VictorJuiz/thesis huggingface dataset:
Analysis of the human B cell repertoire following vaccination

A diverse B cell repertoire is essential for recognition and response to infectious and vaccine antigens. High-throughput sequencing of B cell receptor (BCR) genes can now be used to study the B cell repertoire at a depth which reflects its true diversity. As a relatively new technology, there is little information on the structure of the repertoire at baseline, whether antigen-specific changes can be detected from the total repertoire following antigen stimulus, and what the potential clinical applications of BCR repertoire sequencing are.
In this thesis, robust laboratory and bioinformatic techniques were developed for studying the BCR repertoire. These were then applied to healthy participants to assess inter- and intra-individual variation in the repertoire. Hepatitis B vaccination was then used as a model system to determine how the repertoire responded to both primary and booster vaccination. Tracking repertoire dynamics following booster vaccination identified the presence of time-limited changes in the total BCR repertoire following stimulation. Cell sorting and sequencing of vaccine-specific cells in addition to sequencing the total repertoire allowed deconvolution of the vaccine- specific response from background repertoire fluctuations. Studying the response to primary vaccination showed the same time-limited changes, and revealed that a surprising number of the B cells activated appear to be derived from memory cells, and activated by the vaccine in a cross-reactive manner. More specific applications of BCR repertoire sequencing were then investigated in the context of meningo- coccal and influenza vaccine studies. These were able to distinguish the different cell subsets activated in response to meningococcal polysaccharide and conjugate vaccines, and shed light on how the AS03 adjuvant increases pandemic influenza vaccine immunogenicity.
In summary, presented in this thesis are some of the first BCR repertoire data following Hepatitis B, meningococcal and influenza vaccination. These data have increased our fundamental understanding of the BCR repertoire, and how this responds to vaccination. Insights from these data raise promise for the application of this technology to clinical settings for vaccine evaluation, disease diagnostics and monitoring, and therapeutic antibody discovery, and have provided a foundation for many further studies.

Keywords: Adjuvant
Antibody
Influenza
ACWY
Repertoire
B cell
BCR
VDJ
Hepatitis B
Advisor: Kelly, D
Lunter, G
van der Most, R
Novel interactions of volatile anaesthetics on O2 sensing and TASK channels in carotid body type-1 cells

Hypoxia elicits a carotid body-mediated increase in minute ventilation, called the chemoreflex. Volatile anaesthetics depress this chemoreflex, even at sub-anaesthetic doses. The broad aim of this thesis is to explore how these anaesthetics act on carotid body mechanisms to depress the chemoreflex. The agents studied in this thesis are halothane (a potent depressant of this reflex), isoflurane (a less potent depressant) and sevoflurane (a weak depressant).
Intracellular Ca2+ measurements, mitochondrial NADH and potential measurements, and single channel electrophysiology studies were performed on a primary culture of rat carotid body type-1 cells and HEK cells transiently expressing TASK channels. Cells were exposed to hypoxia and/or volatile anaesthetics.
The results reveal that on all levels studied, the same order of potency of anaesthetics was observed as seen in human ventilatory studies. Volatile anaesthetics depress the hypoxia evoked Ca2+ entry in the carotid body and increase the activity of K+ background channels both in glomus and HEK cells expressing TASK. Furthermore, on all levels studied, when halothane and isoflurane were applied as a mixture, the effect evoked by the mix was of a lesser magnitude than that of the halothane alone, revealing a novel sub-additive observation, which has not been previously reported in the literature.
The anaesthetic action of glomus cells was not exclusive to the TASK channels as application of all three anaesthetics evoked an increase in mitochondrial NADH and caused mitochondrial depolarization in glomus cells. These effects of anaesthetics on mitochondria mimics the effects of hypoxia, the implications of which are discussed in this thesis. Two novel TASK blocking agents A1899 and PK-THPP were able to decrease glomus cell TASK channel activity, even in the presence of a clinically relevant concentration of isoflurane.
These agents may be promising as future respiratory stimulants.

Advisor: Buckler, K
Pandit, J
Introspective classification for robot perception and decision making

In robotics, a classifier is often a core component of the decision-making framework. Precision and recall have been widely adopted as canonical metrics to quantify the performance of a classifier, but for applications involving mission-critical decision making, good performance in relation to these metrics is insufficient. The use of a classification framework which produces scores with inappropriate confidences will ultimately lead to the robot making bad decisions, thereby compromising robot or user safety. In order to select a classifier which will make decisions reflecting the nature of the costs, we should pay careful attention to the ways in which it generates scores. We introduce and motivate the importance of a classifier's introspective capacity: the ability to give an appropriate assessment of confidence with any test case. Classification made confidently must be correct, and mistakes should be made with high uncertainty. A classifier's capacity to do so must remain consistent despite unusual or surprising test cases. We propose that a key ingredient for introspection is a classifier's potential to increase its uncertainty with the distance between a test datum and its training data.
We define the ideal introspective behaviour, and derive idealised classifiers which serve to benchmark a number of commonly used classification frameworks in a variety of decision-making tasks. We show that classifiers that offer predictive variance at test-time are more cautious and less over-confident than those which consider a single hypothesis or discriminant. However, in high-cost (or high-risk) decision making, none of the classifiers evaluated in this thesis are sufficiently introspective to prevent all potential catastrophic mistakes. We show that in sequential decision-making, when the mapping from score to class is explicitly stated, a classifier's ability to behave consistently despite non-stationary test data is of primary importance.

Keywords: autonomous car
semantic mapping
pedestrian
perception
mapping
robotics
introspection
road sign
traffic light
planning
detection
classification
autonomy
autonomous vehicle
computer vision
image
Advisor: Posner, I
Newman, P
Single-cell transcriptional analysis of malaria-specific t lymphocytes following vaccination and protection in humans

Vaccine approaches that confer durable and high-level protection against malaria infection are urgently needed. Development of next-generation vaccines is partially hindered by a limited understanding of the mechanisms underlying protective immunity. In-depth characterization of such responses will be critical in identifying immune correlates and ultimately guiding the development of next-generation vaccine strategies. The aim of this thesis was to dramatically enhance the breadth and depth of phenotypic analysis from cellular immune responses induced by two malaria vaccine candidates that have demonstrated high-level protection against CHMI: the PfSPZ Vaccine and ChAd63/MVA ME-TRAP. Single cell gene expression analysis of antigen-specific CD4+ and CD8+ T lymphocytes following vaccination and/or CHMI revealed a number of important findings. First, PfSPZ-specific CD4+ T cells from vaccinated and protected subjects in a small cohort were enriched in IL21 gene expression compared to unprotected subjects prior to challenge. Average IL21 expression per-subject correlated with antibody responses against the immunodominant CS protein. Analysis of a larger independent cohort confirmed both of these findings and provided greater power to dissect this population of IL21+ CD4+ T cells. Interestingly, these data provided evidence for a class of Th1/TFH-like cells that could potentially provide help for both CD8+ T cells and humoral responses elicited by PfSPZ vaccination. Second, analysis of CD8+ T cells from subjects vaccinated with ChAd63/MVA ME-TRAP provided the opportunity to investigate cellular immune responses that are critical for clearance of infected hepatocytes. There was evidence for multifunctional use of effector molecules in TRAP-specific CD107a+CD8+ T cells and a broad transcriptional signature of monofunctional IFNG+ CD8+ T cells, which have been previously correlated with protection induced by viral vectors. Overall, data presented in this thesis demonstrate that single-cell transcriptional analysis is a powerful tool to expand the characterization of cellular immune responses and elucidate potential correlates of protection in Phase II clinical trials.

Advisor: Ewer, K
Mcshane, H
The strategic logic of international agreement design

Conventional wisdom suggests that weak international actors should avoid concluding ambiguous agreements with much stronger partners because this increases their vulnerability to subsequent exploitation. Why then do we observe so many instances of just such agreements signed under conditions of extreme power asymmetry? I answer this question by emphasising an underappreciated factor shaping the agreement design strategies of actors: Power trajectory. Focusing on international trade, I develop a three-part framework which demonstrates first, that powerful but rising states gain from securing narrow agreements because as the scope of these agreements is broadened, they are provided with more opportunities to use their growing power to secure increasingly favourable deals. Conversely, powerful but declining states are incentivised to conclude broad agreements as a way to lock-in an advantage that will decline over time.
Second, I demonstrate that because of the particular vulnerabilities faced by weak states as a result of these narrow agreements, strong but rising powers are often required to make up-front concessions in order to secure their preferred contract and overcome the fears of their weaker counterparts. Third, I show that powerful but rising states can reap the benefits of subsequent rounds of bargaining because the initial agreement has induced the weaker party to make transaction specific investments which serve to drastically reduce its exit options.
In developing this framework, I make three contributions; first, from a theoretical standpoint I specify more precisely the conditions under which powerful states choose to tie their hands and so qualify both the liberal claim that powerful states must always do so, and the realist suggestion that they strive to maintain freedom of action. Second, I make an empirical contribution by placing the trade policies of four major economic powers in detailed comparative perspective. Finally, I make a substantive contribution by demonstrating yet another mechanism by which the strong secure their preferences at the expense of the weak in international affairs.

Advisor: Snidal, D
Investigating the role of pal-1, the C. elegans caudal homologue, in the development of the stem-like seam cells

An organism’s epithelium provides essential protection against mechanical stress and pathogenic infection, as well as specialised secretory and sensory functions. Intriguingly, at the end of the first larval moult in C. elegans, epidermal P cells, which until now have comprised the majority of the ventral epidermis, migrate and remodel, relinquishing their epidermal role before taking on neuroectoblast fate. This leaves a ventral 'hole' in the architecture of the C. elegans epidermis. This work describes how this hole is filled by a hitherto-overlooked ventral intercalation event that mirrors the well-described dorsal epidermal intercalation that takes place during embryogenesis and forms the dorsal hyp7 epidermal syncytium. Ventral intercalation involves polarised PAK-dependent cytoskeletal remodelling of anterior daughters of asymmetric (seam) stem cell divisions, prior to P cell migration, between the P cells. Conversely, the posterior seam-fated (self-renewing) daughters retain their lateral positions. This ensures the anterior daughters move ventrally to replace the P cells as they migrate into the ventral midline; thus, for the first time, the major syncytial epidermal organ, hyp7, on the ventral side of the animal is completed. Using this novel system, I have shown that patterning of adjacent epidermal tissues by pal-1/caudal, through expression driven by a putative Wnt-dependent intronic enhancer, determines the polarity of apical junction remodelling and thus polarity of migration during intercalation. Furthermore, the change of gene expression, structure and function of the P cells during this major epidermal remodelling event appears indicative of a transdifferentiation event.
An enhancer/suppressor screen for pal-1 epidermal phenotypes during this newly described ventral intercalation has identified a novel role for netrin during posterior embryonic patterning. I have shown that this phenotype is dependent on an interaction with pal-1 of both netrin receptors, UNC-40 and UNC-5, as well as having identified an unc-40-independent role for unc-5 and pal-1 earlier in development. Conversely, I have also discovered a role for pal-1 in post-embryonic netrin-dependent motor neurone axon guidance. Given the high levels of conservation between members of the netrin signalling pathway in many organisms, as well as between pal-1 and caudal genes, both at the sequence and functional levels, these new roles for pal-1 and netrin may find resonance in other systems.
Finally, this work has characterised the expression of a member of the C. elegans Hedgehog-related family of genes, wrt-2, in the epidermis and has provided insight into the possible functions of this gene in vivo.

Advisor: Woollard, A
Diffusion kinetics in radiation chemistry

The study of radiation chemistry is very important because of the wide range of applications. Many of the processes in radiation chemistry evolve randomly and can be modeled using the theory of stochastic process.
The main aim of this thesis is to study correlation effects in model systems of the type found in radiation chemistry, i.e. clusters of reactive particles.
Studies of this type involve a substantial amount of computer simulation. The first work described in the thesis shows how the Message Passing Interface can be incorporated in the algorithms used to simulate radiation chemical kinetics and how that can improve the performance of the programs.
The reaction probability for two diffusing particles is well known, and current theories are based on this, making the approximation that pair distances evolve independently. This work analyses some correlation effects that appear in a system of three particles, with some new results, notably in the distribution of the joint distribution of the distances and the underlying 3-body backward diffusion equation, but it has not yet been possible to use these results to introduce corrections in the working simulations.
The competition between scavenging and recombination is investigated in detail in chapters 4-6. A correction to the Smoluchowski theory for a fully-diffusion controlled reaction is proposed, and it is shown how the Independent Reaction Times method can be used to simulate this competition. The approximation is justified both by comparison to simulation results and theoretically, and is shown to apply to all the ordered scavenging reactions in a multi-particle system.
Finally, the problem of modeling a reversible reaction is briefly investigated in chapter 7. The main result of this chapter is a generalization of previous work on the distance between a pair conditional on its future reaction time, generalized to a radiation boundary condition.

Advisor: Green, N
Assessing cardiotoxicity in randomised trials of anthracycline chemotherapy

Chemotherapy has improved survival in many types of cancer. However, it can lead to a range of toxic side effects that can occur while the patient is on treatment but may also appear months or years later. One of the more serious harmful side-effects of chemotherapy is heart disease and anthracycline chemotherapy is particularly implicated in this. Observational studies have shown that the risk of congestive heart failure in anthracycline treated patients rises rapidly after cumulative doses of about 400 mg/m2, but that there is also some risk below this dose.
This thesis explored several methodological issues that affect meta-analyses of harms. First meta-analyses of harms often include terms for those harms in their search strategies. Evaluation of a trial search including cardiac terms against the trial list maintained by the Early Breast Cancer Trialists' Collaborative Group showed that only 48% of their trials were found. After cardiac terms were removed from the search strategy, 87% of the EBCTCG trials were found. Second, anthracycline cardiotoxicity is often not reported in a manner that enables data to be extracted for meta-analyses. To address this, risk of outcome reporting bias in trials included in this thesis was assessed. There was a high risk of outcome reporting bias for cardiac morbidity in 50% of trials, and 35% of trials had high risk of outcome reporting bias for cardiac mortality. Third, previous meta-analyses of anthracycline cardiotoxicity included only a limited number of trials. In order to increase the amount of information about anthracycline cardiotoxicity available for meta-analysis, a method was devised for including confounded trials in the meta-analysis, taking into account prior knowledge as to the likely effect of other drugs on cardiotoxicity.
Finally, published and individual patient data meta-analyses of cardiac death in randomised trials of anthracycline versus not were undertaken. The published data meta-analysis included 32 trials, 9 of which were unconfounded, and found a 36% (95% CI 1-83%) increased risk of cardiac death in anthracycline-allocated patients compared to those not allocated to anthracycline. No conclusions could be drawn about the effect of confounder drugs on the risk of cardiac death. A meta-analysis grouped by lower and higher dose showed that there was a statistically significant increase in risk of cardiac death in anthracycline allocated patients compared to those not allocated anthracyclines in the higher dose group only (OR=1.74, 95%CI 1.15 – 2.62).
In conclusion, this thesis has generated new insights into the methods used for meta-analyses of harms. It has also produced a new risk estimate of cardiac death in anthracycline-treated patients that clinicians can use to inform their treatment decisions.

Keywords: Chemotherapy - side effects
Anthracyclines
Cardiotoxicity
Advisor: Darby, S
McGale, P
Taylor, C
The origins of American corporatism in the Stuart age

This is the study of the corporation as it was transplanted to colonial Virginia, Massachusetts, and New York in the Stuart age. The ability of this evolving legal form to provide a combination of increasing legal certainty and practical flexibility, proved an appealing combination to protect and promote a range of evolving local private interests in unique colonial circumstances. In the same way, the corporate form was able to facilitate and fulfill certain political and economic interests of the metropolitan government, including for example, the personal interests of the Crown. The empirical basis of this thesis comprises a close examination, comparison, and contextualization of these terms of incorporation used in each of Virginia, Massachusetts, and New York from the time of James I to Anne. These terms become both increasingly formulaic in their grant of core elements, and reflective of their particular environment through the ancillary rights and privileges conveyed. The distinctive interplay between these evolving interests is evidenced through the evolving uses and terms of incorporation. This ability of the corporation to adapt to, and reflect its novel environment presents a fresh perspective on the legal history of the colonies as well as the genesis of the Anglo-American corporation.

Advisor: Getzler, J
Exploring the writer's toolbox: a study of how writers and their use of writing implements and surfaces relate to their ways of thinking for writing

The state of writing abilities throughout the United States presents an urgent issue. Low student achievement in English Language Arts (ELA) exams and standardized English assessments persist (National Center for Education Statistics, 2012), while businesses spend billions of dollars on remedial writing instruction (Dillon, 2008). Technology is increasingly cited as a potential solution to these issues. Evidence for this is limited, as is existing research into the basis of the issues that technology might address. On account of that context, this thesis turns to a basic distinction between digital and non-digital writing: the writing surface and implement, or pen and paper – screen and keyboard. Conceptualizing such artefacts through a view of writing as a way of thinking raises the following question, which is this study's guiding inquiry. Might we use digital implements and surfaces to support the ways of thinking involved in composing written works of semantic cohesion?
Building on research into writing as thinking, the study presented in this document analyses how uses of writing surfaces and implements relate to ways of thinking while writing, and which contextual factors influence those relationships. Drawing on a neuro-anthropological approach, the study focuses on the writer's mind as the driver and source of the lived experience of writing. Expert writers, therefore, are considered to be those who exhibit the ways of thinking while writing to which other writers aspire. To examine a range of uses of writing surfaces and implements with reference to expert writers' ways of thinking, the study was conducted in two parts. Part 1involved a content analysis of published interviews with professional writers. This generated a framework through which to conduct in-depth qualitative research with college student writers – part 2.
This thesis is as much about thinking while writing as it is about the different tools available for writing. As such, the study refutes the hyperbolic and deterministic claims about technology and writing, and finds that technology is not leading to new ways of thinking while writing. Instead, surfaces and implements available allow writers to change how they practise their ways of thinking while writing. By considering this distinction and developing understandings of the dynamics involved and their implications, writers may begin to realize the potential of technology for writing. Ultimately, this thesis contributes to existing theories on writing through an informed discussion of how to think about implements and surfaces in ways that support writerly thinking, and by offering fresh ways to think about the lived practice of writing.

Advisor: Davies, C