VictorJuiz/thesis huggingface dataset:
Autoimmune encephalitis and its implications for the neuroscience of remote memory

Since the field-defining patient HM, consistent links have been made between a region of the brain called the hippocampus and memories that can be consciously declared – so called declarative memories. Declarative memories fall into two categories (1) episodic memories, memories that are highly detailed and re-experiential, and (2) semantic memories, fact-based memories for personal and public information but that have no sense of re-experiencing. It is believed that the intrinsic anatomy of the hippocampus supports episodic memory but not semantic memory. The hippocampus consists of five regions (cornu Ammonis, CA, 1-3, dentate gyrus, subiculum) with each purported to have a specific role in episodic memory acquisition and retrieval. However, controversy surrounds the temporal extent to which episodic memories rely on the hippocampus for retrieval: current consensus suggests the hippocampus supports these memories for five-10 years post-acquisition, but some suggest that it is required for retrieval across the lifetime. Voltage-gated potassium channel-complex antibody-mediated limbic encephalitis (VGKC-complex LE) is a recently described autoimmune disease that causes chronic hippocampal atrophy and mild amnesia on standardized neuropsychological assessment. Two subfields of the hippocampus – CA1 and CA3 – contain the antigenic targets of the disease but it is unknown if specific atrophy of these subfields underlies the hippocampal damage in humans. Here, the human hippocampal subfield volumes of VGKC-complex LE patients (n = 19, mean age: 64.0±2.55; range: 24-71) were investigated using ultra-high spatial resolution MRI at 7.0-Tesla. Assessment also included standardized neuropsychology to examine the impact of the pathology on hippocampal-dependent and –independent memory performance, as well as attention, language, executive function, and perception Declarative memory assessment measured semantic and episodic memory performance across the lifespan.
Manual segmentation detected lesions to just CA3, with no volume loss noted elsewhere in the hippocampus or brain. Patients were impaired on hippocampal-dependent memory domains but not the hippocampal-independent and non-memory domains. Notably, episodic memory assessment revealed episodic amnesia across the lifetime except for their earliest memories. This counters the received convention that the hippocampus has a temporally limited role in episodic retrieval. Conversely, the performance of the VGKC-complex LE patients for semantic memory, including a new test developed herein, was comparable to controls across the lifespan. It was then shown that CA3 volume predicted episodic memory performance across the lifetime. Together, the results suggest that VGKC-complex LE provides a novel model of human hippocampal subfield pathology, with which to explore the roles of hippocampal subfields in episodic memory acquisition and retrieval.

Keywords: Declarative memory
Autoimmune encephalitis
Hippocampus
Advisor: Rosenthal, C
Butler, C
Acquired resistance to HSP90 inhibition in triple-negative breast cancer

Heat shock protein 90 (HSP90), a conserved molecular chaperone, has become a potential molecular target for cancer therapeutics. HSP90 inhibition (HSP90i) causes inhibition of several oncogenic pathways simultaneously and leads to anti-cancer activities in multiple cancers including in triple-negative breast cancer (TNBC). TNBC is a subtype of breast cancer with poor prognosis and lack of approved targeted therapies.
Although HSP90i has shown promising initial clinical data, resistance to HSP90i can still arise in TNBC patients and its resistance mechanisms are not yet understood. In this study, using an in vitro system, we report for the first time the isolation of TNBC cells with acquired resistance to HSP90i. Proteome and whole transcriptome profiling, and a bioactive small molecule screen were performed to identify the molecular basis of resistance to HSP90i and potential therapeutic approaches to overcome acquired resistance to HSP90i in TNBC cells.
Two independent HSP90i-resistant clones were acquired through prolonged exposure of a TNBC cell line (Hs578T) to HSP90i. The clones showed significant resistance to HSP90i, notably to resorcinol-based HSP90i. The HSP90i-resistant clones also shared genomic sequence variants, suggesting a pre-existing population of resistant cells within the parental cells. We demonstrate that upregulated expression of UGT1A9, possibly due to an increased intrinsic oxidative stress, is associated with acquired resistance to resorcinol-based HSP90i in TNBC cells, and sensitivity to HSP90i can be restored with a competitive inhibitor of UGT1A9. The HSP90i-resistant clones also exhibited slower growth and upregulated IL6- mediated JAK2-STAT3 survival signalling pathway, which might contribute to the crossresistance to chemotherapeutics and other targeted therapies seen in the clones. Finally, we demonstrate that inhibition of JAK2-STAT3 signalling pathway is able to increase the cytotoxic effects of HSP90i to TNBC cells.
We conclude that by using in vitro assays, we are able to identify potential mechanisms of acquired resistance to HSP90i in TNBC cells. We propose that expression of UGT1A9 or STAT3 might be a potential biomarker of sensitivity to HSP90i in TNBC cells. A combined inhibition of HSP90 and JAK2 might be a potential therapeutic approach for the development of effective targeted therapies in TNBC patients.

Advisor: Ryan, A
Contributions of COMT and DAT to regulation of phasic dopamine release and reward-guided behaviour

Fine temporal regulation of dopamine transmission is critical to its effects on behaviour. Dopamine can be cleared from the synapse either by recycling via the dopamine transporter (DAT) or by enzymatic degradation involving catechol-O-methyltransferase (COMT). DAT recycling predominates in striatum and contributes to dopaminergic regulation of reward-guided behaviour, while COMT degradation predominates in cortex and modulates executive functions. However, human functional imaging studies demonstrate interactive effects of DAT and COMT genotype, suggesting that the traditional division between DAT and COMT is not so clear-cut. Given the interdependence of mesolimbic and mesocortical circuitry and the presence of COMT in the striatum, it is possible that DAT and COMT interact to a greater extent than previously thought.
We investigated the contributions of DAT and COMT to regulation of dopamine transmission and reward-guided behaviour by combining in vivo electrochemical recording, pharmacology, and behavioural testing in mice. Using fast scan cyclic voltammetry to record evoked dopamine release in anaesthetised animals, we found that systemic DAT blockade increased the size of dopamine transients in the nucleus accumbens (NAc) but not in the medial frontal cortex (MFC), demonstrating that DAT regulates phasic striatal dopamine release and confirming that DAT makes little contribution to regulation of cortical dopamine transmission. Unexpectedly, COMT inhibition did not affect evoked dopamine transients in either the NAc or the MFC. In agreement with these findings, systemic administration of a DAT blocker, but not of a COMT inhibitor, increased motivation to work for reward in a progressive ratio paradigm. COMT inhibition also had little effect on reinforcement learning (RL) strategies during reward-guided decision making. Intriguingly, however, we found that DAT blockade both decreased the influence of model-free RL and increased the influence of model-based RL on behaviour.
Our study confirms that DAT regulates dopamine transmission in striatum but not in cortex and indicates that sub-second changes in dopamine transmission in both regions are largely insensitive to COMT. However, our behavioural data reveal the importance of striatal dopamine in multiple components of reward-guided behaviour, including both motivational aspects traditionally associated with striatum as well as cognitive aspects heretofore mainly associated with cortical function. Together, these findings emphasise that reward processing occurs across corticostriatal circuits and contribute to our understanding of how striatal dopamine transmission regulates reward-guided behaviours.

Keywords: Dopamine transporter
Nucleus accumbens
Reinforcement Learning
Decision making
Motivation
Catechol-O-methyltransferase
Dopamine
Prefrontal cortex
Advisor: Tunbridge, E
Walton, M
Network structure, brokerage, and framing: how the internet and social media facilitate high-risk collective action

This thesis investigates the role of network structure, brokerage, and framing in high-risk collective action. I use the protest movement that emerged in Russia following falsified national elections in 2011 and 2012 as an empirical case study. I draw on a unique dataset of nearly 30,000 online documents and the linking structure of over 3,500 Russian Web sites. I employ a range of computational social science methods, including Exponential Random Graph Modeling, an advanced statistical model for social networks, social network analysis, machine learning, and latent semantic analysis.
I address three research questions in this thesis. The first asks if a protest network challenging a hybrid regime will have a polycentric or hierarchical structure, and if that structure changes over time. Polycentric networks are conducive to high-risk collective action and are robust to the targeted removal of key nodes, while hierarchical networks can more easily mobilize protesters and spread information. I find that the Russian protest network has a polycentric structure only at the beginning of the protests, and moves towards a less effective hierarchical structure as the movement loses popular support. The second research question seeks to understand if brokered text is actually novel, and if that text is more novel in polycentric networks than in hierarchical ones. Brokers are the individuals or nodes in a network that connect disparate groups through weak ties and close structural holes. Brokers are advantageous because they have access to and spread novel information. I find that the text among nodes in brokered relationships is indeed novel, but that information novelty decreases when networks have a hierarchical structure. The last research question asks if a protest movement in a high-risk political setting can be more successful than the government at spreading its preferred frames, and within such a movement, whether moderate or extremist framing is more prevalent. I find that the opposition is far more effective than the government in spreading its frames, even when the government organizes massive counter protests. Within the movement, moderates are more likely to have their framing adopted online than extremists, unless violence occurs at protests.
The findings suggest that movements should build flatter, more diffuse networks by ensuring that brokers tie together diverse protest constituencies. The findings also provide evidence against those who claim that authoritarian governments are more effective in shaping online discourse than oppositional movements, and also suggest that movements should advance moderate framing in order to attract a wider base of support among the general population.

Keywords: brokerage
political protests
collective action
social media
internet
Russia
social networks
framing
Advisor: Hogan, B
Chaisty, P
J. S. Bach at the coffee house: music as edifying practice

This thesis proposes a new critical perspective on Bach's Collegium musicum and its performances at a Leipzig coffee house. Based on a range of fresh literary, architectural, and administrative sources, I argue that coffee houses in Bach’s time were highly prestigious, if often controversial performance-venues. As a cultural sphere, they were guided by a neo-humanist ideal, known as 'useful edification' (nützliche Erbauung), which has not been recognised by scholars so far. Yet, applied to musical practice, the notion of useful coffee-house edification can provide a fruitful paradigm for rethinking the reception of Bach's music in its secular performance-contexts. As the contents of several coffee-house periodicals from the early eighteenth century suggest, edifying thought (also described as pondering, or Nachsinnen) was widely understood as a combination of critical and associative thought, which closely resembled Bach's own preoccupation with exploring musical ideas as rhetorical inventiones. Seen this way, a rich reception context emerges that, as a historical web of anthropological meaning, can shed new light, for example, on the socio-cultural context of Bach's keyboard music that was published under the title of Clavier-Übung. In addition, it can reveal how Bach's musical inventions were often combined with further allegorical signs to result in rich music-dramatic, and arguably also emblematic tableaux in a range of secular cantatas. A newly-recovered document relating to Bach's cantata Blast Lermen ihr Feinde (BWV 205a) suggests, for example, that the dramma per musica was performed as part of a highly theatrical event that staged an emblematic representation of the coronation of August III as Polish King in 1734. But recognising Bach’s reliance on emblematic allegories can also yield new perspectives on, for example, Hercules at the Crossroads (BWV 213) and The Contest between Phoebus and Pan (BWV 201). Viewed as 'useful' and 'edifying' performances, I argue that their music-dramatic symbolism articulated a rich counterpoint of religious, secular and political meanings that can be linked to a corresponding variety of pragmatic, artistic and satirical agendas. .

Keywords: Performance History
Collegium Musicum
coffee-house culture
Music Analysis
JS Bach
18th-Century Leipzig
Advisor: Burden, M
The Arts and Crafts in church-building in Britain 1884-1918

Academic interest in Arts & Crafts architecture has tended – as did the architects themselves – to concentrate on houses. This thesis, for the first time, examines the Arts & Crafts in church architecture: there is no book on ‘Arts & Crafts churches’. Monographs on Arts & Crafts architects include their church work, of course, but there has been little consideration of the form as a type, considering as a group churches by architects working in the Arts & Crafts milieu, and at the same time. The thesis starts by discussing the underlying problems – the lack of a clear definition of Arts & Crafts, and the questionable concept of Arts & Crafts architecture. It establishes definitions, sets out criteria for considering architects and their churches, and identifies a group of 35 ‘core churches’ from which the majority of the evidence is drawn. The second chapter sets out the historical contexts – religious, architectural, and cultural – and how these contexts intertwine to foreground the personal and individualism in both spiritual and architectural expression. The central three chapters examine the interplay of client and architect: how the attitudes and beliefs of the former affected their relationship to their churches and architects; and how architects’ ideas and interests were expressed in their methods, their buildings’ construction and decoration. Chapter six explores the diffusion of Arts & Crafts in churches at the end of the period – the role of enthusiastic amateurs; churches as centres of craft education; manifestations of different, even attenuated forms of the ideas in later churches. After a concluding chapter which suggests that the uncategorisability of the churches – exemplified throughout the thesis – demonstrates the way in which belief moved from the cultural centre to the margins, a substantial Appendix sets out details of the core churches: dates, client, funding, architect, craftsmen, plan.

Advisor: Barnwell, P
Tyack, G
Factors influencing genetic variation in wild mice

The mouse is a premier model organism for mammalian biological research. They have been instrumental in studies illuminating processes of fundemental importance to genetics including the control of recombination and the process of speciation. However, most of these studies are based on laboratory mice, which are an artificial population with a complex relationship to wild mice. Studies of mammalian biology would benefit from understanding how history has shaped the genome of the present day mouse.
In this thesis, I explore factors that contribute to patterns of genetic variation in wild mice, paying particular attention to the process of recombination. I use whole genome sequencing data from three wild populations: 20 French M. m. domesticus; 20 Taiwanese M. m. castaneus; and 10 Indian M. m. castaneus. In addition, I use 13 classical laboratory strains and 6 wild derived inbred strains.
These data show that the French and Taiwanese populations have been through recent, severe population bottlenecks, are recipients of considerable migration, and are partially inbred, with about 15-20% of the genome recently homozygous. All of these features are absent from the Indian mice. Signatures of selection reveal that the Prl gene in Indian mice was the result of a full sweep originating from a highly diverged species of mouse. In terms of recombination, the linkage-disequilibrium based rate map of the French and Taiwanese mice is shown to be highly punctuate, while the Indian rate map is comparatively flat, and devoid of population level hotspots. The recombination landscape is shown to dominate nucleotide substitution, notably in the Indian mice, where it reverses a 2:1 strong (C/G) to weak (A/T) mutation bias in favour of a 2:1 weak to strong fixation rate. Dozens of long-extinct, and active, PRDM9 motifs are identified through a comparative genomic approach, which also reveals a highly localized picture of the distribution of GC-biased gene conversion. Separately, a low-coverage reference-panel free read-aware genotype imputation method named STITCH is presented, and shown to accurately impute genotypes in outbred laboratory mice and humans.

Advisor: Myers, S
Ecclesiastical politics and the role of women in African-American Christianity, 1860–1900

This thesis seeks to offer new perspectives on the role of women in African-American Christian denominations in the United States in the period between the Civil War and the turn of the twentieth century. It situates the changes in the roles available to black women in their churches in the context of ecclesiastical politics. By offering explanations of the growth of black denominations in the South after the Civil War and the political alignments in the leadership of the churches, it seeks to offer more powerful explanations of differences in the treatment of women in distict denominations. It explores the distinct worship practices of African-American Christianity and reflects on their relationship to denominational structure and character, and gender issues. Education was central to the participation of women in African-American Christianity in the late nineteenth century, so the thesis discusses the growth of black colleges under the auspices of the black churches. Finally it also explores the complex relationship between domestic ideology, the politics of respectability, and female participation in the black churches.

Advisor: Carwardine, R
Molecular dynamics studies of P-glycoprotein

Due to its involvement in multidrug resistance in cancer and other disorders, P-glycoprotein has been a subject of many studies, however, the evidence from structural and functional investigations is often conflicting. Homology models of human P-glycoprotein were prepared and analysed to choose the most suitable model for further experiments. Molecular dynamics simulations of the homology models revealed closure of potential substrate entrance gates. The results of the steered molecular dynamics and other simulations suggest that amitriptyline enters the central cavity through the cytoplasmic part of the entrance gates formed by transmembrane helices 4 and 6. P-glycoprotein was inserted in a complex asymmetric bilayer designed to mimic the composition of blood-brain barrier and the system was subjected to coarse-grained simulations and more interesting cases were converted to atomistic resolution. Three major insights were obtained. Firstly, P-glycoprotein affects the local bilayer environment by causing local ordering of lipids and decrease in lipid diffusion constants. Secondly, several potential cholesterol binding sites were observed in the simulations. Lastly, the presence of complex bilayer might affect the exibility of substrate entrance gate-forming helices. Taken together, these results highlight the importance of structural studies that can generate new and testable hypotheses.

Advisor: Biggin, P
Early perspectives on works of the law: a patristic study

In Paul's epistles to the Romans and the Galatians, the Apostle famously opposes "works of the law" within disputes regarding Jews and the law. But what are these works, what do they signify, and why are they rejected? Such questions are widely contested in New Testament scholarship, with responses constituting an important fault line in contemporary debates between "old" and "new" perspectives on Paul. This study engages these debates by investigating the views of the earliest patristic sources on this issue, which carry distinct heuristic value due to their historical, cultural, and personal proximity to Paul. Part I of this thesis presents the theoretical basis for using early reception within a period of "living memory" to engage contested areas of interpretation. Part II outlines the "old" and "new" perspectives on works of the law, with Luther, Calvin, Bultmann and Moo presented for the "old" perspective, and the "new" represented by Sanders, Dunn and Wright. Part III presents a comprehensive investigation of early patristic writings, stretching from the Didache to Irenaeus, which evaluates each source's usage of the relevant Pauline texts and their understanding of the meaning, significance, and reasons for opposing works of the law. Part IV concludes with a synthesis of these early views, an assessment of how they relate to the "old" and "new" perspectives, and implications for what their testimony suggests about Paul's meaning in the biblical texts. While neither perspective aligns uniformly with the patristic sources, it is concluded that contrary to current nomenclature, the "new" perspective finds greater correspondence with Christian antiquity than the "old" on this issue, and given these sources’ proximity to Paul and the consistent and uncontroversial nature of their interpretations, the burden of proof in contemporary debates should be carried by those who would run counter to these early perspectives.

Keywords: Justification
Patristics
Works of the law
New Perspective on Paul
Old Perspective on Paul
Advisor: Edwards, M
Lincicum, D
Strawbridge, J