VictorJuiz/thesis huggingface dataset:
Investigation into pathophysiological mechanisms that alter ryanodine receptor function in cardiovascular disease

Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is a highly malignant cardiac disease caused by mutations to the cardiac ryanodine receptor (RyR2). Mutations at RyR2, including the V2475F mutation, lead to inappropriate diastolic Ca2+ release thereby triggering arrhythmogenesis and sudden cardiac death (SCD).
In order to identify specific alterations to RyR2 caused by the V2475F mutation, this research utilised native RyR2 channels derived from heterozygous (+/-) V2475F-mutated mouse cardiac tissue in single-channel artificial bilayer experiments. Phospho-specific antibodies were used to quantify phosphorylation levels at S2808 of wild-type (WT) or CPVT1-mutated RyR2, and spontaneous Ca2+ release in intact cardiomyocytes was assessed using a Ca2+-indicator.
These experiments revealed that the V2475F mutation caused highly aberrant RyR2 responses to cytosolic Ca2+ and Mg2+, overall demonstrating a hyperactive RyR2 channel in nanomolar and low micromolar cytosolic [Ca2+] alongside insensitivity to inhibition by cytosolic Mg2+. Some V2475F(+/-) RyR2 channels even displayed an agonistic response to cytosolic Mg2+. In agreement with these findings, intact cardiomyocytes derived from V2475F(+/-) hearts revealed a shorter latency to spontaneous Ca2+ release compared to WT. Furthermore, phosphorylation at S2808 was not altered but the Po at every quantified phosphorylation level was higher for RyR2 channels derived from V2475F(+/-) hearts compared to WT hearts.
Other novel findings were observed in this CPVT1-mutant RyR2, including modifications to single-channel Ca2+ conductance, and that atorvastatin was unable to inhibit these hyperactive channels. Moreover, modelling the V2475F single-channel behaviour against the proposed distribution of heterozygosity suggested that greater dysfunction may be caused by RyR2 channels with three or four mutated monomers per tetramer.
This work has revealed changes to RyR2 function that are specific to the V2475F mutation. Some of these dysfunctions have not been observed previously, highlighting the importance of comprehensive and patient-specific study of CPVT1-mutated RyR2 channels.

Keywords: ryanodine receptor
ion channel
single-channel
cardiovascular
catecholaminergic polymorphic ventricular tachycardia
channelopathy
sudden cardiac death
RyR2
electrophysiology
Ca2+ release
Advisor: Sitsapesan, R
Regulation of KATP channel activity

ATP-sensitive potassium (KATP) channels are present in many tissues, most notably pancreatic islets and cardiac cells, where they couple the metabolic state of a cell to its electrical activity by regulating the flow of K+ across the membrane in response to the intracellular ATP/ADP ratio. KATP channels are an octameric complex, comprised of four inwardly-rectifying potassium channel (Kir) subunits, each of which is associated with a sulphonylurea receptor (SUR) subunit. In pancreatic islets, KATP channels are formed by Kir6.2 and SUR1. The physiological regulation of KATP activity by the ATP/ADP ratio is the summed contribution of activation by Mg-nucleotides binding to SUR1, and inhibition by nucleotides binding to Kir6.2. Mutations in either Kir6.2 and SUR1 which lead to diseases of insulin secretion are frequently observed to disrupt the nucleotide regulation of the channel. In this thesis, I describe the development and application of a method to directly measure nucleotide binding to Kir6.2, using a fluorescent congener for ATP and Forster resonance energy transfer (FRET). Measuring binding simultaneously with measurements of KATP channel current inhibition confirms that a Monod-Wyman-Changeaux (MWC) type allosteric model is able to describe KATP channel inhibition by nucleotides, and that a single bound nucleotide is enough to close the majority of channels. The combination of binding and current measurements with MWC modelling is then applied to determine how mutations at different residues of Kir6.2 and SUR1 contribute to nucleotide binding and transduction at the inhibitory binding site.

Keywords: Ion channels
Electrophysiology
Non-canonical amino acids
Fluorescence spectroscopy
Advisor: Ashcroft, F
Stansfeld, P
Mountains, steppes and empires: approaches to the North Caucasus in the early middle ages

People in the valleys and foothills north of the Caucasus mountain range have lived on the edge of empires for over five thousand years, while resisting incorporation into any single empire until recently. This thesis examines interactions between the agrarian empires of the Near East, the nomadic empires of the western Eurasian steppe and the highlanders of the North Caucasus (especially, but not exclusively, the Alans) in the eighth to tenth centuries CE. The North Caucasus was a ‘hinterland’ of empires, where forms of radical social autonomy could be preserved (James Scott). This made its history distinct from imperial ‘peripheries’ in the South Caucasus and around the Black Sea coast. It was a zone of contact, where people from different cultures could sometimes find ‘Middle Ground’ (Richard White), but where patterns of imperial dominance and violence could also cast long shadows (Carolyn Nordstrom).
This thesis approaches the early medieval North Caucasus through writing produced in the Byzantine Empire and the ‘Abbāsid caliphate, and through Russian archaeology of the region. The ‘Abbāsid historian al-Balādhurī (chapter two) offers a perspective on the legacy of Sasanian imperialism and outlines resources that the ‘Abbāsid state could draw on from the region. Burial, settlement and landscape archaeology of the Kislovodsk Basin allow us to see the region from within, where we find a transformation of the region’s social structure between the eighth and tenth centuries (chapter three). The exceptional preservation of textiles in North-West Caucasian burial sites (chapter four) reveal how the highlanders were connected to far-flung places, resources and ideas, even while they maintained political autonomy. This remained so after the growth of Christianity in the region in the tenth century, for which Byzantine written sources and the archaeology of the region provide the crucial evidence (chapter five).

Keywords: Archaeology
Early Islam
Byzantium
History
Early Middle Ages
Steppe history
North Caucasus
Advisor: Shepard, J
Whittow, M
Universal aspects of perturbative gauge theory

Gravity amplitudes, at tree level, can be computed from gauge theory amplitudes using the (field theory) KLT relation. Underlying the KLT relation are the `Kleiss-Kuijf' and 'fundamental BCJ' identities satisfied by gauge theory partial amplitudes. These identities, and the KLT relation, are proved in an elementary way using properties of Lie polynomials, and the properties of a Lie bracket we call the 'S bracket', which has appeared in examples in superstring calculations. The S bracket is also closely related to string-like formulas which express partial amplitudes as sums of residues of rational functions on M0,n. In this context, identities amoung rational functions on M0,n allow us to prove a formula for non-linear sigma model partial amplitudes.
In the last decade, organising the computation of tree and loop amplitudes into the volumes of polytopes has led to new formulas for partial amplitudes in special cases. More generically, the ABHY associahedron is a polytopal realisation of the associahedron that is directly related to the tree level partial amplitudes of all gauge theories. It is known that the ABHY associahedron can be derived by studying An quiver representations. Generalised ABHY polytopes are defined here, associated to Artinian module categories. The faces of an ABHY polytope are themselves isomorphic to ABHY polytopes of lower dimension. When this generalised definition is applied to categories associated to surfaces, the ABHY polytopes relate to the 'loop level' and 'multi-trace' partial amplitudes of the conventional Feynman perturbation series for biadjoint scalar theory. It is suggested that understanding these partial amplitudes and their ABHY polytopes will be important for stating and proving a correct generalisation of the (field theory) KLT relation to the full amplitudes of gauge theory and gravity.

Advisor: Mason, L
Emotional influences on cognitive control: a missing factor in research on 'bilingual advantages'?

Over half of the world’s population is multilingual with globalisation and migration ensuring a steady growth. This fact has inspired several flourishing research fields within the areas of emotion, cognition and linguistics. Yet, existing research on cognitive consequences of bilingualism has not taken into account the effect of emotion on this relationship. This dissertation addresses this gap. Based on the hypothesis that bilingualism leads to adaptations in the mechanisms underlying both emotion and cognitive control, we propose a framework that integrates theoretical and empirical perspectives from emotion, cognition, and linguistics research. To validate our approach, we devise three novel studies in order to test cognition–emotion interactions across different groups of monolinguals and bilinguals.
In Study 1, 24 English monolingual and 24 German–English bilingual adults completed a flanker-go/no-go (FNG) task. The participants viewed sets of three faces side-by-side in the centre of a computer screen and were instructed to press a button if the gender of the central neutral target face corresponded to the ‘go’ gender, which occurred in 66% of trials. The task-irrelevant ‘flanker’ faces expressed either positive, negative, or neutral emotion and were furthermore either gender-congruent or -incongruent to the target. In Study 2, 28 diverse bi- and multilingual adults completed the FNG task alongside 28 monolinguals. In addition, 29 monolinguals and 29 bilinguals completed a forced-choice flanker-only (FO) variant of the task. Study 3 repeated Study 2 with 10–11 year-old monolingual and English–French/German bilingual children. 36 bilinguals and 20 monolinguals completed the FNG task, while 35 bilinguals and 23 monolinguals completed the FO task.
Differences between the monolingual and bilingual groups were observed across all studies in the FNG task, but not in the FO task. Notably, the bilingual children also made significantly fewer errors in no-go trials across all conditions than their monolingual counterparts, providing novel evidence for a bilingual advantage in response inhibition. In Study 2, the multilinguals evidenced different response strategies than the other groups, suggesting that adaptations in cognitive control can vary based on the type of multilingual experience.
We interpret these findings based on an integrative theoretical framework of cognitive control, emotion, and bilingualism, and discuss their implications for research across all three fields.

Keywords: bilingual advantage
bilingualism
cognitive control
executive functions
emotion
Advisor: Murphy, V
Scerif, G
Living with Art: Repositioning the late works of Thomas Bernhard

This study re-evaluates and repositions the late writings of the Austrian author Thomas Bernhard (1931-89). Over thirty years after his death, Bernhard is widely considered to be a writer of international relevance. He is renowned for his bleak portrayals of modern society, his scandalous critiques of his homeland, and his infectious and much-imitated linguistic style. But there is another side to Bernhard—one which existing analyses of his domestic controversies and foreign fanbases are yet to examine fully. In this study, I argue that Bernhard’s late prose and dramatic works are centrally concerned with the relationship between art and social living. He explores forms of learning from art, and how engaging with art can affect ways of behaving towards others and oneself.
This study resituates Bernhard’s late works outside of their more conventional domestic contexts to bring these aspects of his writings more clearly into focus. Starting from a reconsideration of what it means to read Bernhard as world literature, I reposition the author alongside three Anglophone points of comparison: Angela Carter, Timberlake Wertenbaker, and J. M. Coetzee. These authors, who are yet to be compared with Bernhard in scholarship, allow me to re-evaluate his late prose and dramatic works beyond their local controversies in 1980s Austria; they help me to illuminate the humanity and self-awareness of a writer more commonly associated with unremitting negativity; and they enable me to investigate what Bernhard’s late works still have to say about art, decades on from his cultural moment. Reimagining Bernhard beyond his familiar intertexts, his existing international reception, and his own self-staging, this study will be of interest to scholars of Bernhard, late twentieth-century literature, and comparative literature more generally.

Keywords: Austrian Literature
Comparative Literature
German Literature
Art and Society
Thomas Bernhard
Advisor: Morgan, B
Discovering a novel therapy for disorders that feature defects of the neuromuscular junction structure

Background: Congenital myasthenic syndromes (CMS) are a group of inherited disorders that affect signal transmission at the neuromuscular junction (NMJ) and share the clinical feature of fatigable muscle weakness. Downstream of tyrosine kinase 7 (DOK7) is a cytoplasmic-adaptor protein that amplifies the signalling from the muscle-specific receptor tyrosine kinase (MuSK), which is responsible for the formation and stabilisation of the NMJ. It has recently been shown that overexpression of DOK7 protein in muscles, generates enlarged NMJs in mice, which are very efficient in signal transmission, have no reported detrimental effects and can ultimately lead to a complete recovery for disease model mice.
Aim: To study novel therapies for CMS based on DOK7 overexpression.
Results: By using an adeno-associated virus system (DOK-AAV) we generated enlarged NMJs in wild-type mice to further investigate the morphology and electrophysiology of these synapses. The DOK7-AAV gene therapy was shown to generate enlarged synapses that improved the phenotype of two animal models of CMS. In addition, 5431 small molecules from a library of muscle-specific compounds were used in screening experiments to find potential small molecules that could upregulate DOK7. Confirmatory results were performed on an assay of biological activity and revealed two potential small molecule hits. They will provide the basis for a more detailed analysis of the effects of DOK7 upregulation in cell culture biological assays and ultimately for in vivo testing.
Conclusion: These studies demonstrate that DOK7 upregulation would benefit differing CMS subtypes and could potentially improve signal transmission in other NMJ-associated disorders.

Keywords: small molecules
CMS
NMJ
gene therapy
DOK7
AAV
Advisor: Beeson, D
Cossins, J
Karnatic violin techniques in collaborative practice: a violinist's perspective

This thesis examines the study and incorporation of Karnatic (South Indian) violin techniques in contemporary music projects in London. The violin provides a lens for viewing the social and psychological interactions between musicians, instruments and cultures in practice. A series of six case studies document my experiences as a violinist ranging from lessons with Karnatic violinists through to creative projects where the influence of these lessons is present by virtue of incorporating Karnatic violin techniques as part of a toolbox of extended technique. I consider questions surrounding the ways in which knowledge is disseminated from teacher to student and then mediated between musicians, led by my own experiences working with Karnatic violin teachers, including the Mysore Brothers, as well as composers and performers in London. In this way, my research opens up broader questions about the creative potential and complexities surrounding cultural exchange in twenty-first century London. I examine the close relationship between culture and knowledge and the ways that the use of Karnatic violin techniques in collaborative practice can shift the creative emphasis of working relationships between musicians.
Following the trend over the last decade to move away from a disembodied approach to music (Clarke and Davidson 1998: 74), this research aims to draw out the embodied experiences of incorporating Karnatic violin techniques in collaborative practice. An autoethnographic methodology is employed to investigate a mode of collaborative and professional practice in contemporary music, questioning:
(1) How is the knowledge of the violin and Karnatic violin playing disseminated and mediated between musicians?
(2) What can the use of Karnatic violin techniques with musicians in London reveal about the processes of creative collaboration and cultural exchange?
On a practical level, extending the physical and cognitive means of the musical body can bring about new possibilities for contemporary violinists incorporating body and mind within cultural, social and psychological interactions. I will highlight the fact that while creative collaboration has become a prominent topic in recent research, collaborations involving cultural exchange are still relatively unexplored.

Keywords: Karnatic
Culture
Creativity
Music
Violin
Interculturalim
Collaboration
Advisor: Clarke, E
Development of absorbent materials in ammonia synthesis

Ammonia sorbents are important for both the synthesis and transport of so-called green ammonia. Though MgCl2 is currently the most commonly used absorbent for ammonia it has a number of deficiencies and so new materials are needed targeting fast sorption and desorption speed and high temperature and cycling stability.
13X zeolites underwent ion exchange and were studied for ammonia adsorption. The sodium ions in the 13X structure were replaced by protons, magnesium or lanthanum ions. In each case, the ammonia capacity was increased by the ion exchange, most significantly for magnesium, with fast, stable adsorption. Protons generated strong Brønsted acid sites which gave ammonia that was stable at high temperatures, lanthanum generated Lewis acid sites which gave weakly bound ammonia stable only at low temperatures and magnesium generated a combination of strong Brønsted acid and weak Lewis acid sites giving low and high temperature ammonia. In each material the locations of the ammonia binding sites were identified using SXRD, supported by modelling.
Lanthanum ion exchange was shown to cause structural disruption due to the size of the lanthanum ions. This disruption was shown to be related to lanthanum content but detrimental to capacity. The acidity of the lanthanum zeolites could be tuned using varying lanthanum content.
A variety of layered materials, including MgCl2, were studied in greater detail. Treatment of MgCl2 using acetone was found to significantly improve the absorption rate at detriment to the ammonia capacity; this was proposed to be due to reordering of exfoliated MgCl2 layers or nanopore generation. This treatment was found to be unstable with both time and cycling and attempted alternative methods of stable layer disruption were unsuccessful. Instead, layers were exfoliated and supported on zeolite which gave fast, stable sorption even at high temperatures and low pressures.

Keywords: ammonia
energy storage
absorption
Brønsted acidity
zeolites
Lewis acidity
layered materials
SXRD
adsorption
Advisor: Tsang, E
Theoretical and experimental investigation of magnetic layer coupling in spin-valves and magnetic tunnel junctions

Heterostructures composed of ferromagnetic layers that are mutually interacting through a nonmagnetic spacer are at the core of magnetic sensor and memory devices. In the present study, layer-resolved ferromagnetic resonance was used to investigate the coupling between the magnetic layers of a Co/MgO/Permalloy magnetic tunnel junction (MTJ) and Co/Sn/Py spin valves.
Elemental tin in the a-phase is an intriguing member of the family of topological quantum materials. In thin films, with decreasing thickness, a-Sn transforms from a 3D topological Dirac semimetal to a 2D topological insulator (TI). Getting access to, and making use of its topological surface states is challenging and requires interfacing to a magnetically ordered material.
For both types of samples two magnetic resonance peaks were observed for both magnetic layers, as probed at the Co and Ni L3 x-ray absorption edges, showing a strong interlayer interaction through the insulating MgO barrier. A theoretical model based on the Landau-Lifshitz-Gilbert-Slonczewski equation was developed, including exchange coupling and spin pumping between the magnetic layers. Fits to the experimental data were carried out, both with and without a spin pumping term, and the goodness of the fit was compared using a likelihood ratio test.
Evidence of two types of magnetic layer coupling were found for the studied MgO MTJ. A Likelihood ratio test performed between competing models showed that a model with only exchange coupling is insufficient, and the correct description of the experimental data requires inclusion of spin pumping coupling between magnetic layers. The values characterising both the EC and the spin pumping were estimated. A recipe has been developed for spin-vale fabrication incorporating a a-Sn TI spacer layer. Up to 2nm thick a-Sn layers were deposited onto a Co surface. The X-ray detected ferromagnetic resonance (XFMR) study of the a-Sn system has shown a strong exchange coupling interaction between the magnetic layers with no clear evidence for spin pumping.
The methods developed in this work can be used to interpret XFMR data, not only in the discussed cases, but potentially for all types of measurements in general. The explored idea of incorporating the TI a-Sn into a spin-valve has shown promising results, and will serves as a solid basis for further research.

Keywords: likelihood ratio test
magnetic tunnel junctions
XFMR
MTJ
spin pumping
spin-valve
MgO
a-Sn
Landau-Lifshitz-Gilbert-Slonczewski
topological insulator
Advisor: van der Laan, G
Hesjedal, T