VictorJuiz/thesis huggingface dataset:
Modelling the short-T2* signal in the liver with ultrashort echo time magnetic resonance imaging (UTE-MRI)

Liver fibrosis, a consequence of most chronic liver diseases, is characterised by collagen deposition. Collagen has a short-T2* signal that is undetectable with conventional magnetic resonance (MR) sequences. However, collagen signal is measurable with the ultrashort echo time (UTE) sequence, which can achieve an echo time of less than 1 ms. This thesis explored the modelling of the short-T2* signal in the liver with UTE.
Given the implication of collagen in liver disease, MR signal properties, including the R2* and resonant frequency shift, were investigated in oriented collagen. Ex vivo measurements were performed at 3 T in tendon, an example of oriented collagen. Furthermore, the R2* of collagen was investigated in phantoms in vitro.
The UTE sequence was optimised for in vivo imaging on the Siemens Trio 3-T and Prisma 3-T scanners. On the Trio, optimisations included reduced gradient spoiling, the use of a double-echo vs. a single-echo acquisition and the use of spatial saturation. Calibrations were performed on the Prisma for the bandwidth, radiofrequency coil and minimum TE.
From the R2* and resonant frequency shift of tendon, an R2* model was developed for describing isotropic collagen and free water in the liver. Other exponential models were also considered, accounting for short-T2* signal. UTE acquisitions were performed to measure R2* signal in the liver from healthy subjects and liver-disease patients in vivo. The models were used to fit the R2* signal and the most appropriate model was selected. Subsequently, the repeatability and reproducibility of the short-T2* signal fraction were evaluated. Comparisons of the short-T2* signal fraction were made between healthy subjects and patients.
Given the selected model for the short-T2* signal in the liver, potential sources of short-T2* signal were discussed. Future work involves the identification of the constituent(s) giving rise to the short-T2* signal in the liver.

Keywords: UTE
tendon
R2*
fibrosis
T2*
short T2*
collagen
ultrashort echo time
liver
frequency
Advisor: Robson, M
Biasiolli, L
'The Hotel de Luxe': the architectural and social significance of the 'grand hotel' in London 1860-1910

The London grand hotel or hotel de luxe was a new building type, designed to provide luxury for a changing society. These venues were located at the intersection of public and private, and composed of a series of potentially contradictory characteristics. They combined an idealised past with the excitement of the future. They promised an experience of consumption rooted in traditional status which was also innovative. ‘Modern’ in terms of up-to-date technology, they also exhibited the modernity of shifting hierarchies and identities in an urbanised, industrialised society. Their desirability was associated with the excitement of the foreign, but also with their practical role as a convenient base . Monuments to wealth and fashion which constantly adapted, grand hotels both responded to and reshaped identity and social culture.
Luxury is complex and elusive, defined according to place, time and person. Chapter I sets this thesis in the context of other examinations of the concept, its inherent duality as economic fact and medium to communicate social relationships, and its connection to the production of space. It argues for a set of characteristics of luxury around which the thesis is structured. Chapter II: Grandeur examines the hotels’ physical reality, size and status. Chapter III: Magic considers the representational encounter, promoted through a narrative of magical transformation. Chapter IV: Exclusivity examines the tensions between this crucial aspect of luxury and the need to attract clients, balanced via tangible and intangible thresholds of plan, design, and staff performance. Chapter V: Cosmopolitanism considers the attractions of foreign cultures, visible in the public-facing staff and in the gastro-cosmopolitanism of restaurants. Chapter VI: Comfort addresses the influence of changing ideas of physical and social comfort on public and guest rooms, and the new, private bathroom. Chapter VIII: Modernity examines the hidden production systems of luxury, and the social modernity on display in palm courts, where men and women could enjoy novel experiences in a new interior. Combined, these characteristics created the grand hotel.

Keywords: history of travel
production of space
architectural history
waiter
history of tourism
luxury hotel
social history
restaurant
housekeeper
chef
luxury
Advisor: Mahony, C
Regulation of dopamine release by striatal GABA and acetylcholine in health and disease

Dopamine (DA) signalling plays a central role in the normal functions of the basal ganglia, by helping facilitate behavioural processes such as action selection and reinforcement learning. Dysregulation of DA signalling is implicated in a diversity of neurological and psychiatric disorders including Parkinson’s disease and addiction.
Striatal DA release is subject to major local influences besides action potentials generated in the soma. Striatal mechanisms have been shown to drive and gate axonal DA release. Understanding how these factors regulate DA signalling, and how they may be dysfunctional in disease states, is crucial for identifying novel disease therapies.
Firstly, this thesis will describe the role of striatal GABA in regulating DA release. The striatum is one of the most GABAergic nuclei in the brain, however, whether striatal GABA can modulate DA release is not understood. DA release, detected with fast-scan cyclic voltammetry from ex vivo striatal slices, was found to be inhibited by the activation of GABAA and GABAB receptors, independent of cholinergic input. GABA receptor antagonists enhanced DA release, indicating that DA release is under tonic inhibition by striatal GABA. Furthermore, ambient GABA manipulates short-term plasticity of DA release, and K+-mediated changes in short-term plasticity require activity on GABA receptors.
I will then describe the implementation of several approaches to further our understanding of striatal ACh signalling. I will discuss the characterisation of a new mouse cross which will allow for the genetic targeting of striatal cholinergic interneurons (ChIs) within a parkinsonian disease state. These animals show normal parkinsonian deficits and are appropriate for the study of ChIs within the disease context. I will also describe the implementation and results of an immunohistochemical procedure for accessing ChI cell count and activity. This method reveals that parkinsonian mice have higher ChI counts but show less global activity. I also describe a method for detecting choline fluxes within striatal slices, as a proxy for ACh.
Finally, I will discuss a collaborative, standalone set of experiments exploring the impact of conditionally knocking out midbrain DA neuron-derived insulin-like growth factor 1 in striatal DA release. No changes in DA release were found within these animals.
The data presented in this thesis provide novel roles for GABA in the modulation of DA release. Furthermore, the implementation of several new methods for assessing changes in the cholinergic axis allow for further study of striatal ACh in both health and disease.

Advisor: Cragg, S
Rediscovering Rubén Darío through translation

Despite being widely considered one of the most important writers of the Spanish language, Rubén Darío is scarcely known in the English-speaking world. This thesis addresses the question of his obscurity. By approaching Darío’s oeuvre through translation, it sheds light on the history of his reception in English and on the multilingualism of his writing. In addition, it offers new renderings of the modernista’s poetry alongside a critical discussion of the translation of poetry with a view to improving its practice.
The thesis is divided into three different sections which correspond to three different ways of applying translation to the study of Darío’s oeuvre. Section I offers a reading of Darío’s work with an emphasis on his use of translation in his writing, thereby revealing its multilingualism. Section II centres on translation as a critical issue: it analyses the history of Darío’s reception in English by considering historical, cultural, and poetic differences between Spanish- and English-language literature from the turn of the nineteenth century to the present. In addition, it offers a critical discussion of the theory of the translation of poetry vis-à-vis Darío’s writing. Section III puts translation into practice both by offering new renderings of the Nicaraguan’s poetry as well as discussing the issues that arise when looking at existing versions.
This thesis argues that the translation of poetry is by and large literary imitation across languages. In this regard, some of the key elements of Darío’s poetry, notably its prosody, have not been rendered successfully into English; nevertheless, cultural and historical differences between Spanish- and English-language literary traditions, rather than linguistic, have impacted on its reception more heavily.

Keywords: Modernismo
Spanish American Literature
Translation
Rubén Darío
Poetry
Multilingualism
Advisor: Del Pilar Blanco, M
Bollig, B
Method development for the generation and selection of precise genomic edits in human cells

Gene editing is the process of generating targeted changes in the genome of an organism or cell. Changes can be imprecise insertions or deletions (indels) which generate null alleles and permit loss of function studies. Alternatively, an exogenous donor can be provided which allows precise changes to be copied into the genome. Precise editing can be used to advance scientific understanding by generating cell lines with specific mutations. Furthermore, precise editing has therapeutic potential: pathogenic mutations in patient’s cells can be reversed or compensatory mutations can be introduced.
The relatively low efficiency of precise editing limits applicability of genome editing and increases the burden of labour on the researcher. In this thesis, I describe my efforts to improve the efficiency of editing and enrich for correctly edited cells. I study the impact of published methods shown to improve efficiency of editing. I then develop two potential FACS-based methods to enrich for correctly edited cells. Firstly, I attempt to use molecular beacons to directly recognise sequence changes in mRNA, and find that, despite promising in vitro results, the beacons are highly non-specific within cells. I then develop a transient Cas9-based circuit to detect the presence of a genomically-integrated crRNA. This crRNA-expression system can be incorporated beside the intended edit, using an ssODN donor of less than 200 base pairs. Finally, I find that using the transient Cas9-based circuit, I can enrich for precisely edited HEK293T cells by 20-40 fold, achieving final editing efficiencies of 20-60% alleles.

Advisor: Knapp, D
Fulga, T
Recurrent neural networks for time series prediction

Attempting to predict the future long precedes the time where we could first quantify much of our present. But nowadays, performing long-term and reliable time series forecasting remains as relevant as ever across a vast number of application domains, including astronomy, healthcare, meteorology, physiology, energy systems, econometrics, finance and sociology, amongst many others. Practitioners act upon these forecasts, and it is thus mandatory that such forecasts are accompanied by well-calibrated uncertainty assessments so as to enable a better-informed decision-making process.
This thesis proposes a novel time series forecasting framework, namely a scalable and general-purpose recurrent neural network approach which provides probabilistic predictions. Our method recasts time series forecasting as a symbolic sequence learning task by introducing a discrete encoding scheme over measurements. Such symbol sequence tasks have been most successfully dealt with by Long Short-Term Memory (LSTM) models and extensions, such as the sequence-to-sequence model, which form the core of our methodology. This presentation is accompanied by a large-scale experiment where we show the effectiveness of our method over 45 different datasets in comparison with state-of-the-art baselines, such as Gaussian Process Regression (GPR).
Crucially, our framework also offers a number of extensions that address a broad range of use cases beyond univariate time series prediction. For example, we show how predictive densities over the occurrence of critical events within a predictive horizon can be inferred from our forecasts. Whereas this requires access to labelled data, we provide a complementary method for recognising and labelling prototypical time series segments on the basis of the feature embedding learnt by our neural networks. Such motifs can subsequently be used to build predictive densities and characterise time series. Lastly, we extend our framework to allow for multivariate forecasting, enabling efficient inference of joint predictive densities over multiple correlated time series.
Finally, time series data scarcity constrains the choice of a forecasting model, especially as over-parameterised models such as recurrent neural networks cannot generalise from limited data. In this thesis, we propose a novel approach to infer accurate and reliable predictive distributions from scarce time series data. We achieve this through a recurrent neural network approach that infers a joint feature representation over the space of quantised time series by means of a compilation of auxiliary datasets. Cross-task knowledge transfer is readily enabled by assuming an ordinal regression approach, as quantised time series can then be characterised in terms of their ordinal bin sequences.

Keywords: Machine Learning
Recurrent neural networks
Forecasting
Time series
Gaussian Process
Probabilistic
Neural networks
LSTM
Transfer learning
Distributed interactions across multiple brain circuits explain performance in a cued spatiovisual discrimination task

Neurons transiently synchronise their spiking activity to form cell assemblies that can represent information about external sensory inputs and internal cognitive mechanisms in selective brain circuits. However, it remains poorly understood whether, and how, within-circuit spiking can be organised to form brain-wide assemblies at the service of optimal behaviour. The answer to this question, grounded in that everyday life experience is typically composed of a variety of stimuli and sensory modalities, remains elusive because population spike codes have not been investigated across multiple simultaneously recorded brain circuits.
Here we show that in a baseline period neurons in the dorsal hippocampal CA1 (CA1), the amygdala (Amy), the prefrontal cortex (PfC), the ventral tegmental area (VTA) and the nucleus accumbens (NAc) of mice can organise their activity over few tens of milliseconds to form constitutively expressed patterns of short timescale neuronal co-firing in the mouse brain. We found that in a cued discrimination task, where mice used LED-based visual cues to determine their behaviour in response to an auditory stimulus, these same brain-wide assemblies evolve with the successful translation of local sensory representations into behaviour. Moreover, their activity was predicted by a stereotyped, transient oscillatory state which appeared to facilitate the tight coordination of firing patterns between neurons in distal structures.
These insights were facilitated by state-of-the-art algorithms for spike-sorting and multivariate LFP segmentation which we were able to leverage using current best practices in software architecture. Our results thus support the notion of cell assemblies existing at the macro, inter-regional level of brain organisation and show how this may be critical for integrating disparate sources of information.

Advisor: Dupret, D
How subjectivity became wrong: early Hanafism and the scandal of Istihsan in the formative period of Islamic law (750-1000 CE)

Abū Ḥanīfa (d. 150/767) notoriously used istiḥsān (juristic preference) to make apparently subjective rulings. In response, al-Shāfiʿī (d. 204/820) declared istiḥsān invalid. Later Hanafis retorted that al-Shāfiʿī had misunderstood the term, causing modern scholars to similarly disagree on its definition. To resolve this debate, this thesis analyses istiḥsān in early Hanafi practice. However, beyond just understanding the term itself, this dissertation uses it to explore early Muslim attitudes towards a universal legal question: can a jurist overrule the letter of the law based on their own sense of justice or social impact?
The dissertation argues that in early Iraq, subjectivity went from being embraced (8th cen., Chapters 1-3), to contested (9th cen., Chapter 4), to universally denounced (10th-11th cen., Chapter 5). As part of demonstrating the embrace, the dissertation analyses a dataset of every istiḥsān ruling (approx. 500) in the Kitāb al-Aṣl of Muḥammad al-Shaybānī (d. 189/804-5), mapping the pragmatic and moral considerations that early Hanafis incorporated into their doctrine. Analysing the period of contestation then reveals, among other things, a school of 9th- century Iraqis who prized juristic subjectivity but did not survive into classical Islam. The dissertation then explores how, in the period of denunciation, Hanafis theorised istiḥsān to make it abide by objective standards, while in practice it became a potent mechanism for legal change. Throughout these analyses, the dissertation also highlights how istiḥsān is an underutilised tool for addressing perennial questions in the field of Islamic law. In all, this dissertation tells the untold story of istiḥsān, and in so doing, tells a broader story about the rise of Islamic legal orthodoxy.

Advisor: Melchert, C
A third way: Muslim arguments for secular nationalism in mid-twentieth century North India

From the late colonial period, three eminent Indian Muslim nationalists—Abul Kalam Azad, Sheikh Mohammad Abdullah, and Abdul Ghaffar Khan—conceived of a third way to nationalism which had till now been ignored by historians. Drawing confidence from the nationwide strength of the Muslim community and/or presence of their overwhelmingly Muslim regional homelands, these thinker-politicians abjured the separatism of Mohammad Ali Jinnah’s Muslim League and embraced an Indian national movement for the establishment of a secular republic. However, since they wished to avoid being reduced to a subordinate role within the Indian nation from the subject position of minority, they insisted on imagining it in terms of socio-cultural parity between Hindu and Muslim. This separated them from their colleagues Jawaharlal Nehru and M.K. Gandhi who had little need to concern themselves with this question. Nevertheless, by refusing to make religion a determinant of nationality while still retaining it within the public space, this thought must be understood as part of India’s broader secular nationalist tradition.
This endeavour—to establish an unequivocally Indian nationalism marked by Hindu-Muslim equality—did not preclude substantial differences between Azad, Abdullah, and Ghaffar Khan. How they imagined the Indian nation was informed by their contrasting ethnolinguistic inheritances and whether their respective Muslim constituencies—Hindustani, Kashmiri, and Pashtun—occupied the position of a regional majority or minority. But these figures understood that their principle of Indian equality had meaning for other groups, too; they were not parochial thinkers. Therefore, what this thesis uncovers is a new set of perspectives on major South Asian debates about: majority and minority; national history and culture; secularism; and subidentities and their political representation. And by placing these in dialogue with alternative secular and communal nationalisms, it contributes to a wider discussion about the meaning of political concepts in India and Pakistan.

Keywords: Pakistan
Pashtuns
Indian Muslims
Secularism
Kashmir
Sheikh Abdullah
Abul Kalam Azad
Abdul Ghaffar Khan
Indian nationalism
Advisor: Devji, F
Peripheral T cell responses to immunotherapy treatment in metastatic melanoma

Immune checkpoint inhibitor treatment has revolutionised treatment for cancers such as malignant melanoma, producing durable responses in patients with metastatic malignancy. Despite this progress, responses are still only seen in a subset of patients and the phenotype and specificity of the T cells responsible for determining efficacy remain poorly characterised. A better understanding of T cell behaviour during immunotherapy treatment is required to identify markers of response and resistance and to predict effective combination strategies. To address this, we performed longitudinal peripheral immune monitoring of metastatic melanoma patients receiving checkpoint inhibitor therapy. By integrating a variety of single-cell analysis approaches including mass cytometry, MHC Class I tetramer staining, single-cell fluorescence activated cell sorting and single-cell RNAsequencing, we were able to track and analyse in detail tumour-specific T cell responses in the periphery over time. Accumulation of activated effector CD8+ T cells expressing CD38 and HLA-DR was observed in response to treatment, was more pronounced with combination anti-CTLA-4/anti-PD-1 treatment than anti-PD-1 monotherapy, and was correlated with treatment outcome. Activated cells were enriched in tumour-specific compared to microbial-specific T cells, with diversification and expansion of the tumour but not microbial-specific response observed over the course of treatment. This was accompanied by transient alterations in the functional avidity of T cell clones specific for the common tumour-associated antigen MART-1. Single-cell RNA-seq revealed substantial heterogeneity in the transcriptional profile of tumour-specific T cells during therapy with transient activation and persistence of specific clonotypes observed. These results demonstrate both the feasibility of monitoring tumour-specific T cells mobilised in response to immunotherapy in the periphery, and provide insights into the mechanisms underpinning therapeutic efficacy of combination checkpoint blockade. The results also have implications for the identification of T cells and TCR clonotypes with maximum therapeutic potential for other therapeutic strategies such as adoptive cell therapies.

Keywords: Melanoma
Immunotherapy
Checkpoint inhibitor
T cell
Advisor: Middleton, M
Cerundolo, V
Speeches for readers: motives and contexts for the circulation of Ciceronian oratory

This thesis takes as its focus the important relationship between orator and reader, and is especially interested in why Cicero disseminated his speeches and how his contemporary readers would receive them. Various comments in the theoretical literature suggest that producing written versions of speeches was largely a separate activity from delivering the original, oral versions and not just an extension of the same process: it required considerable extra effort and, to a certain extent, a different set of skills. Moreover, in circulation, the speeches do not simply fulfil the original aspirations for delivery, which have already been accomplished — they offer the reader something more. The written versions of speeches circulate among new consumers, with new objects in view. The aim of these inquiries is to scrutinise the important role readers play in construing the meaning and achievement of the speeches. By viewing the speeches less as transcripts of specific oratorical occasions, and more as texts catering to readers and readerly interests, we may begin to uncover whole repertoires of significance, shaped by the readers’ context, beliefs, and assumptions, as well as by the orator’s own literary intentions and motivations for circulation.

Advisor: Hutchinson, G