VictorJuiz/thesis huggingface dataset:
An open source HPC-enabled model of cardiac defibrillation of the human heart
Keywords: Chaste
computational cardiac electrophysiology
parallel computing
software engineering
cardiac defibrillation
linear solvers
finite element method
preconditioning
bidomain equations

Sudden cardiac death following cardiac arrest is a major killer in the industrialised world. The leading cause of sudden cardiac death are disturbances in the normal electrical activation of cardiac tissue, known as cardiac arrhythmia, which severely compromise the ability of the heart to fulfill the body's demand of oxygen. Ventricular fibrillation (VF) is the most deadly form of cardiac arrhythmia. Furthermore, electrical defibrillation through the application of strong electric shocks to the heart is the only effective therapy against VF. Over the past decades, a large body of research has dealt with the study of the mechanisms underpinning the success or failure of defibrillation shocks. The main mechanism of shock failure involves shocks terminating VF but leaving the appropriate electrical substrate for new VF episodes to rapidly follow (i.e. shock-induced arrhythmogenesis).
A large number of models have been developed for the in silico study of shock-induced arrhythmogenesis, ranging from single cell models to three-dimensional ventricular models of small mammalian species. However, no extrapolation of the results obtained in the aforementioned studies has been done in human models of ventricular electrophysiology. The main reason is the large computational requirements associated with the solution of the bidomain equations of cardiac electrophysiology over large anatomically-accurate geometrical models including representation of fibre orientation and transmembrane kinetics.
In this Thesis we develop simulation technology for the study of cardiac defibrillation in the human heart in the framework of the open source simulation environment Chaste. The advances include the development of novel computational and numerical techniques for the solution of the bidomain equations in large-scale high performance computing resources. More specifically, we have considered the implementation of effective domain decomposition, the development of new numerical techniques for the reduction of communication in Chaste's finite element method (FEM) solver, and the development of mesh-independent preconditioners for the solution of the linear system arising from the FEM discretisation of the bidomain equations.
The developments presented in this Thesis have brought Chaste to the level of performance and functionality required to perform bidomain simulations with large three-dimensional cardiac geometries made of tens of millions of nodes and including accurate representation of fibre orientation and membrane kinetics. This advances have enabled the in silico study of shock-induced arrhythmogenesis for the first time in the human heart, therefore bridging an important gap in the field of cardiac defibrillation research.
A POD-Galerkin approach to the atmospheric dynamics of Mars
Keywords: low-order models
atmosphere
Mars
proper orthogonal decomposition

The observation of less chaoticity and enhanced interannual periodicity of transient waves in the Martian atmosphere in comparison with that of the Earth suggests the hypothesis of a low-dimensional underlying atmospheric attractor. Grounded on this hypothesis, two questions can be asked: is there a small set of atmospheric modes, measured and classified by a suitable norm, capable of describing the atmosphere of Mars? If this set exists, are those atmospheric modes able to reproduce the dynamical behaviour of the atmosphere of Mars? The answer to these questions, constituting the central focus of this thesis, has led to the first application of POD-Galerkin methods to a state-of-the-art Mars general circulation model. The proper orthogonal decomposition (POD) as a method for extracting coherent structures, called empirical orthogonal functions (EOFs), provided a means to answer the first question in the positive. An important amount of atmospheric total energy (TE) was found to be concentrated in a few EOFs (e.g., 90% TE in 20 EOFs). The most energetic EOFs were identified with atmospheric motions such as thermal tides and transient waves. The Galerkin projection of the hydrostatic primitive equations onto the span of the EOFs provided a systematic method to establish physically plausible interactions between the most energetic EOFs. These interactions were complemented with closure schemes representing interactions with unresolved modes. This requirement proved to be essential in order to obtain bounded behaviour. In the diagnostic analysis, represented by the POD alone, increasing the number of EOFs directly leads to a better approximation of the atmospheric state. In contrast, the dynamic reconstruction of the atmospheric evolution does not depend only on the number of included EOFs. Other important factors to obtain realistic evolution are the inclusion of every mode involved in the description of a particular kind of motion (diurnal tide, semidiurnal tide or transients) and the retention of higher order modes that may interact strongly with the modes of interest. Once these conditions are satisfied the behaviour of the reduced models is greatly improved. Implications of these findings for future work are discussed.
A semantics for aspects by compositional translation
Keywords: translation
full abstraction
aspect oriented programming
imperative programming
game semantics
programming language semantics

We analyse the semantics of aspect-oriented extensions to functional languages by presenting compositional translations of these primitives into languages with traditional notions of state and control. As a first step, we examine an existing semantic description of aspects which allows the labelling of program points. We show that a restriction of these semantics to aspects which do not preempt the execution of code can be fully abstractly translated into a functional calculus with higher order references, but that removing this restriction requires a notion of exception handling to be added to the target language in order to yield a sound semantics. Next, we proceed to show that abandoning the labelling technique, and consequently relaxing the so-called obliviousness'' property of aspectual languages, allows preemptive aspects to be included in the general references model without the need for exceptions. This means that the game model of general references is inherited by the aspect calculus. The net result is a clean semantic description of aspect-orientation, which mirrors recently published techniques for their implementation, and thereby provides theoretical justification for these systems. The practical validity of our semantics is demonstrated by implementing extensions to the basic calculus in Standard ML, and showing how a number of useful aspect-oriented features can be expressed using general references alone. Our theoretical methodology closely follows the proof structure that often appears in the game semantics literature, and therefore provides an operational perspective on notions such as bad variables'' and factorisation theorems.
Perisomatic-targeting interneurons control the initiation of hippocampal population bursts
Keywords: sharp waves
population bursting
ripple oscillations
inhibition
interneurons
CA3
hippocampus

Replay of spike sequences can be seen during sharp wave – ripple population burst activity in the hippocampus. It is thought that this activity, which occurs during rest and sleep, is involved in memory consolidation. The cellular mechanisms underlying the initiation of these replay events are not well understood. To investigate this, a hippocampal slice model, showing spontaneous sharp wave – ripple activity, and a combination of planar multi-electrode array recordings and whole-cell patch-clamp recordings of anatomically identified hippocampal neurons were used. Firstly, the spatial and temporal profile of sharp waves in vitro was analysed in detail. Sharp waves were generated by changing subpopulations of pyramidal neurons in the CA3 region and had characteristics similar to those found in vivo. Secondly, four major receptor types present in hippocampal CA3, namely NMDA, AMPA, GABAA and GABAB receptors, were investigated for their involvement in sharp wave generation. Surprisingly, not only AMPA receptor-mediated events, but also phasic GABAA receptor-mediated inhibition, were necessary for sharp wave generation. Thirdly, single perisomatic-targeting interneurons were activated. This experiment showed that induced spiking activity of an individual perisomatic-targeting interneuron can both suppress and subsequently enhance local sharp wave generation. Spiking activity of other neuron types (i.e. pyramidal neurons, dendritic-targeting interneurons and interneuron-selective interneurons) had no significant effect on sharp wave incidence. Finally, it is suggested that this post-inhibitory enhancement of sharp wave generation can be mediated by a transient increase in the ratio of excitation to inhibition in the local network. In conclusion, these results suggest a new role for perisomatic-targeting interneurons in controlling the local initiation of sharp waves by selectively suppressing and subsequently enhancing recruitment of a subpopulation of pyramidal neurons. These results further imply that interneurons may play an integral part in the local information processing that takes place in the hippocampal network.
Comparative analysis of derived mutations across human populations.
Keywords: Human population genetics

Multiple factors, including the rate of mutation of different types, the action of natural selection, recombination and population history all influence the distribution of genetic variation within and between populations. Here, we seek to explore the relative contributions of different factors to notable aspects of the derived site frequency spectrum in different populations from the 1000 Genomes Project. Specifically, we ask whether individuals from different populations carry different numbers of mutations (indicative of differences in the mutation rate or average generation time of populations) and whether patterns differ between types of mutation in different sequence contexts. Our results indicate that the average mutation rate (per year) in African populations has been slightly, but significantly, higher than in non-African populations which has led to an enrichment in the number of derived alleles harbored in African populations. In a departure from the literature, we find that the non-synonymous mutation load does not vary between populations. We present weak evidence for differential mutational processes at CpG sites in African individuals and estimate a TMRCA of the human population as approximately 3.5 mya. Last, we suggest ways in which our knowledge of derived alleles can allow us to make improvements to existing population genetic methods, such as the sequentially Markov coalescent.
HR23B, a biomarker for HDAC inhibitors
Keywords: HDAC inhibitor
apoptosis
cancer
HDAC 6
autophagy
biomarker
HR23B

As our understanding of cancer biology increases and novel therapies are developed, an increasing number of predictive biomarkers are becoming clinically available. Aberrant acetylation has been strongly linked to tumourigenesis and the modulation of acetylation through targeting histone deacetylase (HDAC) has led to the introduction of many HDAC inhibitors. To date, two have had regulatory approval for the treatment of cutaneous T cell lymphoma (CTCL). Modifications in chromatin control underpin the mechanism of action of HDAC inhibitors. A genome wide loss-of-function screen identified HR23B as a gene that governs sensitivity to HDAC inhibitors. HR23B shuttles ubiquitinated cargo proteins to the proteasome and elevated levels may contribute to cell death mediated by this pathway. It also governs cell sensitivity to drugs that act directly on the proteasome. HDAC inhibitors influence proteasome activity and there may be a synergistic interaction with proteasome inhibitors. HR23B and HDAC6 interact and HDAC6 may be a negative regulator of apoptosis and a positive regulator of autophagy and through its ability to down-regulate HR23B, may impact on the cellular outcome of HDAC inhibitor treatment. Expression of HR23B has been correlated with clinical response to HDAC inhibitors in a retrospective analysis of CTCL patients. The tissue expression of HR23B and the autophagy marker LC3 has been investigated and there may be a reciprocal relationship in their expression in some tumours which may provide prognostic information and patients with low HR23B expression but high levels of autophagy appear to have a particularly poor prognosis. Well designed, biomarker-driven prospective clinical trials are needed to clarify the predictive and prognostic roles of HR23B.
Emergent social structure and collective behaviour from individual decision-making in wild birds
Keywords: Social behaviour
Interspecific interactions
Social selection
Ornithology
Wytham Woods
Mixed-species flocking
Self-organisation
Social networks
Collective behaviour
Paridae

Social behaviour is shaped by complex relationships between evolutionary and ecological processes interacting at different scales. Benefits gained from social associations can range from predator dilution to collective sensing, but little is known about how these can be influenced by social structure and phenotypic composition. In this thesis, I investigated how individual decision-making affects phenotypic social structure, and how this mediates social behaviour through emergent properties of collective group behaviour.
First, using mixed-species flocks as a model system, I showed individual tits (Paridae, chapter 2) and thornbills (Acanthizae, chapter 3) varied significantly in their social positions. Within-species variation in network position was as large as between-species variation, sug- gesting that prescribing functional roles at the species level may not sufficiently account for potential differences in fitness operating at the individual level. Rather, this suggested that structure may be driven by phenotypic traits, underpinning network structure (chapter 4).
Next, I used an extensive data set of foraging records to explore factors determining the composition, of flocks of great tits (Parus major, chapter 5). For example, assortment by dispersal phenotype (immigration status) was the result of spatial disaggregation, and I showed that this may facilitate social selection for breeding territories (chapter 6).
Finally, I investigated how decision-making shaped mixed-species social structure. I found that tits used a common strategy for managing pressures of predation and starvation by shifting from exploration to exploitation at different times of the day (chapter 7). I then found that a very simple interaction rule successfully replicated mixed-species group structure (chapter 8). Strikingly, the same rule was applied to both conspecifics and het- erospecifics, potentially playing an important role in the maintenance of flock structure. Through experimental manipulation of ecological conditions, I found that heightened per- ceived predation resulted in stronger social attraction overall, whereas increased competition led to a reduction in attraction to conspecifics (chapter 9). Simulations suggested this could be one potential mechanism underpinning fission-fusion dynamics in these species.
Together, the results in this thesis form a framework linking social behaviour to individ- ual fitness where natural selection is shaped by the social environment. This approach may prove useful for testing whether following common social rules reduces variance in benefits accrued by individuals, and how within-species variation in social behaviour can impact emergent properties of groups.
Measurements of vector boson production in association with jets at the LHC using the ATLAS detector
Keywords: QCD
Standard Model
jets
Z boson
W boson

This thesis presents measurements of the cross section for the production of a W boson in association with jets and the ratio of the cross sections for the production of a W boson and a Z boson in association with jets. Both measurements are performed in proton-proton collisions at √s = 7 TeV with the ATLAS experiment at the Large Hadron Collider using a dataset corresponding to an integrated luminosity of 4.6 fb-1. The dataset allows for the exploration of a large kinematic range, including jet production up to a transverse momentum of 1 TeV and multiplicities up to seven jets. Results are presented as a function of jet transverse momenta and rapidities and as a function of event variables such as the scalar sum of the transverse momenta of the jets. Results as a function of dijet angular variables are also presented. The measurements are compared to several state-of-the-art QCD predictions including next-to-leading-order perturbative calculations, resummation calculations and Monte Carlo generators. Finally, the effect of the results on parton distribution functions is explored.
Development of novel hyperpolarized magnetic resonance techniques for metabolic imaging of the heart
Keywords: magnetic resonance imaging
hyperpolarisation
energy metabolism
dynamic nuclear polarisation

The advent of hyperpolarized magnetic resonance (MR) has provided new potential for real-time visualization of in vivo metabolic processes. The aim of the work in this thesis was to use hyperpolarized substrates to study rapid metabolic processes occurring in the healthy and diseased rat heart. Initial work, described in Chapter 2, optimized the hyperpolarization process to reproducibly generate tracers. Chapter 3 describes use of hyperpolarized 1-13C-pyruvate to investigate in vivo flux through the regulatory enzyme pyruvate dehydrogenase (PDH). Cardiac PDH activity was altered in several physiological and pathological states, namely fasting, type 1 diabetes, and high-fat feeding, and in vivo flux through PDH was measured using hyperpolarized MR. These measurements correlated with measurements of in vitro PDH activity obtained using a validated biochemical assay. The work in Chapter 4 investigated the physiological interaction between hyperpolarized tracer and cardiac tissue. The effect of hyperpolarized 1-13C-pyruvate concentration on its in vivo metabolism was analyzed using modified Michaelis-Menten kinetics. It was found that hyperpolarized MR could non-invasively follow mechanisms of metabolic regulation, in addition to reporting enzyme activity. In Chapter 5, hyperpolarized MR was incorporated into the isolated perfused rat heart. 1-13C-pyruvate in normal and ischaemic hearts revealed significant differences in lactate metabolism, and provided the foundation for a novel intracellular pH probe. Infusion of 2-13C-pyruvate in the isolated rat heart enabled the first real-time visualization of Krebs cycle intermediates. In summary, the work in this thesis has highlighted the potential of hyperpolarized MR to reveal novel information on heart disease.
Three-dimensional analysis of tunnelling effects on structures to develop design methods
Keywords: settlement
tunnelling

The subject of this thesis is the verification of a three-dimensional numerical modelling approach for the prediction of settlement damage to masonry buildings due to tunnelling in soft ground. The modelling approach was developed by previous researchers at Oxford, and was applied to three sites, representative of a range of practical configurations. The first involved the excavation of a shaft close to the corner of an eighteenth century church in London. The second involved tunnelling with very low cover beneath the foundations of a terrace of cottages at Ramsgate, Kent. The third was the relatively well-known case of tunnelling beneath the Mansion House, London, for construction of the extension to the Docklands Light Railway in the late 1980’s. The overall conclusion of the project is that the modelling procedures are suitable for application to the detailed assessment of the response of buildings to tunnelling. Particular features of the procedures are that the building is modelled together with the ground and a representation of the tunnel excavation, and in three dimensions. It has been confirmed that all these features are necessary to model the building response, which may include a combination of shear deformation, arching and bending behaviour. Further lessons have been learned concerning the importance of the self-weight of the building in determining overall settlements, how to model openings such as doors and windows in façades, and whether it is necessary to model the building foundation. It has not proved possible, through lack of time, to model the advance of tunnels beneath buildings within this thesis. This, however, is observed to be an important effect in the field, particularly in causing damage to internal walls. It is recommended that further research be carried out in this area. This project made use of large-scale non-linear finite element analysis. The demand on computing resources was high, stimulating many enhancements to the software, the most important of which was parallelisation of the analysis program for use on the Oxford Supercomputer. To obtain optimum results, larger model sizes are required. The computing resources to enable this should become more commonly available within the next few years, enabling the modelling techniques to be used routinely.