VictorJuiz/thesis huggingface dataset:
Examining the role and plasticity of cognitive biases in adolescent pain experiences

Acute pain is a common experience in childhood and adolescence. However, a significant minority of young people experience persistent, chronic pain that impairs their physical, emotional, and social functioning. Research presented in this thesis examines cognitive and affective factors in the emergence and chronicity of pain experiences in adolescence. In Chapters Two and Three, data are presented showing that, in community samples of adolescents, associations between pain-related attention biases and pain-related anxiety and catastrophizing are moderated by adolescents’ ability to exert effortful attention control. Attention control is also shown to moderate associations between anxiety and tolerance of experimentally-induced pain. In Chapter Four, Attention Bias Modification (ABM) training methodology is used to investigate the plasticity and causal impact of pain-related attention biases in adolescents with chronic pain. Findings indicated that ABM, compared with placebo or no training, did not manipulate attention bias or attention control, nor did it significantly impact pain symptoms, pain catastrophizing, anxious and depressive symptoms, or physical functioning. In Chapters Five and Six, a novel measure of pain-related interpretation bias was developed; the Adolescent Interpretations of Bodily Threat (AIBT) task. Data from this task indicated that, in a community sample of adolescents, the tendency to interpret ambiguous information as indicative of pain and bodily threat mediated associations between pain catastrophizing and recent pain experiences. Additional data indicated that adolescents with chronic pain were less likely to believe benign interpretations of ambiguous bodily-threat information than healthy controls. This interpretation pattern was associated with increased disability among adolescents with chronic pain. In summary, studies in this thesis support the contribution of cognitive biases to pain experiences in adolescence, although the efficacy of ABM was not supported. Further studies investigating the interaction of attention bias and control, as well as biased interpretations of bodily threat, may be particularly useful going forward.

Advisor: Lau, J
Self-locating credences

In this essay, I will argue for a theory of self-locating credences based on Nick Bostrom’s Observation Equation. A theory of self-locating credences should constrain a rational observer’s credence function given their prior credences in non-self-locating propositions and their beliefs about how many observers exist in the world and what kind of evidence they have. Two notable theories of this kind have been proposed: one by Frank Arntzenius and Cian Dorr, and another by Nick Bostrom. In the essay, I argue that Arntzenius and Dorr’s theory of self-locating credences has strongly counter-intuitive results when applied to certain kinds of cases, as Nick Bostrom has shown. On the other hand, Bostrom’s theory is incomplete—Bostrom says that observers should be separated into reference classes in order to avoid the results that a theory like Arntzenius and Dorr’s gives, but does not say anything about how observers should be separated into reference classes. In this essay, I develop a principled reference class definition to complement Bostrom’s theory. I first give a preliminary reference class definition that is adequate in a special case—namely, whenever every observer knows what reference class they are in according to this preliminary definition. I then formulate a general reference class definition that I claim works generally, even when observers do not know what reference class they are in according to the preliminary definition. Following this, I apply the reference class definition to the Sleeping Beauty problem and conclude that her credence in heads should be 1/2 throughout. In the last part of the essay, I defend the theory from some potential objections.

Advisor: Thomas, J
Hydrogen Sulfide (H2S) as a regulator of myocardial redox state and the redox-sensitive regulation of cystathionine γ-lyase (CSE)

In advanced stages, cardiac disease causes millions of deaths each year. Superoxide anions (O2.-) and their derivative peroxynitrite (ONOO-) contribute to cardiac disease pathogenesis, yet strategies to reduces these reactive oxygen species through antioxidants in large scale clinical trials have largely been unsuccessful. Better understanding of pathways regulating enzymatic sources of O2.- like NADPH oxidases, uncoupled nitric oxide synthases (NOSs) and mitochondrial oxidases are required to regulate myocardial oxidative stress in patients with advanced stages of cardiac disease. Hydrogen sulfide (H2S) is a gaseous signalling molecule generated by transsulfuration pathway enzymes cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MST). H2S regulates oxidative stress in animal models and shows promise for cardiovascular therapeutic strategy. This thesis investigates whether H2S/CSE biology is related to human myocardial redox state in a cohort of individuals with advanced cardiac disease (Oxford Heart, Fat, Vessels Cohort; Ox-HVF). Individuals with varying levels of myocardial oxidative stress and function were extensively phenotyped for H2S biology. Individuals with high myocardial oxidative stress from NADPH oxidases and NOSs were found to have high expression of myocardial CSE. To examine first the positive association with NADPH oxidase activity, CSE expression was examined after myocardial oxidative injury and CSE was found to be redox-sensitive. Furthermore, direct effects of two exogenous H2S donors (NaHS and GYY4137) demonstrated a direct regulation of O2.- from NOSs in myocardium from individuals with advanced cardiac disease, further supporting H2S’s direct role in the regulation of NOS biology. Finally, identification of a SNP in CSE further demonstrated CSE’s causal role in the regulation of O2.- generation from mitochondrial oxidases. Taken together, we demonstrate for the first time that H2S and CSE biology are linked to human myocardial redox state and have a causal role in redox regulation in the human heart. These findings suggest H2S/CSE biology are important endogenous regulators of myocardial redox state in humans and continued exploration of these pathways may develop novel therapeutic strategies against myocardial oxidative stress in cardiac disease.

Keywords: Oxidative Stress
Hydrogen Sulfide
Cystathionine γ-Lyase
Myocardium
Advisor: Antoniades, C
Casadei, B
Ketone synthesis via rhodium-catalyzed traceless chelation-controlled hydroacylation reactions

This thesis documents the development of rhodium-catalyzed traceless chelation-controlled hydroacylation reactions for the synthesis of a variety of ketone products.
Chapter 1 provides an overview of rhodium-catalyzed hydroacylation chemistry, focusing on the origin of chelation-controlled strategies and the benefits thereof.
Chapter 2 describes a sequential reaction involving alkene hydroacylation, sulfide elimination and boronic acid conjugate addition, which affords products with the initial sulfide coordinating group replaced by a stereochemically defined aryl group.
Chapter 3 demonstrates a sequential process involving alkyne hydroacylation, boronic acid conjugate addition and sulfide elimination, which provides enantioenriched β’-arylα,β-unsaturated ketones in a highly efficient and selective manner.
Chapter 4 illustrates a versatile chelating group, triazene, for hydroacylation reactions. Subsequent functionalization of aromatic C-H bonds, promoted by the same chelating unit, offers highly substituted phenyl ketone products.
Chapter 5 documents experimental procedures and data.

Keywords: asymmetric catalysis
cascade reaction
rhodium catalyst
Advisor: Willis, M
Instrumentation for HARMONI and the mass ratios of ring galaxy systems

HARMONI is the visible and near-infrared integral field spectrograph due to be one of the first light instruments on the European Extremely Large Telescope. The prototype HARMONI lens mounts were cryogenically tested, to measure the radial decentre of the lens as it was cooled to 130 K. Initial problems of the epoxy cracking the lens were solved by switching to a silicone RTV adhesive. The lens in the baseline mount design was found to move radially by 18 µm: just below the tightest radial positioning tolerance.
The Oxford SWIFT Spectrograph spare camera was rebuilt using lens mounts based on the proposed HARMONI designs. A procedure to align spherical lenses to their mounts was developed that could position the lenses to within 10 µm both radially and axially. However, the performance of the camera did not meet expectations, as the lenses were moving in their mounts. This was attributed to either the adhesive or the cotton paper buffer between the lens and its mount; also, at least one bond had failed. These issues are thought to be solvable by using an automatic, rather than manual, adhesive dispenser, though this has yet to be proven.
A commercial off-the-shelf shutter was also tested to see if it would work in the HARMONI cryostat. Although it could be used at these temperatures, it could not be made fully reliable. Its lifetime of 9321 actuations was also much lower than the estimated 88000 actuations for the lifetime of HARMONI.
Ring galaxies are annulus-shaped galaxies thought to be formed from a disc galaxy when a companion galaxy passes directly through it close to its centre at a nearly-normal angle. The kinematics of three ring galaxies were measured from MUSE observations and used to estimate their dynamical masses. A simple analytic model was used to refine the fits to the kinematics, though this did not change the measured masses very much.
Stellar population synthesis models were fit to the integrated spectrum of the companions of two of the ring galaxies to estimate their stellar masses via their mass-to-light ratios. The mass ratios of the companions to the rings were both found to have a lower bound of 1/6, though possibly increasing to 2/5 when dark matter is taken into account. This value is comparable to other observational results of ring galaxy mass ratios, and is within the range of values used for simulations of ring galaxy formation.

Advisor: Thatte, N
O'Brien, K
Transcriptome-wide study of the role of arginine methylation on E2F1

The transcription factor E2F1 can have diverse phenotypic effects on the cell, from stimulating cell cycle progression and proliferation, to inducing apoptosis. These seemingly opposite effects are regulated by a multiplicity of post-translational modifications. Three sites of arginine methylation have been shown to cause a switch in E2F1 function, with PRMT5 mediated symmetric dimethylation at R111/113 associated with a proliferative outcome and asymmetric dimethylation at R109 by PRMT1 resulting in apoptosis. Importantly, these sites of arginine methylation by PRMT1 or PRMT5 were shown to be mutually exclusive, eliciting an either / or response. Furthermore, a reader for the R111/113Me2s mark was found to be the tudor-domain containing transcription co-activator and RNA binding protein p100-TSN. In this study we have used genome-wide sequencing techniques to explore the role of arginine methylation on E2F1 and identify how it is exerting these diverse effects. We found that, although there were few transcription level changes upon expression of an R111/113K mutant derivative compared to the wild-type expressing cells, these cells exhibited dramatic changes at the RNA isoform level across many E2F1 target genes, including increased levels of proapoptotic isoforms of p73 and BCL-X. Interestingly, the vast majority of these differentially spliced genes did not overlap with the genes showing transcription level changes, suggesting a new role for E2F1 to modulate target gene expression via RNA processing. Furthermore, we discovered that E2F1 can bind to nascent RNA via its interaction with p100-TSN and that this complex is spliceosome associated. Additionally, E2F1 can influence the RNA isoforms of p73 and BCL-X found interacting with p100-TSN. Thus, we present a model suggesting that E2F1 may be directly impacting on RNA processing by aiding assembly of splicing components as transcription occurs.

Advisor: Coutts, A
La Thangue, N
Russian-American cooperation in the Middle East  – an analysis of Moscow’s interests, leverage,  and strategies of linkage

This study assesses the drivers of Russia’s security cooperation with the United States in the Middle East since 11 September 2001. The four empirical case studies analyze Russian-US cooperation: (1) in stabilizing Iraq after Operation Iraqi Freedom
in 2003; (2) in eliciting Syria’s troop withdrawal from Lebanon in 2005; (3) in imposing UN sanctions against Iran in 2010, and (4) in demilitarizing Syria’s chemical weapons in 2013-2014. Through these cases, I probe to what extent Russian cooperation is driven by linkage diplomacy and expectations of US reciprocity, as opposed to Russian interests in the Middle East itself. The analysis also unpacks Russia’s pursuit of leverage vis-à-vis the US in the context of cooperation.
The study argues that Russia’s security, non-proliferation, and economic interests in the Middle East are the principal drivers of its cooperation with the US in this region. This remains the case during moments of rapprochement and deteriorating diplomatic relations alike. Moreover, Moscow’s co-operative strategy entails measures to counter-balance its support for US policy by building leverage for itself and its regional allies. However, there is sparse evidence of Moscow making its cooperation conditional upon gains on other issues in the Russian-US bilateral agenda.
The infrequency of explicit linkage diplomacy in Russian-US cooperation reflects principled policy on both sides, and American perceptions of the meaningfulness and costliness of Russia’s cooperation. Unlike what is implied in the cooperation literature, the concrete institutional form of cooperation has little explanatory value for the infrequent evidence of linkage. That said, a Russian expectation of what is termed diffuse reciprocity is always a contextual driver of cooperation, especially when Russian-US relations are on an upward trajectory. Moscow routinely hopes that its cooperation will make an atmospheric contribution to its bilateral relationship with Washington, which can then be used to seek accommodation over other bilateral issues.

Advisor: MacFarlane, S
Penslar, D
Discovery of small molecule epigenetic modulators

Target validation is increasingly becoming a central tenet to successful execution of drug discovery campaigns. An emerging approach towards the development of novel therapies for previously untreated diseases is the development of small molecule chemical probes which can be used as early stage tools for pertinent biological questions to be explored about a molecular target within the context of disease. A number of proteins which regulate epigenetic mechanisms have been correlated with disease onset and progression. Despite disease links, there remains a paucity in the understanding by which many of these pathologically relevant proteins exert their phenotypic effect when dysregulated. The discovery of novel chemical probes will facilitate further understanding of the underlying biology of these epigenetic targets. This thesis reports on the discovery and development of chemical probes and inhibitors of epigenetic proteins. A series of synthetic medicinal chemistry efforts is described towards the multiIfaceted improvements of lead compounds by means of potency, selectivity and cell activity against their cognate targets.
In chapter 1 the associated concepts, primary literature and core principles of the subsequent chapters are comprehensively examined. In chapter 2 a report on the discovery of the first chemical probe for the bromodomains of p300/CBP Associated Factor (PCAF) and General Control Nonderepressible 5 (GCN5) proteins, previously untargeted and disease relevant protein domains is described. Following this, chapter 3 describes the development of inhibitors of the second macrodomain of polyadenosine diphosphate ribosylating protein 14 (PARP14) building on the understanding of SAR around the target and reporting the most potent ligand described to date. Chapter 4 then goes on to describe the discovery a chemical probe for the YEATS domain containing proteins ENL and Af9. Up to this date there have been no reported inhibitors or chemical probes for the YEATS domain containing proteins despite numerous links to cancers.
The final chapter 5 describes the outputs from the industrial placement period of my doctoral training during which synthetic methodology and total synthesis research at Vertex Pharmaceuticals was carried out. In this chapter the substrate scope of an additive free UVIA promoted photocyclisation of arylI enamines to spiroindolines is described. The utility of this additiveIfree complexity building reaction is demonstrated through the formal synthesis of an alkaloid natural product (±)Ihorsfiline.

Advisor: Brennan, P
Dixon, D
Canopy of everlasting joy: an early source in Tibetan historiography and the history of West Tibet

A more descriptive title for the dissertation might be "Early historiography in Pu rang - Gu ge and its relationship between orality, kingship, and Tibetan identity: a close study of a recently uncovered 12th century historical manuscript from Tholing monastery in West Tibet." The present study is therefore a close textual analysis of all the outer and inner features of the Tholing Manuscript. When reading the text, there is the gradual realization that the archaic peculiarities in script, binding, spelling, vocabulary, prose, and narrative twists, all highlight the work as a wholly rare and different version from those early histories typically found in Central Tibet. The key difference lies primarily in the focal point of the narrative. Whereas most similar narratives from the time of the phyi dar (11th - 13th centuries) onwards place at the core of their structure the history of Buddhism in Tibet, the Tholing text puts as its central focus kingship and the history of kings in Tibet. For this reason, while Buddhism plays an essential and integral part of the story as a whole, the text can be viewed as a more secular work then any comparable monastic history of the period.
The narrative structure of the manuscript, with its heavy use of rhythmical prose, similes, archaic topoi and motifs, is hauntingly familiar to those parallel passages found among Old Tibetan Documents and is emblematic of the liminal period in which the text was written. At this time, histories were transitioning from disperse and possibly oral transmissions to predominantly formal organized written traditions. The poetic nature of the text, together with its unusual physical features, raises questions relating to its purpose and function, with the possibility of its use as a ritual manuscript for royal legitimization. Through a close study of the text, I offer some insights on the formative nature of early Tibetan historiography in establishing the sacred and political power of the kings of West Tibet.

Keywords: Tibet
Tibetan Studies
West Tibet
Kingship
Orality
Historiography
Advisor: Ramble, C
Roesler, U
Lexical gaps and morphological complexity: the role of intermediate derivational steps

In this thesis, we present a multi-method investigation of how lexical gaps, defined here as morphologically and phonologically viable formations, are processed in derivational chains. Due to a focus on the processing of single-affixed words in the experimental literature, little is known about the role of intermediate steps of derivation during morphological decomposition.
In a series of four behavioural experiments, we show that while all morphologically well-formed items activate a base word that is two derivational steps away, speakers are sensitive to the internal composition of visually matched novel forms. Items like *Spitzung (spitz &GT; spitzen &GT; *Spitzung) primed their stem more than pseudowords containing two lexical gaps in their derivational chain such as hübsch &GT; *hübschen &GT; *Hübschung. Similar patterns emerged in an ERP (Event-related potentials) experiment using cross-modal priming: novel forms in the *Spitzung set displayed significantly stronger attenuation of the N400 response to the target spitz than items for which the intermediate position in the derivational chain is a lexical gap such as *Hübschung, thereby demonstrating a stronger link between pairs without a lexical gap in the intermediate position.
Building on previous neuroimaging research on the processing of derivational depth in morphological complexity (cf. Meinzer et al., 2009; Pliatsikas et al., 2014), we subsequently turned to a functional magnetic resonance imaging investigation of the neural correlates of morphological complexity processing with lexical gaps. Both sets of pseudowords showed greater activation in the left inferior frontal gyrus relative to existing complex words as an index of prolonged lexical search. A direct comparison between the two sets of novel forms revealed stronger activation in the right superior parietal lobule and precuneus for pseudowords with lexical gaps in the intermediate position.
These findings lend support to the idea that morphological decomposition involves the inspection of intermediate levels of morphological composition as a stepwise procedure that is informed by the structural rules of the language.

Advisor: Lahiri, A
Mechanistic studies of the adhesion-GPCR latrophilin and its interactions in neural guidance

The adhesion GPCRs are a poorly understood and evolutionarily ancient family of cell surface receptors, several of which have emerging functions in the development of the nervous system. aGPCRs comprise a large extracellular domain, providing binding sites for a variety of ligands, alongside a seven transmembrane domain characteristic of GPCRs. It has been proposed that aGPCRs may function as "context-recognisers", using their large ectodomains to bind different combinations of ligands depending on the molecular make- up of the environment. However there is a lack of direct evidence for this at a molecular level. The ectodomain of one subfamily of aGPCRs, the Latrophilins (Lphns) has been shown to directly interact with several ligands with roles in synaptogenesis and neural guidance. The best-validated of these interactions are those with Fibronectin Leucine- Rich Transmembrane (FLRT) proteins and the Teneurins. In addition, FLRT proteins, also interact with Uncoordinated5 (Unc5) proteins, mediating cell repulsion. Here I reveal that the FLRT-binding site of Lphn is bifunctional, mediating both cell adhesion and repulsion, and that Unc5 is capable of influencing the functional outcome of this interaction. Biophysics and structural studies show that fragments of the Lphn, FLRT and Unc5 ectodomains interact in an unusual and homologue-dependent stoichiometry. Despite the fact that Teneurin interacts with Lphn at a distinct site, Teneurin seems incapable of interacting with the Lphn-FLRT-Unc5 complex, but can form a ternary complex with Lphn and FLRT in the absence of Unc5. Alongside this I present a crystal structure of a large portion of a Teneurin ectodomain, revealing the ancient evolutionary origins of this receptor. Together these data provide strong molecular evidence for a role of Lphns as context-recognisers, by their abilities to bind diverse ligands in distinct combinations and variable stoichiometries.

Advisor: Seiradake, E
Sansom, M