a structured prediction problem and show how to optimize with respect to two realistic loss functions. We present experiments in which we learn to recover scene structure from both single and multiple views — from the perspective of our learning algorithm these problems differ only by a change of feature space. This work constitutes one of the most complicated output spaces (in terms of internal constraints) yet considered within a structure prediction framework.

Keywords: computer vision
geometry
artificial intelligence
statistical inference
Advisor: Reid, I
Murray, D
Gas and particle dynamics in transdermal powdered drug delivery

Transdermal powdered drug delivery is an emerging technology for the injection of drugs through human skin, in which particles of solid drug are entrained in a high-speed gas flow and directed towards the skin at a high enough velocity to penetrate the outer layer of dead cells. Hand-held devices based on this idea offer a means of safe, painless and effective delivery of many drugs and vaccines. This thesis describes a programme of research into the fluid dynamics which determine the particle velocity distribution, the most important mechanical characteristic of the system, in prototype drug delivery devices.
Pressure measurements are described which enable characterisation of the gas flow in the drug delivery devices. These are complemented by optical particle detection experiments, which provide a record of the timing of drug particle delivery with respect to the gas flow. Doppler Global Velocimetry (DGV) has been used to measure the velocity field of drug particles. Various tasks involved in the application of DGV to these flow-fields are described. In particular, the use of time-integrated DGV for measurements of unsteady, short-duration flows is discussed. Time-integrated DGV, applied at a range of operating conditions, has provided information on the variation of particle delivery velocity with particle size and with total mass of particles. Time-resolved DGV measurements reveal that particles first emerge in a slow-moving cloud which is driven by transient starting process in the gas flow, followed by a faster stream of particles entrained in a quasi-steady gas flow. The experimental results are complemented by numerical computations of certain aspects of the drug delivery flows. These computations are compared with experimental results, and used to gain additional information on the functioning of the system as a whole.
Investigation of leukocyte transcriptomes using serial analysis of gene expression

Two tag-based gene expression technologies (serial analysis of gene expression, SAGE, and massively parallel signature sequencing, MPSS) were used to profile a variety of lymphocyte transcriptomes. By combining these libraries with publicly available genome and transcriptome data, both immunological and general aspects of gene expression could be considered. Unexpectedly, analysis of the expression of currently known cell surface components and the proteins corresponding to "immune specific" tags in a cytotoxic T-cell (CTL) library suggested that the current knowledge of the immune specific composition of the cell surface components of a resting CTL is largely complete. An analysis of the "immune specific" tags in a natural killer cell library revealed that a small number of tags could not be matched to any previously sequenced transcripts, suggesting the presence of functionally important but previously uncharacterised transcripts or exons in these cells. To examine the entire transcriptome large libraries are required, implying that MPSS would be the most appropriate technology. A comparison of libraries produced by the two tag-based technologies to characterise CD4+ T-cells revealed a relatively poor correlation, suggesting bias in the two techniques. Investigations into this bias led to the conclusion that despite its great depth, the random sampling events involved in the production of a library limit the breadth of MPSS sampling, making it inappropriate for characterising entire transcriptomes. Finally, with the availability of large LongSAGE libraries it is now possible to examine weakly expressed transcript classes. A panel of LongSAGE libraries was used to conduct the first large scale quantitative study of the expression of cis-natural antisense transcripts (cis-NATs). cis-NATs were found to be expressed at approximately one tenth of the level of sense transcripts and across the panel of libraries cis-NATs were found for approximately two thirds of all observed sense transcripts. This suggests antisense transcription is more widespread than previously thought.

Advisor: Davis, S
Gene expression in P. falciparum: statistical patterns and molecular determinants

This thesis investigates patterns and mechanisms of gene expression in P. falciparum. The rapidly cycling patterns of genes during the asexual stages confounds the analysis of gene expression in culture and in patients. In order to overcome this problem, we develop statistical models to estimate the temporal progression of malaria parasites by using the observed gene expression values and known reference sets. We extend this framework to account for lineage commitment, and show that, similar to asexual development, it is also possible to recover information about parasite sexual differentiation given observed gene expression values. Using datasets from our own lab as well as those available in the literature, we establish that the patterns of expression in patients are similar to those observed in culture but in additive mixtures whose proportions can vary between patients.
We then investigate epigenetic and spatial factors that are important in regulating gene expression. Using second-generation DNA sequencing, we generate genomic maps of chromatin state and chromosome interactions. These maps provide the first global view of chromosome folding and locus-specific affinities in malaria. They also highlight the importance of epigenetic modifications in imposing structure on the spatial organization of the genome. After generating an initial set of genomic maps, we apply these tools to study chromatin reconfigurations during var gene switching. We show that when the active var gene changes, reconfigurations can be seen in the local three-dimensional chromatin structure of the activated locus.
Overall, our results contribute new methods for analyzing malaria microarray data, highlight the importance of lineage mixtures in patient infections, generate an atlas of spatial interactions in the nucleus at a resolution of approximately 5 kilobases, and establish a link in malaria between the spatial configuration of active loci and the local chromatin environment.

Keywords: malaria
chromosome conformation capture
gene expression
Advisor: Newbold, C
The role of p53 in hypoxia-induced apoptosis

Tumour hypoxia is associated with resistance to therapy, increased aggressiveness and a poor patient prognosis. The tumour suppressor p53 causes apoptosis in response to hypoxia and therefore hypoxic tumours select for the loss of p53.
In this work was we have investigated the post-translational modifications and binding partners of p53 in hypoxia. Furthermore, we investigated the p53-dependent gene expression changes in hypoxia.
We have shown that p53 is stabilised and phosphorylated in hypoxia, and that there are some differences between p53 modifications in hypoxia and those in response to DNA damage. We have also shown that N-terminal phosphorylations of p53 at serines 20 and 46 are important, but not essential for induction of apoptosis in hypoxia. Strikingly we observed that DNA binding of p53 is essential for hypoxia-induced apoptosis. We have seen, for the first time, that p53 induces a subset of its targets in hypoxia and that these proteins do have previously reported roles in apoptosis. In addition, it is possible that p53 can induce miRNA expression in hypoxia. Moreover, preliminary work suggests that p53 is part of a complex in hypoxia. Elucidating the proteins that make up this complex could prove important for understanding the mechanism of p53-induced apoptosis in hypoxia.

Keywords: p53
apoptosis
tumour hypoxia
Advisor: Hammond, E
Spatial control and symbolic politics at the intersection of China, India and Burma

The Chinese, Indian and Myanmar governments share the borderlands in the corners of their respective territories where East, South and Southeast Asia meet. In this region of common concern the capacities of these three systems of post-colonial government are regulated so as to prevent excessive political conflict and discourage territorial fragmentation. My research focus is how the governments seek to exert spatial control in areas occupied by the closely-related Jingpo, Singpho and Jinghpaw peoples. As part of their efforts to shape interactions with the central governments, local elites among these peoples have defended and expanded elements of their Jingpo, Singpho and Jinghpaw cultures, particularly their annual Manau festivals. Seeking a way to analyse the relationship between governments and those they govern I draw on the illustrative potential of these large-scale events. It is the symbolic politics of these festivals that suggest an argument about spatial control that refines the state-repelling “Zomia” model proposed by van Schendel (2002) and Scott (2009a). I argue that nodes of control are sites where the governments concentrate power in order to manage their geopolitical ambitions. These nodes succeed when they encourage the acquiescence of local economic and cultural elites. By opening up opportunities for such collaboration, the nodes buttress the strategic links—cultural, political, economic, transportation and communications—that are the main interests of all central governments. It is, moreover, the intrinsic limitation of government ambitions, and their willingness to allow creative ambiguities, that suggests the direction in which ideas about spatial control at the intersection of China, India and Burma can be re conceived.

Keywords: China
Jingpo
Kachin
Jinghpaw
Singpho
Burma
India
Advisor: Gellner, D
Gooptu, N
Characterisation of pitch: an early onset model of sensorineural deafness

At MRC Harwell n-ethyl-n-nitrosourea (ENU) mutagenesis coupled with auditory phenotyping is utilised to generate new mouse models of hearing loss. This approach identified pitch, an autosomal recessive model of early-onset, sensorineural deafness (+90dB). Mapping studies identified a 1.6Mb critical region comprising a novel deafness locus on chromosome 9 and prioritised candidate gene sequencing identified a coding mutation in Neuroplastin (Nptn).
This thesis details experiments to investigate the role of Neuroplastin in the auditory pathway. Complementation studies using a second nonsense allele (NptnY219X ) confirmed Neuroplastin as the causative gene in pitch. Modelling of Nptnpitch in silico suggested that the pitch mutation is likely harmful to protein function and in vitro studies using Nptn-tagged constructs revealed that the pitch mutation affected protein processing, and was thus likely a loss-of-function mutation. Expression studies identified that the 65kDa Nptn isoform, Np65, is expressed in the inner hair cells (IHCs) and outer hair cells (OHCs) of the cochlea in wild type mice. However, Np65 is absent in the cochleae of Nptnpitch/pitch animals. Inner ear morphology appears grossly normal in Nptnpitch/pitch mice at postnatal day (P)16, even though a severe auditory deficit is already present at this age. Electrophysiological studies suggest that whilst the IHCs of Nptnpitch/pitch mice begin to mature normally, their maturation arrests shortly after the onset of hearing. Immunolabelling of the auditory ribbon synapse identified an increased number of mismatched pre-synaptic ribbons (RIBEYE) and post-synaptic densities (GluR2) in Nptnpitch/pitch compared to wild type controls.
In conclusion, my studies demonstrate that Np65 regulates the physiological and morphological differentiation of cochlear inner hair cells at the onset of hearing and as such coordinates one of the most distinctive functional refinements of the mammalian auditory system. These data also confirm that Nptn is a new deafness-related gene.

Keywords: Auditory
Np65
Deafness
Sensorineural
Neuroplastin
Advisor: Bowl, M
Brown, S
Hodgkin, J