VictorJuiz/thesis huggingface dataset:
Environmentally-assisted fracture events in high strength nickel-based superalloys

There is significant interest in defining and quantifying the performance of polycrystalline Ni-based superalloys – particularly high strength ones produced via powder processing for turbine disc applications – at temperatures between 700 and 800◦C. This is because the outer rims of a high pressure turbine disc in turbine applications for jet propulsion can experience such temperatures during a significant portion of the flight cycle while also being exposed to oxidative/corrosive gases which cause intergranular environmentally-assisted crack growth. In this work, a testing methodology involving slow strain-rate tensile tests on a electro-thermal mechanical testing device is presented which is capable of the rapid assessment of an alloys susceptibility to environmentally-assisted cracking. It makes use of miniature test pieces which are shown to be of sufficient size to characterise macroscopic properties. This approach is first validated and then utilized to perform systematic experimentation involving the control of the important microstructural and compositional variables such that the effects of others can be isolated, identified and confirmed. The need to better understand the embrittlement mechanism was addressed at the most appropriate lengthscale using high resolution characterisation techniques which are capable of providing the most revealing information including scanning and transmission electron microscopy and nanoscale secondary ion mass spectrometry. Our results have implications for alloy design efforts – rationalising the effect of heat treatment and demonstrating that for a given strength level, both more and less damage tolerant variants can be designed.

Advisor: Reed, RC
Armstrong, DEJ
Crudden, DJ
Quantifying collateral flow pathways in the brain

Ischaemic stroke is a major cause of death and disability worldwide. Cerebral autoregulation, which can be impaired during acute stroke, and collateral flow to brain tissue through the circle of Willis, both play a role in preventing tissue infarction. The configuration of the arterial circle varies between individuals. Thus, personalised modelling of the cerebral arterial network, to determine the potential for collateral flow, can be of significant value in the clinical context of stroke.
The interaction between autoregulation and collateral flow remains poorly understood. In this study, steady-state physiological models of the cerebral arterial network, including several common variants of the circle of Willis, were coupled to a spatially variable mathematical representation of cerebral autoregulation. The resulting model was used to simulate various arterial occlusions, as well as bilateral and unilateral impairment of autoregulation, in each structural variant. The work identified few circle of Willis variants that present either particularly high-risk or particularly low-risk of cerebral ischaemia. Instead it was found that most variants are dependent upon the bilateral function of autoregulation to facilitate collateral flow and preserve cerebral blood flows. When autoregulation was impaired unilaterally, downstream of an occlusion, blood flows in the contralateral hemisphere were preserved at the expense of the ipsilateral tissue at risk.
Arterial network models have in the past been personalised using structural, rather than functional, angiography measurements. This thesis presents a novel model-based method for absolute blood volume flow rate quantification in short arterial segments using dynamic magnetic resonance angiography data. The work also investigated the additional information that can be obtained from such functional angiography. The flow quantification technique was found to accurately estimate flows in shorter arterial segments than an existing technique. However, improvements to noise performance, and strategies for rejection of contaminating signals from overlapping vessels within the imaging plane, are required before the technique can be applied to personalised cerebral arterial network modelling.

Keywords: Blood flow
Arterial spin labelling
Ischaemia
Collateral flow
Haemodynamics
MRI angiography
Cerebral autoregulation
circle of Willis
Advisor: Payne, S
Chappell, M
Okell, T
Hybrid energy harvesting towards a sustainable energy system

Soaring energy demands are inevitable because of the continual increase in the global population as well as the greater reliance on electronic technologies. Current energy generation systems are highly dependent upon fossil fuels, for which the imminent risks and limitations are well known. First of all, we are confronting an energy crisis due to the depletion of these fossil fuels. However, current sustainable and renewable energy sources are not in a position to fully replace them as of yet. In fact, less than 10% of energy that is generated is from renewable energy sources, such as from hydroelectric power and solar power. Secondly, the emission of carbon dioxide (CO2) and greenhouse gases (GhGs) from fossil fuels is currently at a serious level. As a result, today we are facing and experiencing abnormal climate changes.
In order to mitigate and potentially resolve the energy crisis, energy generation systems are now shifting from fossil fuels to sustainable and renewable energy sources. Developments in energy harvesting technologies are considered to be a practical and promising way to deal with this crisis. Energy harvesting is a process that involves the generation of electrical energy by harnessing ambient environmental energy that is otherwise wasted. Generally, energy harvesting refers to a small amount of power for technologies such as portable electronic devices and wireless sensor networks. However, going forward, energy harvesting technologies beyond these would enable a bottom-up approach from ‘the cell’ scale to ‘a large farm’ scale.
My DPhil thesis deals with energy harvesting technologies that involve harnessing different environmental energy sources, such as solar and mechanical energy, using quantum dots for solar cells and polyvinylidene fluoride (PVDF)-based polymers for mechanical energy harvesting applications. Via novel approaches, such as the fabrication of a multi-junction quantum dot solar cell (QDSC) and the development of a room temperature polymer crystallisation method (solvent annealing), a significant enhancement in energy harvesting performance has been achieved. In addition, I have demonstrated more advanced energy harvesting devices by combining two alternative technologies together. Initially, a high efficiency QDSC is presented using the ferroelectric and piezoelectric coupling effect in PVDF-based polymer. Secondly, the integration of a QDSC with a mechanical energy harvester is demonstrated, which showed a combined enhancement by generating higher power beyond that observed from the individual components. Lastly, the thesis concludes with a demonstration of an application of these hybrid devices to self-powered electronics, which shows promise for future sustainable energy systems using energy harvesting technology.

Advisor: Sohn, J
Cha, S
Kim, J
Morris, S
The interaction between the Marek’s Disease Virus (MDV) neurovirulence factor pp14 and the host transcription factor, CREB3

Marek’s Disease Virus (MDV) induces a wide range of neurological syndromes in susceptible hosts; however, the mechanisms behind the MDV-induced neuropathology are still poorly understood. The immediate-early 14kDa phosphoprotein, pp14, is associated with the neurovirulence phenotype of the virus. Yeast-two-hybrid screening identified the ER-bound transcription regulator, human CREB3 (cAMP Response Element-Binding protein), as an interacting partner of pp14, and fluorescence colocalisation between pp14 and chicken CREB3 (chCREB3) in MDV infected cells suggested an interaction between these proteins. The primary focus of this DPhil project was to further investigate this putative interaction using in vitro studies, with a view to determining if the interaction is linked to the neurovirulence of MDV. This investigation, which employed a combination of biochemical, cellular, and functional assays, found no conclusive evidence in support of the predicted interaction.
In addition, this project aimed to gain structural and functional insights into the MDV neurovirulence factor pp14 and the host transcription factor, chCREB3. Biophysical characterisation of recombinant pp14B identifies pp14 as a molten globule. The results reveal the protein, while possessing substantial secondary structure, is largely disordered lacking a stable tertiary structure. Multiple lines of evidence from this study also indicate pp14 is a putative zinc-binding protein. Moreover, phosphorylation analysis of recombinant pp14B, extracted from DF1 cells, by mass spectrometry provides conclusive evidence for the presence of two phosphorylation sites in the shared C-terminal region of pp14—serines 72 and 76 of pp14B. Structural flexibility, through a lack of a definite ordered tertiary structure, and functional features that can induce structural modifications indicate pp14 might interact with a number of binding partners and therefore could play multiple roles during MDV infection—a strong possibility due to the expression of the protein in all the different stages of virus infection.
Furthermore, this thesis presents the crystal structure of the homodimeric chCREB3 bZIP. The chCREB3 bZIP possesses a structured DNA binding region even in the absence of DNA, a feature that could potentially enhance both the DNA-binding specificity and affinity of chCREB3. Significantly, chCREB3 has a covalent intermolecular disulphide bond in the hydrophobic core of the bZIP, which may play a role in promoting stability. Moreover, sequence alignment of bZIP sequences from chicken, human and mouse reveals only members of the CREB3 subfamily possess this cysteine residue, indicating it could act as a redoxsensor. These results indicate members of the CREB3 subfamily, by possessing a putative redox-sensitive cysteine with the capacity to form an intermolecular disulphide bond, may be activated in response to oxidative stress.

Advisor: Grimes, J
Owens, R
Nair, V
The genetic control of microtubule-mediated tip-growth stability in the liverwort Marchantia polymorpha

Polar growth is an important mechanism for plant cell morphogenesis. Tip-growth represents an extreme mode of polar growth where cell expansion is stably restricted to a narrow domain of the cell periphery resulting in the formation of a tubular cell projection. The microtubule cytoskeleton controls the stable positioning of the growth region in tip-growing cells of flowering plants and mosses. I show that this holds true in the earliest diverging clade of land plants, the liverworts. In Marchantia polymorpha, pharmacological destabilization of the microtubule cytoskeleton leads to the formation of wavy or bifurcating rhizoids, a tip-growing cell type analogous to root hairs of flowering plants and to caulonema cells of mosses. Characterization of the organisation of the microtubule cytoskeleton in growing rhizoids of Marchantia polymorpha revealed longitudinally oriented microtubules that grow towards and converge into the apical dome. Because microtubule-associated proteins (MAPs) control the organisation of the microtubule cytoskeleton I generated the first de novo genome assembly of Marchantia polymorpha and compared the MAP repertoire of the liverwort model with that of existing model organisms of the green lineage. A mutant screen in Marchantia polymorpha identified the function of MpWAVE DAMPENED LIKE (MpWDL) and MpNIMA-RELATED KINASE (MpNEK) in microtubule-mediated tip-growth stability. MpWDL localizes preferentially to microtubules in the shank of growing rhizoids, where it promotes the longitudinal orientation of the microtubule cytoskeleton. These results are discussed in the context of the evolution of microtubule-mediated tip-growth stability and the tentative hypothesis that the underlying mechanism differs between flowering plants and bryophytes is proposed.

Advisor: Dolan, L
Culinary civilization: the representation of food culture in Ford Madox Ford, Gertrude Stein and Virginia Woolf

This thesis addresses the literary representation of food in the period from 1900 through 1945 in the work of Ford Madox Ford, Gertrude Stein and Virginia Woolf. Taking up nineteenth-century fascinations with sensual and aesthetic taste, these authors explore the implications of food preparation and consumption in Britain, America and France. They use representations of everyday culinary practices as a way to examine articulations of anxiety about the state of civilization, a fear that is amplified and altered by both World Wars. The thesis approaches the question of the significance of food to literary modernism in two ways. The first is a theoretical analysis of modernist ways of thinking about the dialectic between the concepts of civilization and barbarism. The second is grounded in material history, establishing the contexts and conditions of food culture in the first half of the twentieth century. Drawing on sociological thinking from Norbert Elias's conception of the civilizing process and Pierre Bourdieu’s theory of distinction, and using a combined methodology of close reading, biographical and historical analysis, I show that food acts as a lens for these authors' ideas about civil society and modernity.
My original contribution to knowledge is threefold. The first is my interpretation of 'culinary Impressionism' as an extension and repositioning of current scholarly thinking about Ford’s literary Impressionism. The second is my reading of Stein's and Toklas's jointly-authored cookbook draft as evidence of their collaboration. This forms the crux of my argument about Stein adapting domestic culinary techniques into her other writing. The third is in my chapter on Virginia Woolf. My original archival research shows that in A Room of One’s Own Woolf’s representation of the financial and culinary difference between men’s and women's dining in colleges at the University of Cambridge is justified and the material inequality was in fact worse than previously understood. I argue that the disparity in institutional food intensifies Woolf’s later reimagining of the term ‘civilization’ in Three Guineas. While drawing on the work of modernist studies scholars on modernism and the everyday, civilization, and food, my project is unique in demonstrating that food reflects modernist conceptions of civilization and barbarism. My thesis contributes to the understanding of transatlantic aesthetics and gendered productions of modernism by illuminating the centrality of agriculture, cookery, domestic work and institutional dining to modernist authors.

Keywords: Civilization
Virginia Woolf
Domesticity
Transatlantic literature
Modernism
Food history
Gertrude Stein
Ford Madox Ford
Food culture
Advisor: Lee, H
Investigating TGFβ signals in cell fate specification in the early mouse embryo

TGFβ signalling via Smad transcription factors is essential for axis patterning and subsequent cell fate specification during mammalian embryogenesis. However, the cellular and molecular mechanisms have been difficult to characterise in vivo due to early embryonic lethality of mouse mutants and redundant functional activities. Here I show that combined deletion of closely related Smad2 and Smad3 in mouse embryonic stem cells impairs induction of lineage specific gene expression during differentiation, while extra-embryonic gene expression is up-regulated. Preliminary data suggest that the underlying mechanism of this differentiation defect reflects the inability of Smad2/3-/- cells to establish lineage priming. Collectively, these findings identify novel downstream target genes controlled by Smad2/3 and an absolute requirement for Smad2/3 during embryonic differentiation. TGFβ signalling via Smad1 and Smad4 is essential for induction of the transcription factor Blimp1 required for primordial germ cell specification. The direct upstream regulators of Blimp1 are unknown, but T-box factors have recently been suggested to play a role. In a second project, I performed tissue- specific ablation of the T-box transcription factor Eomes as well as components of the TGFβ signalling pathway in either the visceral endoderm or the epiblast to examine tissue-specific functions for Blimp1 induction. I show that Eomes and Smad2 functions in the visceral endoderm as well as Eomes function in the epiblast are dispensable for Blimp1 induction, but rather are required to restrict Blimp1 induction to posterior epiblast cells. In contrast, epiblast-specific Smad4 or Smad1 mutants fail to robustly induce Blimp1 in the epiblast. My preliminary analysis suggests that competence to induce primordial germ cell fate is dependent on the interplay of Smad2/Eomes functions in the visceral endoderm and Smad1/4 functions in the epiblast. Collectively, this thesis provides insight into the transition from pluripotency to cell fate specification in the mammalian embryo that is impossible to obtain from human embryos in vivo.

Keywords: lineage priming
extra-embryonic
TGFβ signalling
Bmp signalling
Smad2, Smad3
embryonic stem cells
mouse embryo
Nodal signalling
cell fate allocation
Advisor: Robertson, E
Bikoff, E
Mechanisms underlying apathy in health and Parkinson's disease

Apathy or lack of motivation is increasingly recognized to be a major factor affecting quality of life and prognosis in many neurological conditions. It is particularly prevalent in Parkinson’s disease, impacting on every disease stage, including de novo cases, and has been reported to affect up to 70% of cases. Despite the pervasiveness of apathy, challenges remain in its detection, clinical assessment and treatment. Several lines of evidence have implicated fronto-striatal reward related neural pathways in the genesis of apathy but the precise processes remain to be fully explained.
This thesis examines the potential mechanisms of apathy using Parkinson’s disease as a model to study the condition. Novel oculomotor tasks that used eye movement and pupillary responses were developed to help assess if insensitivity to incentives could be an underlying component of apathy. This was examined in healthy young and elderly participants as well as in patients with Parkinson’s disease. Patients were tested both ON and OFF their normal dopaminergic medication so that the effect of dopamine could be assessed and the association with apathy determined. This was also performed in a pharmacological study in young participants with the use of Haloperidol, a dopaminergic D2-selective antagonist.
Insensitivity to rewards modulated by dopamine was regarded to be a contributory mechanism of apathy in Parkinson’s disease and also applicable to general mechanisms of motivation in healthy populations.

Keywords: Parkinson's disease
Reward
Motivation
Pupillometry
Saccades
Dopamine
Apathy
Advisor: Husain, M
Brown, P
Identification of anti-resorptive and anti-cancer activities of epigenetic inhibitors

Multiple myeloma is a plasma cell malignancy and develops in the bone marrow. The myeloma bone disease is present in the majority of the myeloma patients and is characterised by the excessive numbers and increased resorptive functions of osteoclasts. In order to identify novel targets controlling both osteoclastogenesis and myeloma cell growth, a library of epigenetic compounds was screened in an osteoclast differentiation assay and myeloma cell viability assay. Some compound classes, such as BET bromodomain inhibitors and HDAC inhibitors, showed inhibitory effects on both osteoclast differentiation and myeloma cell proliferation, suggesting that chromatin modifying reagents are possible therapeutic targets in multiple myeloma treatment. To rapidly screen for anti-osteoclast effects, an osteoclast RANKL gene card was successfully developed and applied to selected inhibitors in osteoclast assays. Moreover, the transcriptomic analysis was used to investigate the underlying mechanisms of selected epigenetic compounds in myeloma cells, and we found that cell cycle related pathways have been regulated by several inhibitors. Furthermore, an antibody panel for CyTOF (Mass cytometry) has been developed to characterise the bone marrow microenvironment of myeloma patients, and the CyTOF experiments demonstrated that GSK-J4 and rocilinostat activate the apoptosis marker caspase3 only in myeloma cells without affecting other cell populations. GSK-J4, an inhibitor for KDM5 and KDM6, was shown to upregulate the metallothioneins and induce the ATF4-mediated stress response in myeloma cells, whereas the KDM5B inhibitors causes cell cycle arrest rather than apoptosis.

Advisor: Oppermann, U
Modelling perineural tumour invasion

Perineural Tumour Invasion (PNI) describes a particularly aggressive mode of tumour spread where cells exhibit a propensity to infiltrate neural structures very rapidly. Clinical observations in the case of Non-Melanoma Skin Cancer (NMSC) suggest that cells of an epidermal tumour can invade the nerve endings lying in deeper tissue (up to 4mm) within, at most, six weeks. Various hypotheses exist regarding the mechanism behind PNI. One such hypothesis is that random motion alone may be sufficient to produce invasion within the observed time frame. Other hypotheses consider an up-regulated proliferation rate, a reduced apoptotic rate or the existence of a chemical gradient that attracts tumour cells towards the nerve sheath.
We explore simple models of cellular processes such as migration, proliferation, death in the absence (and presence) of spatial gradients from a discrete stochastic cell-based perspective. We then associate a continuum description at the collective (tissue) level via deterministic models. These are obtained analytically as mean-field approximations of the stochastic setting in the thermodynamic limit. This enables comparison of the mean time of invasion produced by stochastic simulations of simple position- and velocity-jump processes to corresponding analytical estimates derived from the deterministic models. We, thus, formulate an appropriate mathematical framework which is used to predict the rates of the aforementioned cellular processes required for such rapid invasion.
Our framework illustrates how analysis of the first moments of the distribution of first-passage times to an absorbing barrier by specific position- and velocity-jump processes enables a comparison between the different hypotheses. The setting is extended to include branching and annihilation processes. Finally, we use this ensemble of model mechanisms to compare both analytical and numerical predictions to biological observations so as to assess the validity of the different hypotheses. Testing each hypothesis using this framework shows that for realistic parameter values, derived from the biochemical literature, the existence of chemical or other spatial gradients is necessary to achieve sufficiently rapid invasion. All other hypotheses are rejected because they predict slower invasion by several orders of magnitude.

Advisor: Gavaghan, D
Maini, P