VictorJuiz/thesis huggingface dataset:
The of endothelial cells in the regulation of the vascular response to Angiotensin II

Aortic dissection is a detrimental disease with a high mortality. However, the mechanisms regulating the susceptibility to aortic dissection remain unknown. We hypothesize that endothelial oxidative stress due to the activation of the reactive oxygen species (ROS)-generating Nox2 enzyme may play an important role in the development of aortic dissection. To investigate this, we generated transgenic mice (C57BL/6J background) with endothelial specific over-expression of Nox2 (Nox2 Tg) under the control of a tie-2 promoter. Expression of the human Nox2 transgene was confirmed by qRT-PCR to be found only in endothelial cells (EC) isolated from transgenic mice, and not in Wt EC or vascular smooth muscle cells (VSMC) and macrophages isolated from either genotype.
Wild-type (Wt) littermates and Nox2 Tg male mice (22-24 weeks old, n=11) were treated with saline or Ang II (1mg/kg/day) via subcutaneous mini-pump for 28 days. There was no significant difference in the pressor responses to Ang II between Wt and Nox2 Tg mice (Wt 121±7mmHg vs. Nox2-Tg 122±6mmHg). However, 5/11 Nox2 Tg mice developed aortic dissections compared to 0/11 Wt mice (P<0.05). Immunohistochemistry revealed significant increases in endothelial VCAM-1 expression, MMP activity and CD45+ inflammatory cell recruitment in the aortas of Nox2 Tg mice after 5 days of Ang II infusion. Inflammatory cell recruitment was confirmed by FACS analysis of cells from digested aortas (P<0.05). Explanted aortas from Nox2-Tg mice had significantly greater secreted pro-inflammatory cytokine, Cyclophilin A (CypA) both at baseline and after 5 days of Ang II infusion compared to Wt littermates. Compared to primary Wt EC and VSMC, Nox2-Tg primary EC, but not primary VSMC, had increased ROS production which was accompanied by increased endothelial CypA secretion and ERK1/2 activation. Furthermore, conditioned media from Nox2-Tg EC induced greater ERK1/2 phosphorylation compared to conditioned media from Wt controls. Knockdown of CypA from sEND.1 endothelial conditioned media by siRNA knockdown abolished VSMC Erk1/2 phosphorylation.
In conclusion, we demonstrate for the first time that a specific increase in endothelial ROS through the over-expression of Nox2 was sufficient to induce aortic dissection in response to Ang II stimulation. Endothelial secreted CypA could be the signalling mechanism by which increased endothelial ROS regulates the inflammatory response and the susceptibility to aortic dissection.

Keywords: redox signalling
NADPH oxidase
mouse model
Nox 2
aortic dissection
Advisor: Channon, K
Railways and Spanish economic growth in the late 19th century

The object of this thesis is to examine the contribution of Spanish railways to accelerated economic growth in the period. 1855-1913. Although it has not been estimated, there is reason to believe that there was some growth in the period before the 20th century but, from all accounts, it was constrained by an inefficient, highly seasonal and costly road transportation system.
The contribution of railways will be assessed in three ways, First, by estimating the cost of the non-construction of the railway network through an estimate of the social savings. This estimate suggested that the contribution cf railways accounted for 12 per cent of Spain's national income in 1878 and 23 per cent in 1912. I/hen the full employment assumption embodied in these calculations is released, social savings diminished to the 'plausible' level of 7.5 per cent in 1878.
Second, as consumers of iron and steel, railways had little linkage effects on the iron industry because they imported the bulk of the iron required to lay down the network. The implications of an alternative policy which protected the local iron industry from the begiiining of railway expansion are treated at length. Railways had, on the other hand, important feedback effects upon the domestic coal production and one fifth of the coal mined in Spain was consumed by railways.
Thirdly, connections between railways and the spread of the market reveal that they were a fundamental factor in the integration of the home market. Railways carried increasing volumes of grain, flour, wine and coal consumed in Spain.
Finite element simulation of a poroelastic model of the CSF system in the human brain during an infusion test

Cerebrospinal fluid (CSF) fills a system of cavities at the centre of the brain, known as ventricles, and the subarachnoid space surrounding the brain and the spinal cord. In addition, CSF is in free communication with the interstitial fluid of the brain tissue. Disturbances in CSF dynamics can lead to diseases that cause severe brain damage or even death. So-called infusion tests are frequently performed in the diagnosis of such diseases. In this type of test, changes in average CSF pressure are related to changes in CSF volume through infusion of known volumes of additional fluid.
Traditionally, infusion tests are analysed with single compartment models, which treat all CSF as part of one compartment and balance fluid inflow, outflow and storage through a single ordinary differential equation. Poroelastic models of the brain, on the other hand, have been used to simulate spatial changes with disease, particularly of the ventricle size, on larger time scales of days, weeks or months. Wirth and Sobey (2008) developed a two-fluid poroelastic model of the brain in which CSF pressure pulsations are linked to arterial blood pressure pulsations. In this thesis, this model is developed further and simulation results are compared to clinical data.
At first, the functional form of the compliance, which governs the storage of CSF in single compartment models, is examined by comparison of two different compliance models with clinical data. The derivations of a single-fluid and a two-fluid poroelastic model of the brain in spherical symmetry are laid out in detail and some of the parameters are related to the compliance functions considered earlier. The finite element implementation of the two-fluid model is described and finally simulation results of the average CSF pressure response and the pressure pulsations are compared to clinical data.

Keywords: poroelasticity
cerebrospinal fluid
brain
hydrocephalus
infusion test
Advisor: Sobey, I
The facilitatory crossmodal effect of auditory stimuli on visual perception

The aim of the experiments reported in this thesis was to investigate the multisensory interactions taking place between vision and audition. The focus is on the modulatory role of the temporal coincidence and semantic congruency of pairs of auditory and visual stimuli. With regards to the temporal coincidence factor, whether, and how, the presentation of a simultaneous sound facilitates visual target perception was tested using the equivalent noise paradigm (Chapter 3) and the backward masking paradigm (Chapter 4). The results demonstrate that crossmodal facilitation can be observed in both visual detection and identification tasks. Importantly, however, the results also reveal that the sound not only had to be presented simultaneously, but also reliably, with the visual target. The suggestion is made that the reliable co-occurrence of the auditory and visual stimuli provides observers with the statistical regularity needed to assume that the visual and auditory stimuli likely originate from the same perceptual event (i.e., that they in some sense 'belong together'). The experiments reported in Chapters 5 through 8 were designed to investigate the role of semantic congruency on audiovisual interactions. The results of the experiments reported in Chapter 5 revealed that the semantic context provided by the soundtrack that a person happens to be listening to can modulate his/her visual conscious perception in the binocular rivalry situation. In Chapters 6-8, the timecourse of audiovisual semantic interactions were investigated using categorization, detection, and identification tasks on visual pictures. The results suggested that when the presentation of the sound leads the presentation of a picture by more than 240 ms, it induces a crossmodal semantic priming effect. In addition, when the presentation of the sound lags a semantically-congruent picture by about 300 ms, it enhances performance, presumably by helping to maintain the visual representation in short-term memory. The results indicate that audiovisual semantic interactions constitute a heterogeneous group of phenomena. A crossmodal type-token binding framework is proposed to account for the parallel processing of the spatiotemporal and semantic interactions of multisensory inputs. The suggestion is that the congruent information in the type and token representation systems would integrate, and they finally bind into a unified multisensory object representation.

Keywords: Vision
Attention
Multisensory Perception
Audition
Object
Advisor: Spence, C
Physiological and biological mechanisms of bisphosphonate action

Bisphosphonates (BPs) are stable analogues of pyrophosphate widely used for the treatment of bone diseases characterised by increased bone resorption. Studies over the years have shown that the pharmacological potencies of BPs are dependent both on their binding affinities for bone mineral and on their inhibitory actions on osteoclasts. In addition, potential effects on other cell types present locally in the environment of skeletal tissues have been reported.
The present study systematically evaluated the relative mineral-binding affinities of individual BPs of clinically relevance in mixtures of these compounds and the changes with elution pH by using column chromatography with ceramic hydroxyapatite and fluoroapatite combined with mass spectrometric identification and quantitation of the individual BPs. The results indicate that pH has a profound effect on the ionisation of the phosphonate and R2 functional groups, with BPs having greater affinities at lower pH as shown by increased retention times. Moreover, two other approaches, namely using Langmuir adsorption isotherms and competition assays based on fluorescent BP, have been developed to assess the mineral-binding capacities and dissociation constants of BPs. These results suggest that there are substantial differences among BPs in their binding to hydroxyapatite.
From the cellular aspect of my study, I present evidence for the anti-apoptotic effects of BPs in osteocytes and osteoblasts. However, the study of prosurvival signalling pathways involved in these cells needs to be optimised.
The work described in this thesis provides novel insights into the physiological and biological mechanisms of BP action. My project has provided a better knowledge of the physicochemical properties of BPs, which are highly relevant to their differential distributions within bone, their biological potencies, and their durations of action. Additionally, the cell culture studies may provide new information on the cellular effects of BPs on osteocytes and osteoblasts.

Keywords: osteocytes
bone
mineral binding
bisphosphonates
Advisor: Russell, G
Triffitt, J
The Interaction Point Collision Feedback System at the International Linear Collider and its sensitivity to expected electromagnetic backgrounds

An Interaction Point Collision Feedback System is necessary to achieve design luminosity at the future International Linear Collider (ILC). This is proposed to include a stripline beam position monitor (BPM) positioned 3 m from the Interaction Point (IP). The BPM is required to be able to measure the position of the outgoing electron or positron beam with a resolution of 1 m. Prototype feedback systems have been built and tested at the Next Linear Collider Test Accelerator (NLCTA) at the Stanford Linear Accelerator Center in the USA (SLAC) and also at the Accelerator Test Facility (ATF) at the High Energy Research Laboratory in Japan (KEK). The successful correction of position osets is demonstrated with the lowest latency achieved 24 ns, the best position resolution 4 m and the best correction ratio 23:1. To make the feedback system a more powerful tool, a digital processor is added. It raises the total latency of the feedback system to 140 ns. Its ability to perform algorithms is demonstrated with charge normalisation. Preliminary results indicate a resolution of 8 m and correction ratio 7:1. Backgrounds at the ILC comprise mainly electron-positron pairs from the beam-beam interaction. For the high luminosity 1TeV accelerator parameters, 105 pairs are produced per bunch crossing. This is the worst case for ILC pair backgrounds. These pairs produce 5 105 particle hits on a stripline of the IP feedback BPM. In two experiments at End Station A (ESA) at SLAC, a stripline BPM was exposed to secondary particle backgrounds to determine if the particle hits degraded the ability of the stripline BPM to resolve micron-level position osets. The experiments agree that the worst ILC pair backgrounds degrade the resolution by less than 8.5 nm (95% confidence level). It is concluded that micron-level resolution will not be aected by the ILC pair backgrounds. Studies of stripline signals caused by backgrounds led to the development of a GEANT3- based tool that could predict the signals. The prediction tool was tested against one of the experiments at ESA and used to predict the signals on the ILC feedback BPM striplines. The results confirm that the ILC pair backgrounds do not produce micron-level errors in position measurement, indicating that the degradation in resolution by the worst pair backgrounds expected was under 13 nm.

Keywords: Accelerator
ILC
Backgrounds
FONT
Advisor: Burrows, P
Ethics and recognition in postcolonial literature: reading Amitav Ghosh, Caryl Phillips, Chimamanda Adichie and Kazuo Ishiguro

This thesis undertakes a critical study of ethics in the postcolonial novel. Focusing on four authors, namely Amitav Ghosh, Chimamanda Adichie, Caryl Phillips, and Kazuo Ishiguro, I conduct a comparative analysis of the ethical engagement offered in a selection of their novels. I argue that the recognitions and related emotional responses of characters are integral to the unfolding of these novels’ ethical concerns. The ethics thus explored are often marked by the complexity and impurity characteristic of the tragic – an impurity which is productively thought together with Jacques Derrida’s understanding of “radical evil”. I arrive at this through deploying an approach to ethics in the postcolonial novel that is largely drawn from the work of Martha Nussbaum, David Scott, and Terence Cave. This approach is attentive to both the particular contexts in which the novels’ ethical concerns unfold, as well as the general ethical questions in relation to which these can be understood. Crucial to this is the concept of anagnorisis, that is, the recognition scene. Functioning as both a structural and a thematic element, it serves as a hinge between the general and the specific ethical considerations in a novel. There are three ethical themes that I consider across the thesis: the ethics of remembrance, the human, and religion. The works of these four authors cluster around these concerns to differing degrees and with differing perspectives. What emerges is that while each engagement is focused on the particular details that the novel represents, the range of perspectives can nevertheless be productively read alongside one another as interventions into these general concerns. Following from this I also conclude that as a suitable, if not privileged, form in which to engage questions of the ethical, the postcolonial novel hosts the ethical difficulty that I name as the tragic, and which is characterised by the term radical evil.

Keywords: ethics
Kazuo Ishiguro
postcolonial literature
ethics and literature
Caryl Phillips
Chimamanda Adichie
anagnorisis
Amitav Ghosh
recognition
postcolonial theory
Advisor: Boehmer, E
Agreement, case assignment and nominal coordination

The topic of this dissertation is agreement and case assignment, with particular reference to conjoined noun phrases. The initial chapters look at the different possibilities available in such contexts, including agreement with the features of each individual conjunct, agreement with the features of only one conjunct, or agreement with features computed on the basis of those of the individual conjuncts but not necessarily possessed by them. We propose a way of handling all of these patterns with a single formal mechanism, later applying the same intuitions to the assignment (or non-assignment) of case values by a head to its dependents. Attempts are also made to explore in greater depth some of the factors that might influence the choice of alternative agreement configurations, as well as to extend the scope of the model which we elaborate as we go along to non-conjoined environments where variable agreement occurs. Special emphasis is laid throughout on fluctuations in agreement, either because the controller has mismatched attributes or because the syntactic structure and/or the semantic interpretation allow variation. The final conclusion is that a modular approach to grammar is best placed to deal with the empirical facts. The complexities of the data call for bringing together purely morpho-syntactic, declensional information, syntactic hierarchy, order and constituency, coupled with semantics and pragmatics. The successful, appropriately regulated, interaction of these modules is shown to offer a satisfactory explanation which is difficult to obtain by exclusively relying on syntax or semantics alone.

Keywords: case assignment
Serbian/Croatian
Bulgarian
coordination
English
agreement
Advisor: Dalrymple, M
TbISWI and its role in transcriptional control in Trypanosoma brucei

ISWI is a member of a versatile family of ATP-dependent chromatin remodelling complexes involved not only in transcription regulation (initiation, elongation and termination), but also in other cellular functions like maintenance of higher order chromatin structure and DNA replication. TbISWI, a novel ATPase of the ISWI family in Trypanosoma brucei, is involved in the transcriptional repression of silent VSG expression sites (ESs) in both bloodstream form (BF) and procyclic form (PF) life cycle stages of the parasite.
Using in silico analysis, I have found that TbISWI is well conserved across the eukaryotic lineage, including those members of the order Kinetoplastida that do not exhibit antigenic variation. Compared to the ISWIs of higher eukaryotes, TbISWI has greater representation of random coils within its structure, an indicator of more structural fluidity and flexibility of interaction with multiple protein partners.
Using an eGFP reporter based assay, I have studied the role of TbISWI in transcriptional repression of silent areas of the T. brucei genome. TbISWI was found to be involved in preventing inappropriate transcription of the silent VSG repertoires. TbISWI was also found to downregulate transcription in RNA pol I, but not pol II, transcription units. These results argue for the presence of at least two functionally distinct TbISWI complexes in T. brucei.
Using DNA staining and fluorescence in situ hybridisation (FISH), I have investigated the potential effect of TbISWI depletion on cell cycle progression and minichromosome segregation. I did not find any evidence for the role of TbISWI in the maintenance of centromeric heterochromatin in T. brucei.

Keywords: chromatin remodelling
transcriptional regulation
ISWI
African trypanosome
trypanosomiasis
VSG expression sites
Advisor: Rudenko, G
High resolution nuclear magnetic resonance studies of kringle containing proteins

The kringle is a name given to a sequence of seventy nine residues linked by three disulphide bridges, multiple copies of which have been found in a number of proteins involved in haemostasis. Kringles from plasminogen and prothrombin have been studied using high resolution nuclear magnetic resonance (NMR) spectroscopy.
Preliminary experiments demonstrated the kringles to be globular proteins in aqueous solution having well defined tertiary folds. Resonances have been assigned in the NMR spectrum to all but two of the aromatic residues of kringle 4 of human plasminogen and in addition a number of aliphatic residues have also been assigned. The majority of these assignments have been made to specific protons in the protein with the aid of chemically modified kringle 4 derivatives and comparison with other kringle protein spectra. Nuclear Overhauser enhancement studies have demonstrated a number of structurally significant side chain interactions. The lysine binding site of kringle 4 has been explored using two ω-aminocarboxylic acids as ligands. Further structural probes have included copper and lanthanide ions as well as chemically modified kringle 4 species. Combining all the data has allowed a preliminary molecular model to be built of part of kringle 4 incorporating all the residues between the second and third disulphide bridges. Preliminary studies demonstrate the possibility of being able to refine parts of this structure to an accuracy approaching that of X-ray crystallographic studies.
A similar number of assignments have been made in the spectrum of bovine prothrombin fragment 2. Comparison of the data on the kringles of both fragment 2 and kringle 4 shows the two proteins to have preserved structural elements, and in particular one of these involves the conserved residues Trp 25, Leu 45 and Trp 61. Furthermore, the two tryptophan residues have been shown to have quite unique spectral charateristics. Brief studies of human prothrombin fragment 2 reveals similar findings.
The results discussed indicate that the kringle sequence gives rise to a well defined fold. In kringle 4 of human plasminogen this is seen to provide a highly specific binding site for certain ω-aminocarboxylic acids. The data is all in accord with kringles being autonomous units within the non protease portion of zymogen molecules and which are ideally suited to include the mediation of protein-protein interactions amongst their biological functions.

Advisor: Williams, R
Topics in Ricci flow with symmetry

In this thesis, we study the Ricci flow and Ricci soliton equations on Riemannian manifolds which admit a certain degree of symmetry. More precisely, we investigate the Ricci soliton equation on connected Riemannian manifolds, which carry a cohomogeneity one action by a compact Lie group of isometries, and the Ricci flow equation for invariant metrics on a certain class of compact and connected homogeneous spaces.
In the first case, we prove that the initial value problem for a cohomogeneity one gradient Ricci soliton around a singular orbit of the group action always has a solution, under a technical assumption. However, this solution is in general not unique. This is a generalisation of the analogous result for the Einstein equation, which was proved by Eschenburg and Wang in their paper "Initial value problem for cohomogeneity one Einstein metrics".
In the second case, by studying the corresponding system of nonlinear ODEs, we identify a class of singular behaviours for the homogeneous Ricci flow on these spaces. The singular behaviours that we find all correspond to type I singularities, which are modelled on rigid shrinking solitons. In the case where the isotropy representation decomposes into two invariant irreducible inequivalent summands, we also investigate the existence of ancient solutions and relate this to the existence and non existence of invariant Einstein metrics. Furthermore, in this special case, we also allow the initial metric to be pseudo- Riemannian and we investigate the existence of immortal solutions.
Finally, we study the behaviour of the scalar curvature for this more general situation and show that in the Riemannian case it always has to turn positive in finite time, if it was negative initially. By contrast, in the pseudo-Riemannian case, there are certain initial conditions which preserve negativity of the scalar curvature.

Keywords: homogeneous spaces
Ricci solitons
cohomogeneity one manifolds
Ricci flow
Advisor: Dancer, A