VictorJuiz/thesis huggingface dataset:
In silico investigations into human ventricular pro-arrhythmic mechanisms combined with in vivo and in vitro experiments

Sudden cardiac death (SCD) is one of the largest causes of natural mortality throughout the world. SCD can be triggered through ventricular arrhythmias due to many pathological conditions, including coronary artery diseases, arrhythmogenic cardiomyopathies and genetic mutations of ionic channel proteins. Although considerable research has been conducted to study proarrhythmic mechanisms, most studies were in animal models due to ethical limitations in human cardiac research. Therefore, more research is needed to investigate the proarrhythmic ionic mechanisms in human.
In this thesis, we use biophysically-detailed models of human cardiac electrophysiology to explore the ionic mechanisms underlying several proarrhythmic conditions. A first study is to use traditional modeling approach to explore the effect of ionic remodelling in human epicardial border zone (EBZ) cells post myocardial infarction by introducing the analogous remodelling observed in canine. Sensitivity analysis of the human EBZ models leads to our interest in developing new techniques to include general variability into human cardiac electrophysiology research.
Therefore, a novel methodology to include the effect of in vivo cardiac variability in human electrophysiology is developed in this study by constructing a population of models calibrated using in vivo human data. The experimentally-calibrated population of human ventricular cell models is then applied to investigate the proarrhythmic ionic mechanisms underlying cardiac alternans, and to test the effects of potential anti-arrhythmic drug therapies on alternans. We then explore the interaction between cardiac variability and a mutation of slow delayed rectifier potassium channel. Our simulation results reveal the complex interactions between different ionic components in the integrated electrophysiological system, highlighting the importance of cardiac variability in the development of proarrhythmic conditions.

Advisor: Rodriguez, B
Orovio, A
Burrage, K
Mechanism of action and functional role of the two-pore channels (TPCs) in key vertebrate physiological processes

Two-pore channels (TPCs) represent a strong candidate for being pivotal components of the endolysosomal cation channels regulated by nicotinic acid adenine dinucleotide phosphate (NAADP), a novel Ca2+-releasing second messenger. A substantial body of evidence has implicated TPCs functional roles in key physiological processes, such as autophagy, osteoclast formation, neuronal differentiation, etc. Given the importance of Ca2+ signals in regulating skeletal muscle development and differentiation, and the rising prominence of NAADP/TPC signalling in regulating different aspects of physiological events, the first part of my research project sought to determine whether this lately-established Ca2+ mobilization also plays a role in myogenesis. By using morpholino-based knockdown of TPC2, together with bioluminescence-based Ca2+ imaging, a significant disruption of the characteristic Ca2+ signalling profiles generated by slow muscle cells of intact zebrafish embryos was noted. In addition, impairment in the gross and fine structure of the trunk of zebrafish embryos was apparent in TPC2 morphants. Thus suggesting involvement of TPC2 in regulating slow muscle cell development. On the other hand, whole-mount in situ hybridisation of intact zebrafish embryos revealed an expression of Tpcn3 mRNA, implicating TPC3 a role in zebrafish embryogenesis.
Previous study showed that TPC2 was transiently upregulated during the early stages of C3H10T1/2 adipocyte differentiation in vitro, the second part of my project aimed to investigate whether TPC2 plays a functional role in such process, also to identify the upstream mediators involved in regulating Tpcn2 expression and potential downstream effectors mediated by TPC2. My findings demonstrated impairment of adipogenesis in TPC2 knockdown cells and in cells depleted of lysosomal stores, indicating an involvement of TPC2 and lysosomal stores in such process. Besides, PKA and Epac were found to be required for the observed Tpcn2 upregulation, probably via a mechanism involving CREB activity, based on the findings that CREB bound to CRE element of Tpcn2 promoter. Preliminary results further suggested that calpain might be a potential effector of TPC2 in regulating C3H10T1/2 adipogenesis.
In view of the accumulating evidence showing the participation of NAADP in the nervous system, the third part of my work presented evidence of expression of Tpcn1 mRNA in several regions of the brain, implicating potential role(s) for TPC1 in those areas.

Advisor: Parrington, J
Ducks and decussation: information in the avian brain

A vertebrate brain must acquire, store, and process vast amounts of information. For birds, the majority of the incoming sensory information is visual, and like all vertebrates – except eutherian mammals – their visual system is bifurcated, with each eye feeding incoming information to the contralateral brain hemisphere. As a result, the bird must integrate these two banks of information to produce unified responses. This arrangement raises several questions about how a bird acquires, manages, and represents incoming visual information, and this thesis explores three of these questions. First, two studies investigate information integration across the two brain hemispheres in a long-term and short-term assay of birds trained monocularly with one eye and then tested with the other. The first finds that over a long term learning task in pigeons, some interhemispheric transfer of learned information occurs, but that complete integration does not occur. The second, using imprinting in ducklings, shows that the eye occluded during training has no demonstrable access to the learned information for at least three hours. A third study demonstrates that New Caledonian crows hold tools laterally in order to prioritize visual contact with the tool by their dominant eye during foraging, offering a potential underlying cause of this previously unexplained behavioural laterality. The fourth study explores the nature of information itself in the avian brain, showing that the maternal imprint formed by a newly hatched duckling can include abstract concepts defining the maternal stimulus, rather than just memory for visual images. This extends relational concept learning to a new species and suggests a much broader phylogenetic distribution of this ability. Combined, the studies suggest that the avian brain coordinates action managing two somewhat independent banks of information, biasing body positions in monocular tasks to allow control by a preferred eye, and has hitherto unsuspected capacity for abstract concept formation.

Keywords: tool use
crow
homing
abstraction
interhemispheric transfer
duck
pigeon
imprinting
corpus callosum
cognition
Advisor: Kacelnik, A
Biro, D
Guilford, T
Multi-gravity: can you have too much of a good thing?

The ongoing quest to map the space of possible, consistent field theories, and to determine their properties, is extremely interesting from a purely theoretical perspective, as well as being a prerequisite for the phenomenological application of any such theories. To that end, this thesis is concerned with various theoretical aspects of multi-gravity theories—that is, theories which contain multiple, interacting spin-2 fields.
The analysis presented here will proceed by using the Stueckelberg trick to reintroduce the multiple copies of diffeomorphism invariance which the theory would possess if none of the spin-2 fields interacted, and it is discussed in detail how to apply this to multi-gravity, and in particular how this differs from massive and bi-gravity.
The structure of the interactions which arise from the helicity-0 modes of the massive gravitons is examined in the so-called decoupling limit. It is found that the structure these take in bi-gravity is generalised to that of multi-Galileons, although this is not always manifest; an extension of the so-called Galileon duality is used to probe this.
Multi-gravity theories can be elegantly described using graphs to encode the network of interactions between the different fields, and this forms the basis for the other two questions which will be covered. When the theory contains a cycle of interactions, it is explicitly shown how this leads to the introduction of a ghost-like instability which is not present otherwise, and how this lowers the cutoff of the effective theory. In the absence of cycles, the structural properties of the graph which represents a given theory continue to play a large role in determining the scale at which the effective theory breaks down. This is the final topic, which is studied in detail, and upper and lower bounds on this scale are derived which depend on various properties of the graph.

Keywords: bi-gravity
multi-gravity
modified gravity
massive gravity
Advisor: Ferreira, P
March-Russell, J
A reception history of the letter to the Hebrews in England, 1547-1685

The interpretation of the letter to the Hebrews made a distinctive contribution to doctrinal construction, polemical controversy, and evolution of scripture-critical technique in the early modern period. This was because many of its themes and passages were considered significant to contemporary theological debates. Hebrews therefore offers an important case study for biblical reception history. This thesis adopts a diachronic approach, highlighting the priorities and worries of English Hebrews exegetes between the reigns of Edward VI and Charles II, and asks how these shifts catalysed hermeneutical advances towards higher biblical criticism.
Calvin interpreted Hebrews’ theology of sacrifice as an antidote to Catholic christology, soteriology, and beliefs about the mass. His thinking was adopted by Elizabethan Protestant readers, popularised through public documents like the Reformation Bibles (chapter one), and analysed in detail by sermons and lectures (chapter two). The reception of Hebrews also illustrates established historiography about the break-down of Reformed hegemony in England. Chapter three demonstrates how the use of the epistle by anti-puritans clashed with the censored Reformed exegete William Jones.
Scholars of the seventeenth century have largely ignored how Hebrews’ latent supersessionism promoted innovation in Church and society. Chapter four explores the way in which civil war Socinians expounded Christ’s priesthood in terms of heavenly expiation, while radicals seized on the epistle’s potential to support their vision of politico-religious liberation. Initially the Reformed countered by defending the trinity and Chalcedonian christology, as shown from mid-century exegesis in chapter five. However, two writers realised the underlying challenge of supersessionism and wrote Hebrews commentaries which served as systematic rebuttals. William Gouge deployed typology and Ramism to rebind the two dispensations (chapter six), and John Owen revised received expressions of the covenant in order to permit more development within God’s plan while retaining unity of purpose before and after Jesus (chapter seven).

Advisor: Rowland, C
Apetrei, S
Quantifying biases in a long-term field study: finding Wytham’s missing tits

Inferences drawn from long-term field studies of animals are vulnerable to biases in observability of different classes of individuals, which may lead to biases affecting ecological and evolutionary conclusions. Advancing statistical techniques are providing increasing evidence that individuals missing from population samples show consistent individual differences, although any resulting biases remain poorly understood. In this thesis, I investigate how biases can occur in estimating individual variation in reproductive success and residence behaviour within a natural great tit (Parus major) population. The primary objective of this thesis is to investigate whether individuals that are detected using standard sampling techniques are representative of the entire population. To do so, I use RFID technology to sample more completely across seasons, investigating individual detectability throughout the year.
I show that females that fail early in their breeding attempt, before they are identified under standard sampling protocols, are more likely to be young and immigrants from outside the study population and breeding in poorer quality habitats. As a consequence, estimates of the fitness of immigrants versus residents, age effects on fitness, and the age and immigration specific effects of habitat quality derived from standard survey methods are likely to be underestimates. I show that the high failure rate amongst immigrant females may be a result of late arrival time to the breeding grounds. These findings imply that costs of dispersal might impact on reproductive success. Moreover, I show that the exclusion of early nest failures from analyses can lead to underestimates in the effects of dispersal on reproductive success; as a consequence, current work concluding that immigrants have lower fitness than residents is likely to underestimate the size of this effect.
This thesis also provides some of the first baseline data tracking the presence or absence of passerines within a population across seasons. Our findings suggest that certain individuals are less likely to be detected as a function of their phenotype. We identify sex as a predictor of failure to be detected breeding, with males less likely to be detected. We also find that the likelihood of detection during successive breeding and winter surveys is repeatable across years. This adds to a gathering body of knowledge suggesting that sampling at certain times of the year selects for specific phenotypes. This thesis represents the first large-scale investigation of individuals that remain undetected in a long-term great tit population study, demonstrating that more attention should be given to the question of whether methods for surveying natural populations introduce systematic biases that influence conclusions about ecological and evolutionary processes.

Keywords: Parus major
Wytham Woods
Great Tit
Advisor: Sheldon, B
Cole, E
'Local, loyal and constant'? On the dynamism of terroir in sustainable agriculture

Terroir is a concept that is used in France, and increasingly elsewhere, to evoke character and quality in food and drink in relation to the place it comes from. In this thesis, I investigate how terroir has attained its present-day economic value and cultural resonance; how it is subject to multiple forms of articulation across France; and how it is put to use as part of the philosophies and practices of environmentally sustainable modes of production. I use cultural and historical modes of enquiry and I draw upon interviews, participant observation, discourse and archive analysis carried out on fieldwork in three production chains in eastern France; being wine production in Burgundy, walnut production in the Isère valley, and Reblochon cheese production in the Alps. In the course of this thesis, I elucidate the cultural significance and epistemology of the concept, and make arguments that propositions for terroir consist of both specific geographical extent and historical density of explanation; that the rhetorical assembly of stories about terroir permits claims for continuity in production and tradition; and that the adoption of organic and biodynamic methods of farming troubles inherited understandings of what terroir is, through the intervention of the lively propensities of biotic actors. This is a story about food, farming and culture in France that I tell to critically examine the local, loyal and constant predicates of terroir, and to make an original contribution to our understanding of the cultural and historical background to the French and European systems of geographical protection in food and drink.

Keywords: Drink
Terrior
France
Advisor: Whatmore, S
Materiality in numerical cognition

Using the Material Engagement Theory of Cognitive Archaeologist Lambros Malafouris as its framework, the thesis offers a unique synthesis of data from neuroscience, ethnography, linguistics, and archaeology to outline how number concepts are realized, manipulated, and elaborated. The process is described as an interactivity of psychological processes like numerosity, behaviors that manipulate objects into concept-generating stimuli, and material objects with semiotic qualities distinct from those of language and agency distinct from that of brains and bodies.
The counting technologies of the Ancient Near East (ANE) are then analyzed through archaeological and textual evidence spanning the late Upper Paleolithic to the Bronze Age, from the first realization of number concepts in a pristine original condition to their elaboration into one of the ancient world’s greatest mathematical traditions, a foundation for mathematical thinking today. Insights from the way numbers are realized through psychological–behavioral–material interactivity are used to challenge three dominant conceptualizations of ANE numbers: first, the idea that the ANE numerical lexicon would have counted only to very low numbers; second, that Neolithic tokens were the first counting technology; and third, that numbers were ‘concrete’ before they became ‘abstract’. Considering archaeological evidence from the Epipaleolithic Levant and drawing on linguistic and ethnographic evidence to characterize the regional prehistory, the thesis suggests that the numerical lexicon would have included relatively high numbers prior to the Neolithic; that finger-counting (linguistically attested) and tallies (archaeologically attested) would have preceded tokens; and that numbers are ‘abstract’ concepts whose content changes in conjunction with the incorporation and use of different material forms. The evidence provided to support these alternatives implies that numbers may have originated in the late Upper Paleolithic and arithmetic early in the Neolithic, pushing the onset of these capabilities further back than is commonly held.
In addition to tallies and tokens, the thesis explores fingers and numerical notations as material artifacts, enabling an analysis of how materiality might structure numerical concepts, influence a number system’s capabilities, limitations, and elaboration potential, and affect brains and behavior over cultural spans of time. Insights generated by the case study are then applied to the role of materiality in cognition more generally, including how concepts become distributed across multiple material forms; the reasons why materiality might be transparent (or invisible) in cognition; and the differences between thinking through and thinking about materiality.

Keywords: Cognitive Archaeology
Numeracy
Numerosity
Advisor: Malafouris, L
Gosden, C
Imitation: evaluating neurophysiological signatures and clinical significance

Imitation and its neural basis has been the subject of great interest, particularly for researchers interested in autism spectrum disorders (ASD). Research has reported imitation deficits in ASD, which have been theoretically linked to the condition’s sociocommunicative difficulties. Abnormalities in the mirror neuron system (MNS), as measured using EEG techniques, have also been reported in autism, and linked to imitation skills. In this thesis, I examine questions both around behavioural imitation deficits, and the validity of EEG techniques used to investigate the MNS. I consider whether children with other communication disorders show similar imitation deficits to children with autism, examining verbal and motor imitation. I report data from non-autistic children with and without language problems, and children with autism and normal language (ANL) and children with autism and language-impairment (ALI). In contrast to previous studies, I find similar verbal imitation performance in children with ALI and non-autistic language impaired children, but limited motor imitation impairments in the disorder groups. I also examine the evidence from mu suppression studies for the role of the MNS in language, social processes and the development of ASD. I present findings from a preregistered study that show that methodological factors such as baseline condition have important effects on mu suppression studies’ results, and question its validity as an MNS measure. I also examine how imitation skills, self-reported communication abilities and autistic traits relate to individual differences in mu suppression. I find limited support for the theory that mu suppression correlated with behaviours and traits proposed to be underpinned by the MNS. I discuss the implications of these two projects for future research and clinical interventions for children with communication disorders.

Keywords: autism
imitation
mirror neurons
language impairment
Advisor: Bishop, D
Investigating primary and secondary B cell responses in cattle after immunisation with existing and novel vaccines

Antibodies play a pivotal role in protecting against viral infection, maintenance of this protective response is provided by plasma and memory B cells. Foot and mouth disease virus (FMDV) is a highly contagious pathogen and studies in cattle have shown that protection from the virus is antibody-mediated. However, FMDV vaccines are unable to achieve long durations of immunity. Therefore, understanding the FMDV-specific B cell responses in cattle is essential to inform future vaccine design.
Antigen-specific ELIspot assays were used to determine the kinetics of the bovine B cell response to T-dependent and -independent antigens. An ELIspot assay was developed to allow enumeration of FMDV-specific plasma and memory B cells following vaccination and live-virus challenge. In addition, a novel surgical technique was also developed to allow enumeration of antigen-specific B cells when exiting a regional lymph node, following vaccination. The bovine immunoglobulin repertoire was investigated at the peak of the B cell responses using deep sequencing.
T-dependent B cell responses in cattle were characterised by a small burst of antigen- specific plasma cells occurring after the primary vaccination, which was coupled with an increase in antigen-specific IgG titres. In keeping with the central dogma of immunolog- ical priming, the plasma cell burst post booster vaccination was larger and more rapid. Antigen-specific memory B cells were detectable for over 6 months. In contrast, immu- nisation with a T-independent antigen resulted in no detectable plasma or memory B cells. Vaccination with inactivated FMDV, novel FMDV antigens and live-virus chal- lenge induced in a burst of FMDV-specific plasma cells but low numbers of memory B cells. Deep sequencing of immunoglobulin transcripts at the peak of the antigen-specific plasma cell response post vaccination, detected increases in bovine IgG transcripts in both blood and efferent lymph following booster vaccination, indicating that they are likely to be FMDV-specific. Deep sequencing has also revealed that cattle exhibit a broad range of heavy chain CDR3 lengths and highly similar light-chain transcripts that are shared between animals. Overall, this data suggests that the kinetics of the bovine plasma and memory B cell response to antigen is similar to that demonstrated in humans and mice. However, the bovine antibody V region structure is different and is likely to interact with its cognate antigen differently.

Keywords: foot-and-mouth disease virus
bovine
B cell
Advisor: Pollard, A