VictorJuiz/thesis huggingface dataset:
The structural and cellular biology of endogenous TLR4 activators in inflammatory disease

Toll-like receptors (TLRs) are critical to detecting the presence of dangerous infections, initiating a protective innate immune response, and triggering a long-lasting adaptive immune response. TLRs initiate defensive, pro inflammatory signalling following direct binding to pathogen-associated molecular patterns (PAMPs), which are exogenous molecular fingerprints derived from infectious pathogens like bacteria, viruses, and fungi. In addition to this role, more recent evidence demonstrates that TLRs can also initiate pro-inflammatory responses upon detection of damage-associated molecular patterns (DAMPs), which are endogenous self molecules released at sites of tissue damage or stress. Under normal conditions, TLR activation via DAMPs contributes to tissue repair; however, during autoimmune diseases like rheumatoid arthritis, persistent DAMP accumulation creates a chronically pro-inflammatory extracellular milieu that drives disease progression. Despite the therapeutic importance of the DAMP:TLR axis, the molecular mechanism behind TLR-mediated detection of DAMPs remains unclear: while there are dozens of structures of TLRs bound to PAMPs, there are no structures of any TLRs bound to any DAMPs from any organism. In order to clarify these molecular details, herein I employ primarily biophysical techniques to probe a model TLR:DAMP interaction between TLR4 and a class of proteins known as the fibrinogen-related proteins (FRePs). After presenting novel expression and purification methodologies for both TLR4 and the FRePs, I demonstrate with an assortment of biophysical techniques that TLR4 does not directly bind to the FRePs. Next, using an unbiased proteomics workflow to probe the cell-surface FReP interactome, I provide evidence to suggest that integrins and lipoprotein receptors, not TLR4, may be the direct FReP receptors. Based on my data and the existing literature, I synthesize these results into a broader general hypothesis regarding TLR-mediated detection of DAMPs which I call the "receptorome". Taken together, this work presents an updated model for DAMP activation of innate immunity: rather than a direct TLR:DAMP binding event, I contest that context-specific receptor mega-complexes are required to indirectly communicate the presence of DAMPs to TLRs. This conclusion clarifies some conflicting reports in the DAMP literature and provides a route to understanding the fundamental molecular mechanism behind the important but mysterious activation of TLRs in the presence of endogenous DAMPs.

Advisor: Marsden, B
Midwood, K
Yue, W
The afterlife of the Great Society: Richard Nixon vs. the permanent government, 1969-1974

Richard Nixon assumed the presidency promising to rid the United States of Lyndon Johnson’s Great Society programmes that he believed had ‘reaped an ugly harvest of frustration, violence, and failure across the land’. Yet despite repeated and determined attempts across five-and-a-half years in office, Richard Nixon’s presidency came and went, and – for the most part – the social programmes of the Great Society persisted. The question which this dissertation seeks to answer, then, is a simple one: why? This question will be answered through an examination of three domestic programmes that began or dramatically expanded during the Great Society – the Legal Services Program, Volunteers in Service to America, and the Food Stamp Program.
The Afterlife of the Great Society argues that true domestic political power in the United States resided in a powerful network of interests that this dissertation terms the Iron Diamond. This Iron Diamond comprises the bureaucracy, Congressional Committee staffers, District Court judges, and public interest lawyers. These actors were each individually powerful in the formulation and implementation of domestic policy, but it is when they work together that their true power is seen. Centering these actors causes us to reconsider the nature of power within the U.S. political system and corrects a historical literature which exaggerates the domestic power of the President.

Keywords: political history
bureaucracy
US History
Richard Nixon
Advisor: Davies, G
Advancing machine learning in astrophysics

This thesis explores four projects applying supervised deep learning to help answer astrophysical questions.
I first consider faint tidal features. Tidal features are a long-lasting signature of galaxy mergers, making them useful for measuring merger rates. However, current automated methods struggle to detect faint tidal features in complex galaxies. I use convolutional neural networks to identify galaxies with tidal features in the CFHTLS- Wide Survey, improving on previous methods applied to the same dataset. I show that my networks can identify which pixels are associated with tidal features, potentially enabling researchers to not only identify but also characterise tidal features.
I then turn to Galaxy Zoo, a citizen science project measuring galaxy morphology. Galaxy Zoo is being gradually outpaced by the increasing scale of new surveys. Au- tomated classifiers can be trained using volunteer responses; however, such classifiers are often unable to consider uncertainty in either volunteer responses or predictions, leading to wasted volunteer effort and overconfident classifications. I introduce a probabilistic approach that allows classifiers to flexibly express uncertainty. I use this probabilistic approach to build a machine learning system that ‘asks’ volunteers to label the galaxies it could best learn from. I relaunch Galaxy Zoo with images from the Dark Energy Camera Legacy Survey and run my system live, collecting 1.8 million volunteer responses. My final models are around 99% accurate on every question for galaxies with confident volunteer answers and are otherwise correctly uncertain.
Next, I help the Canadian Hydrogen Intensity Mapping Experiment (CHIME) detect fast radio bursts. CHIME only attempts to detect FRB above a signal-to- noise threshold of σ = 8.5, in part for lack of expert time to review candidates. I created and launched a citizen science project to classify the 7.8 ≤ σ < 8.5 signal-to- noise candidates detected by CHIME each week. Candidates found by this project may be the most distant fast radio bursts ever detected, which I hope will serve as useful cosmological probes of the intergalactic medium.
Finally, I show that neural network emulation can efficiently recover posteriors of galaxy parameters from photometry. Galaxy SED simulators are too slow to use MCMC inference on large samples. I train a neural network to emulate an SED simulator, providing both faster likelihood evaluations and known gradients. These gradients can then be used for efficient Hamiltonian Monte Carlo inference.
Together, these projects show how deep learning can help astronomers make ef- fective use of limited and uncertain data.

Keywords: astronomy
computer vision
galaxies
deep learning
machine learning
Advisor: Lintott, C
The Russian opera libretto as preached and practiced in the nineteenth century

This thesis analyses the formal qualities of the nineteenth-century Russian opera libretto and its status as neither a literary nor musical object in order to consider broader questions that can help rethink how to write the history of Russian opera. Such questions include the nature of operatic authorship, collaborative partnerships during the creation of the libretto, the use of Western European models and forms in Russian opera, and the use of anthropological or folkloric sources. I use four specific case studies drawn from across the century, allowing the development of these broader questions to be traced over roughly ninety years of Russian cultural history. Building on existing interdisciplinary scholarship on Russian opera, this thesis seeks to argue that scholars need to look beyond a prevalent ‘page-to-stage’ model of operatic adaptation and explore instead a more multifocal and collaborative approach to the history of Russian opera and its relationship to literature. In the Introduction I outline my aims and methodology, while also providing an account of the interdisciplinarity of the subject and a brief history of the institution of Russian opera in the nineteenth century. In Chapter One I discuss Ivan Susanin (1815) by Aleksandr Shakhovskoy and Catterino Cavos, examining the prevalence of a particularly eighteenth-century model of operatic adaptation and nationalist sensibility in the decades before the rise of Romanticism. Chapter Two explores the institutional barriers against the development of new Russian opera and the continued influence of European formal models through an analysis of Dargomyzhsky’s Rusalka (1856). Chapter Three explores Tchaikovsky’s Charodeika (1887), adaptation as a composer’s personal reading of a literary text, and the influence of prominent singers on operatic development. Chapter Four positions Rimsky-Korsakov’s Sadko (1895) as a collaboratively produced work of operatic ethnography, tracing a history of folklore-inflected opera. Throughout, I position each as members of a ‘problematic’ tradition of Russian opera as opposed to the canonical page-to-stage paradigm, discussing how each pushes against a particular assumption about the genre.

Advisor: Bullock, P
Magnetic resonance assessment of portal hypertension and liver function

In liver disease, measurements of portal hypertension and liver function can predict clinical outcomes and help guide management, but are either invasive or lack accuracy. This thesis explores magnetic resonance imaging (MRI) techniques with gadoxetic acid administration to assess portal hypertension and liver function non-invasively. This adds to the existing capabilities of multiparametric MRI to assess liver fibrosis, fat and iron.
Spleen extracellular volume fraction (ECV) and platelet count to spleen volume ratio identified portal hypertension accurately (both 0.79 area under the receiver operator curve (AUROC)). A combination of spleen T1 and spleen diameter identified oesophageal varices needing treatment (VNTs) in patients with compensated advanced chronic liver disease (cACLD) with the highest accuracy (AUROC 0.87) of all markers tested and could save 66% of screening endoscopies for VNTs without missing any VNTs.
Liver T1 reduction with gadoxetic acid (%rT1) correlated well with serum-based liver function markers and clinical scores and identified patients with impaired liver function with AUROC 0.86.
MRI-based markers of portal hypertension (spleen ECV; platelet count/spleen diameter ratio; spleen T1 x spleen diameter) and %rT1 were predictive of liver-related clinical outcomes in patients with cirrhosis, who are at high risk of complications, but did not add to the predictive ability of age, albumin, sodium and APRI.
In conclusion, MRI provides accurate markers of portal hypertension and liver function. Of particular importance, spleen T1 and spleen diameter criteria could be used to avoid more screening endoscopies in cACLD than any other VNT exclusion criteria reported to date. Although prognostic in the high risk cohort studied here, the MRI markers of portal hypertension and liver function do not surpass the prognostic value of simpler measures.

Keywords: oesophageal varices
cirrhosis
magnetic resonance
non-invasive tests
liver function
extracellular volume fraction
portal hypertension
Advisor: Barnes, E
Neubauer, S
Robson, M
The making and unmaking of cosmopolitan elites: hierarchy, diversity, and Indian diplomats in international society

This is a thesis about belonging. With the analytical sensibilities of reflexive sociology, inspired by Pierre Bourdieu, it examines how Indian diplomats have sought to navigate the hierarchies of international society, re-enacting colonial “standards of civilization” as they perform the role of confident cosmopolitans, at home in the world.
The chapters cohere around an analysis of the Indian diplomatic cleft habitus, suspended between two radically different conceptions of international society that stand in tension with one another: one, a caricature-like notion of a white, European-dominated society paralleling classic English School notions of a homogenous club; two, a postcolonial international society founded on diversity, difference, and the symbolic representation of the global subaltern. Both imageries come with their own social codes of belonging, imbibed through the cleft habitus.
The thesis argues that membership in international society involves a recurring set of behaviours and dispositions aimed at finding recognition (membership in international society is about rehearsed, continuous cultural belonging). These behaviours not only reflect imbalances of power between states, but also reveal which groups within a nation and its diplomatic service find acceptance as legitimate insiders in diplomatic circles (membership in international society is tied to domestic hierarchies). Indian diplomatic performances of belonging reproduce, contest, and legitimate a particular set of international as well as domestic hierarchies, prominent among them race, class, gender, and caste.
The chapters analyse the Indian diplomatic cleft habitus through its colonial origins (Chapter 2), demographic implications (Chapter 3), pedagogical imperatives (Chapter 4), outward projection (Chapter 5), and the double challenge posed to its performance and ideals by the emergence of a “post-Western” world and a Hindu nationalist India (Chapter 6).
This analysis builds on 85 interviews with Indian diplomats, ministers, and academics, as well as on archival research at the Nehru Memorial Library and the National Archives of India, conducted in New Delhi and Bangalore in 2019.
The thesis concludes that understanding the much-debated challenge to our so-called liberal international order requires a critical reading of the ways in which its cosmopolitan creed has reproduced many of the same social hierarchies it claims to reject. In fact, attempts at imbibing “actually existing cosmopolitanism” often stand in the way of respecting pluralism and diversity.

Keywords: Indian Foreign Service
habitus
standard of civilisation
cosmopolitanism
India
diversity
decolonisation
diplomacy
caste
Advisor: Hurrell, A
The role of prediction error in linguistic generalization and item learning: evidence from an online eye-tracking study

The discriminative learning framework, grounded in principles of learning theory, was recently revitalized as a specific mechanism to carry out language acquisition within a domain-general, input-driven constructivist account. It specifies that language learning, rather than being guided by an innate linguistic system like Universal Grammar, could be constrained by obtaining negative evidence using prediction errors. Previous studies have tried to indirectly show the effect of prediction making on word-referent mapping by comparing the learning performance of two groups of learners who experienced language input with different input order conditions, where only one condition allowed cue competition. The current study applied eye tracking to the learning process and demonstrated direct evidence for the predictive behaviors during discriminative learning. Two learning experiments with a learning phase where cues predicted visual linguistic outcomes (labels) were conducted. Experiment 1 was a replication of an earlier word learning study – with eye tracking added – and showed that participants made predictive saccades towards positions of labels before they appeared for both high and low frequency conditions. Experiment 2 used a new cross-situational learning paradigm and did not demonstrate default fixations. Offline results showed weaker learning than previous studies and did not show above-chance accuracy for the low frequency trials. However, plot analysis of the individual variation for low frequency trials suggested that participants who failed to learn low frequency cues could have been persistently overgeneralizing in training. This overgeneralization pattern is discussed in the context of adult L2 learning.

Keywords: discriminative learning
eye tracking
second language acquisition
psycholinguistics
word learning
learning theory
Advisor: Wonnacott, E
Viviani, E
Guangdong culture and identity in the late Qing and the early Republic

This thesis examines the construction of Guangdong identity in the late Qing and the early Republic. It does that by examining five aspects that relate to provincial identities. They are, first, the drawing of ethnic boundaries within Guangdong as reflected in the local literature; second, the literati perception of Guangdong vernacular writings as represented by the Cantonese dialect;third, the people and institutions which substantiated the high culture of Guangdong; fourth, the Republican intellectual trends which possibly broadened the definition of Guangdong culture, and fifth, regional identity from a county's perspective in the 1940s. It argues that the formation of provincial identities in China was tied to the evolution of the Chinese state. It also argues that although local customs and popular customs were drawn into questions of provincial identity, the literati in the Qing dynasty and the educated elite in the Republic played a crucial role in deciding what counted as elements of the provincial identity. As a result, provincial identity is subsumed under the realm of a unified Chinese culture, and “regional particularities” become the exception rather than the rule in the context of the province.

Keywords: identity
ethnicity
Guangdong Sheng
republic
China
civilization
Advisor: Faure, D
Learning about the distribution of rewards through dopamine and the basal ganglia pathways

The basal ganglia pathways and their dopaminergic innervation are essential for reinforcement learning and are thought to play an important role in value-based decision making. Yet, it is not fully understood how these components interact and which computations they perform. In this thesis, we aim to improve this understanding, building on the Actor learning Uncertainty (AU) hypothesis of Mikhael and Bogacz (2016). According to this hypothesis, the basal ganglia might learn statistics (averages and uncertainties) of reward distributions and use them to inform choices, with dopamine acting as a teaching signal as well as a modulator.
First, we reapply the AU model, shifting the focus from reward uncertainty to tasks in which subjects need to work for rewards. We test whether the model can learn the payoffs and costs of actions and whether it can reproduce the effects of dopaminergic medication on the willingness to work for food. Second, we develop a new variant of the AU model—the scaled prediction error model—to understand how tracking uncertainty can improve learning. We investigate the new model’s performance, biological plausibility and consistency with behavioural data. Third, we test the AU model empirically, using behaviour in a learning task. The model predicts that there should be an association be- tween unexpected rewards and subsequent risk-seeking. We test that prediction, controlling for alternative explanations using trial-by-trial modelling.
We find that the AU model can learn the payoffs and costs of actions and repro- duce related behavioural effects. We further find that tracking uncertainty can improve learning if the estimate of uncertainty is used to scale reward prediction errors. This also makes the model consistent with the empirical phenomenon of dopaminergic range adaptation. Finally, we confirm the AU model’s prediction: unexpected rewards are associated with risk-seeking. Our results consolidate and extend our theoretical understanding of the role that dopamine and the basal ganglia play in learning about the distribution of rewards.

Keywords: basal ganglia
reinforcement learning
dopamine
Advisor: Bogacz, R
Manohar, S
The Commedia dell'Arte in the English imagination, 1571-1611

This thesis examines how the commedia dell’arte manifested in the English imagination in the period 1571-1611. This form of professional, semi-improvised performance practice emerged from Italy in the mid-sixteenth century to capture the hearts of audiences across Europe and introduce regional dramaturgies to the literary and theatrical innovations of the Cinquecento. There are frequent references to the masked stock characters and extemporising routines of the arte in extant English print, and scholars have often found parallels between the dramas and performance practices of English playwrights and Italian practitioners. However, these studies are complicated by the lack of direct exposure to the arte in performance. The Italians made only a handful of visits to England in the 1570s, after which they would not set foot on English soil again for over twenty years.
Utilising methods from contemporary transcultural theory, this thesis approaches the commedia dell’arte as a culturally porous theatrical apparatus of constituent parts that became disentangled from the whole during their migratory journey. These constituent parts were transferred at different rates, at different times and through different means, and as such were adapted and repurposed to the demands of specific cultural and political moments along the way. In other words, the commedia dell’arte did not pass into the English imagination all at once, a direct exchange from one culture to another through sustained exposure to Italian performance, but rather percolated through a series of piecemeal translations and appropriations. As such, this thesis contends that the commedia dell’arte found in extant print and manuscript records in the period has little resemblance to or bearing on the activities of the Italian practitioners on the continent. Rather, it was highly situated and syncretic, constructed by writers and dramatists to interrogate and reflect anxieties over difference, belonging, and what it meant to be English.

Keywords: Commedia dell'arte
early modern drama
Shakespeare
sixteenth-century
transculturality
Italian theatre
renaissance