VictorJuiz/thesis huggingface dataset:
Eomesodermin governs the hemogenic competence of murine mesodermal progenitors

During mouse gastrulation pluripotent epiblast cells traverse the primitive streak (PS) and diversify into mesoderm and endoderm subtypes. The T-box transcription factor Eomesodermin (Eomes) is expressed during PS formation and is critical for the development of the cardiac mesoderm and definitive endoderm lineages. The earliest wave of progenitors to traverse the posterior PS give rise to extraembryonic mesoderm (ExM) that differentiates into the endothelium and hematopoietic progenitors of the yolk-sac (YS). How a specific subset of ExM becomes committed to a hematopoietic fate remains unclear. Here we report that Eomes is transiently expressed in Flk-1+ ExM progenitors that generate virtually all YS hematopoietic and endothelial cells. Using an embryonic stem cell differentiation model of YS hematopoiesis, we find Eomes activity is essential for the production of primitive erythrocytes and pro-definitive hematopoietic progenitors but dispensable for the development of endothelial cells. Single-cell RNA-seq experiments demonstrate that in the absence of Eomes function Flk-1hi/PdgfRa- hematoendothelial progenitors are specified but fail to transition into hematopoietic cells.
Strikingly, Eomes regulates Runx1 expression in the hemogenic endothelial (HE) lineage. Furthermore, ATAC-seq experiments demonstrate that the accessibility of enhancers, that SCL normally utilizes to specify primitive blood cells, are governed by Eomes functional activity. ChIP-seq experiments suggest that Eomes coordinates the development of hematopoietic mesoderm in the context of Activin/Nodal and Tead-Yap signalling. Finally, the potencies of Eomes+ progenitors that arise during gastrulation remain ill-defined; therefore, I additionally generate two temporally regulatable Eomes.CreERT2 lines that will be used for clonal lineage tracing experiments in the future. Collectively, these results demonstrate that Eomes promotes hemogenic competence of the YS mesodermal lineage by regulating Runx1 expression and SCL functional activity at the outset of gastrulation. These findings suggest that hemogenic competence is endowed earlier during murine embryogenesis than previously appreciated and have widespread implications for the generation of HE from pluripotent stem cell sources.

Keywords: Eomesodermin
hemogenic endothelium
mouse
hematopoiesis
gastrulation
Advisor: Robertson, EJ
Bikoff, E
Fabrication and characterization of Si doped ZnO and Cu2P2O7 thin films

Transparent conductive oxides (TCOs) are a group of materials that have good electrical conductivity, high visible and low near infrared (NIR, 790–2500 nm) transparencies. They are widely used in flat-panel displays, thin film solar cells and low-emissivity windows. The current material that dominates over 90% of the TCO market is tin doped indium oxide (ITO), which has superior electrical and optical properties. However, the two issues of ITO are the high cost of indium as well as its incomplete coverage of blockage in the NIR range, especially in the 790–1100 nm range that contains nearly 60% of the NIR solar irradiance. For decades, ZnO has been considered as a potentially low-cost replacement for ITO. But even after years of empirical explorations, the conductivity of the doped ZnO films are still not as good as ITO in many cases. The lack of fundamental studies such as the understandings on the relationships between processing conditions and the microstructure and the chemistries of the films is believed to be an important factor that limits further optimization. In this study, a variety of advanced microscopy techniques such as texture X-ray diffraction, transmission electron microscopy and transmission Kikuchi diffraction were used to study the Si doped ZnO films deposited and processed under different conditions. The results suggest several possible reasons for the large improvement of conductivity after the vacuum annealing and provide a few ideas on avoiding the defects observed in the thin films for future research.
In terms of the NIR properties, a more complete coverage of blockage was achieved by the production of Cu2P2O7 thin films, which shows an absorbance of up to 66% of solar irradiance in the 790–1100 nm range while maintaining a good visible transparency (85% of transmittance at 550 nm). Given the little research reported on Cu2P2O7, here for the first time a complete route from the analysis of powder, the production of sputtering targets to the deposition of thin films as well as further analysis on the structure and chemistry of the films is presented. These films are suitable for making low-cost and highly efficient inorganic NIR coating, which can be used in many applications such as energy efficient windows and electromagnetic shielding devices.

Advisor: Grovenor, C
Speller, S
The idea of conquest in early modern British political discourse

This thesis studies Anglophone discourses of conquest in seventeenth-century British political debates. It focuses on the development and deployment of conquest arguments across a series of moments during the first half of the seventeenth century. No such study has thus far been undertaken. The present thesis, therefore, aims to offer the first substantial treatment of early modern Anglophone discourses of conquest. It is structured around four case studies, spread out over four main chapters, each examining an extended moment of importance in the development of conquest arguments. These four chapters are flanked by the Introduction and the Conclusion & Epilogue. The Introduction delimits the topic under investigation, surveys the relevant modern literature and explains the methodological approach. Chapter 1 looks at ideas of conquest in the context of James I’s accession. It shows how debates over conquest emerged from the reception of James’s political thought against the backdrop of his accession and the Anglo-Scottish union debates. Chapter 2 considers conquest discourse during the last stages of the union debates and as part of an ancient constitution narrative that developed in their wake. Chapter 3 investigates uses of conquest arguments in the civil war of the 1640s. It focuses on the pamphlet debates of 1642/3 and conquest rhetoric as part of Leveller conceptions of the Norman Yoke. Chapter 4 concentrates on conquest arguments in the Engagement controversy of 1649-51 and looks at how conquest theories developed during the Engagement’s pamphlet debate. Finally, the Conclusion & Epilogue summarises the main findings and demonstrates that the conquest theories that had been developed over the course of the century came to be used in the years following the Revolution of 1688/89.

Advisor: Parkin, J
Histaminergic modulation of striatal development

Inadequate synthesis of the neurotransmitter histamine in the brain has been suggested to be one of causes of Tourette’s syndrome and several psychiatric diseases. Previous findings suggested that dysfunction of the corticostriatal circuits are associated with such mental disorders. Indeed, recent research has reported a hypofunction of histamine in patients with Tourette’s syndrome and obsessive-compulsive disorder in human and animal studies. However, the functional role of histamine in young developing animal brains is poorly known. Firstly, this study investigated whether and to what extent histamine plays a significant role in the corticostriatal circuit in the developing mouse brain. Secondly, the study investigated whether and to what extent histamine affects neurogenesis in the striatum in the embryonic mouse brain. Towards the first aim, the study recruited three postnatal young age period mice (postnatal (P)3-6 days, P9-12 days and P21+ days) and applied extracelluar field recordings of the corticostriatal transmission. As a result, the study found that histamine negatively modulates the corticostriatal synaptic transmission in all of young age period mice, acting at the H3 receptors. In addition, histamine facilitated long-term potentiation of the corticostriatal synapses in the P9-12 period, but blocked it in the P21+ period, whereas the baseline condition showed long-term facilitation in the P21+, not the P9-12 periods. Collective analysis of this long-term plasticity experiment revealed that the dorsolateral striatum (DLS) is more likely to be facilitated than the dorsomedial striatum (DMS). Histamine’s negative modulation on the corticostriatal synaptic transmission is found in developing age periods, which was found in only adult mice brains in past studies. Also histamine’s opposite effect on the corticostriatal long-term plasticity in the P9-12 and P21+ periods implies that histamine may cause significant change in the dynamics of synaptic properties in particular developing age periods. For the second aim, the study injected α-fluoromethylhistidine (α-FMH) into the ventricle of embryonic mouse brain at embryonic day (E)12.5 and E15.5. The study then collected their brains 2-3 days after the application of α-FMH to compare the size of the striatum and proliferative zones between control and α-FMH conditions. Finally, a reduced size of striatum was observed in E15.5 brains (medial section) treated with α-FMH than those in control conditions. However, the study could not make further conclusions due to the small number of samples.

Keywords: corticostriatal development
synaptic plasticity
histamine
histamine H3 receptor
basal ganglia
mice brain
extracelluar field recording
corticostriatal transmission
striatum
histamine receptors
Advisor: Ellender, T
Sharp, T
Development of bisulfite-free DNA methylation sequencing methods and their application to cell-free DNA for cancer detection

5-Methylcytosine (5mC) is the most abundant epigenetic mark in DNA regulating gene expression and influencing crucial cellular processes. Aberrant DNA methylation is involved in pathogenesis of human malignancies. Detection of cancer-specific methylation patterns in cell-free DNA (cfDNA) is a promising approach for development of minimally invasive, liquid biopsy assays. Most of methylation sequencing methods are based on bisulfite treatment that causes an extensive DNA damage, therefore are not ideal for analysis of minute amount of cfDNA. Unfortunately, technological limitations affect whole-genome methylation analysis of cfDNA. During the course of this project, we developed and validated novel approaches addressing the most important drawbacks of currently available technologies.
First, we developed and validated enrichment-based cfMeSeal approach by combining enzymatic and chemical labelling for cost-effective 5mC sequencing in cfDNA.
Second, we designed and developed a bisulfite-free method, Tet-assisted Pyridine Borane Sequencing (TAPS) for base-resolution 5mC sequencing. We demonstrated that TAPS is a mild reaction and outperforms bisulfite sequencing (BS-seq) at many aspects including improved sequence quality, better mapping statistics and direct conversion of modified sites. Finally, we confirmed that TAPS can be applied for cfDNA methylation sequencing and provides comprehensive information of cfDNA methylation and fragmentation. Information gained from cfDNA TAPS sequencing enables detection of hepatocellular carcinoma and pancreatic cancer with high accuracy.
Together, we demonstrated that newly developed sequencing tools can outperform existing technologies and facilitate comprehensive cfDNA methylation sequencing and provide multidimensional information about cfDNA with high cancer predictive potential.

Keywords: methylation sequencing
epigenetics
HCC
liquid biopsy
DNA methylation
PDAC
cell-free DNA
Advisor: Kriaucionis, S
Song, C
Exploring protein folding mechanisms to enable the protein structure prediction of previously intractable targets

The prediction of a protein structure from its amino acid sequence is one of the grand challenges of computational biology. In this thesis, we describe extensions to our biologically-inspired fragment-based protein structure prediction pipeline, SAINT2, to improve the prediction of previously intractable targets.
While template-free protein structure prediction protocols can now produce good quality models for many targets, modelling failure remains common; users need to be able to identify if a good model exists among the many models produced for a given target. We describe Random Forest Quality Assessment (RFQAmodel), which assesses whether models produced by a protein structure prediction pipeline have the correct fold. By iteratively generating models and running RFQAmodel until a model is produced that is predicted to be correct with high confidence, we demonstrate how such a protocol can be used to focus computational efforts on difficult modelling targets.
It is common for a target of interest to have an incomplete structure or a partial homologous template. We describe Flib-Flex, a method for incorporating known structural information into the fragment library that is used during prediction, and its combination with SAINT2-ScafFold to complete partial protein structures. We demonstrate that the missing regions can be modelled accurately in the presence of the known structure, and correct models can be identified using a modified version of RFQAmodel.
Long proteins remain a challenge for template-free protein structure prediction. There is experimental evidence that proteins can adopt the native conformation via the sequential folding of small units known as foldons. Inspired by this folding pathway hypothesis, we have divided long protein structures into smaller, semi-stable segments, and predict these individually in succession. This protocol, ScafFoldOn, enables the prediction of previously intractable targets.

Keywords: bioinformatics
protein informatics
computational biology
protein structure prediction
structural biology
Advisor: Deane, C
Kelm, S
Shi, J
de Oliveira, S
Advanced measurements for quantum photonics and quantum technologies

Measurements on states of light underpins the entire fields of classical and quantum optics. Without measurement we are unable to gain any information about the light we are studying or about the processes it has undergone. The property of the density matrix of light prior to measurement that we want to measure also relies heavily on the measurement technique we employ. We can use a single-photon detector to measure the particle nature of light--the photon--the discrete quanta of the electromagnetic field. We can conversely measure the wave nature of the light field by making phase-sensitive measurements. In this thesis, we shall explore some advanced implementations and applications of these measurement schemes.
First, we shall focus on a specific type of single-photon detector: the Superconducting-Nanowire Single-Photon Detector. We will first consider the integration of these detectors on optical waveguides, and discuss their optical characterisation. Then we will consider a practical application of these detectors by investigating a method to perform broadband spectroscopy with a single detector.
We shall then progress to phase-sensitive measurements, and consider the intermediate regime between measuring the wave-like and particle-like nature of light. First we will perform a fundamental investigation of the transition between both measurement regimes. We will see how varying the phase reference itself allows us to tune between both regimes. Following this we will discuss an application of this intermediate regime, by considering an experimental setup to perform state tomography with a weak phase reference.
The final consideration of this thesis will be a theoretical benchmarking scheme for a practical application of quantum optics. The manipulation of certain quantum states of light followed by a photon-number measurement can have practical applications in a variety of fields, and therefore validating the results is of extreme importance. On this final topic, we will discuss an experimentally friendly technique to benchmark the output of such measurements by considering smaller subsystems, and the practical requirements of this technique.

Keywords: Physics
Quantum optics
Photon
Single photon detector
Quantum physics
Advisor: Walmsley, IA
Flexible use of attentional templates to guide adaptive behavior

Attentional templates are the mental representations that we use to facilitate efficient ongoing behavior, including the detection and identification of task-relevant sensory input. These templates are traditionally studied within the context of visual search. In this case, a template containing target-defining features is used to guide attention to possible targets. In this doctoral thesis, I will expand the concept of the attentional template in several important ways, on the basis of an inter-related series of empirical studies. I propose that templates carry information along several dimensions in addition to item identity, such as space, time, and associated actions. I further demonstrate that attentional templates are adaptable and action-oriented. They do not necessarily represent the veridical properties of the target item, but rather are adapted to better serve future behavior. Additionally, I show that attentional templates can be retrieved from associations in memory, rather than being explicitly provided as in more conventional tasks. In the General Introduction I review past literature related to attentional templates. Moreover, I list the axes I consider necessary for the study of attentional templates. Chapters 2 through 5 describe empirical studies probing the nature and flexibility of attentional templates. In Chapter 2, I investigate the behavioral benefits and electrophysiological signatures of memory-guided identity-based anticipation. In Chapter 3, I probe the extent to which attentional templates retrieved through memory associations can be adapted to task demands and differ from veridical representations. In Chapter 4, I explore whether and when prospective actions are incorporated into the attentional template. Finally, in Chapter 5, I test whether spatiotemporal information can be incorporated into an attentional template during a dynamic visual search task. Across these studies, the results reveal the flexible nature of attentional templates that are used to guide our behavior. In the General Discussion I place these results in a wider context and suggest potential avenues for continued research.

Keywords: Attentional Templates
Attention
Memory
EEG
Advisor: Nobre, A
van Ede, F
Stokes, M
Hyperreal estate: the production of new urban real estate markets

Recent years have witnessed a surge in the development of real estate data analytics platforms. These devices variously promise a revolution in investment and valuation, leading to a more transparent knowledge of market reality and more objective decision-making. To examine these claims, this research adopts a theoretical framework from STS and critical data studies to examine the ethnographic case study of one prototype data analytics product throughout the early stages of its development and marketing. This product, Dashboard X, was designed to provide large institutional investors with a way to better know which areas of London were currently undergoing gentrification for the purpose of investing in Build-to-Rent housing. This study was followed by a series of interviews and participation in several industry events.
By examining the actors emerging around this would-be ‘market device’, this research explains that Dashboard X and similar platforms are in fact producing and circulating entirely new, subjective, and distinctly situated forms of real estate values, knowledges, and even assets. Furthermore, it is argued Dashboard X entails a series of theoretical and political implications that range from the co-performation of planetary gentrification and the expansion of rentier capitalism, to a ‘new urban colonialism’ and the greater ontological politics associated with bringing new real estate assets and markets into being. The key theoretical contribution is that these data analytics platforms do little to objectively increase investor rationality in the sense of knowing reality, but that the use of these technologies can nevertheless powerfully control the future trajectories and possibilities of a global real estate market by circulating the values and knowledges needed for its realisation. Hence, these new urban real estate values can precede their realisation in material marketplace reality through data analytics platforms as hyperreal estate.

Keywords: financialisation
platforms
dashboards
real estate
value
metrics
valuation
market devices
digital technology
data analytics
finance
platform real estate
gentrification
Advisor: Graham, M
Dorling, D
Physiological modulation of learning and decision-making

Many of the decisions we make in our day-to-day lives are influenced by internal physiological states and external environmental factors. In my thesis, I employed an interdisciplinary approach to investigate how internal physiological states, such as hunger, affect various aspects of decision-making. Neurobiological research has shown that food deprivation enhances dopaminergic signalling and increases the incentive salience of food. However, classical reinforcement learning theory only maps learning of external factors onto dopaminergic signalling. I extended the reinforcement learning theory in a biologically relevant manner to incorporate mechanisms by which internal physiological signals interact with the dopaminergic system to influence learning and action selection (chapter 3). This new theory predicts that food deprivation enhances learning, promotes approach behaviour, and reduces avoidance behaviour by enhancing the dopaminergic activation and teaching signals. I tested these theoretical predictions for decision-making in human volunteers. This study showed that hunger increased the valuation of food, but not of monetary rewards or nonfood items (chapter 4). Hunger reduced the biases for approach and avoidance behaviour that sated people exhibit by modulating the trade-off between positive and negative consequences of actions (chapter 5). Hunger also interacted with economic choice, but only when outcomes of choices had to be learned, not when they were explicitly described (chapter 6). Lastly, this study showed that hunger enhanced the reliance of "gut-instinct", without affecting cognitive control (chapter 7). In summary, this thesis characterises mechanisms by which motivational drives, such as hunger, could affect valuation, learning, and action selection in a biological manner. It provides empirical evidence that hunger also affects decision-making for monetary rewards, which could have significant implications for both real-world economic transactions and for aberrant decision-making in eating disorders and obesity.

Keywords: reinforcement learning
learning
dopamine
hunger
computational modelling
physiology
risk-taking
decision-making
Advisor: Magill, P
Bogacz, R
Manohar, S