VictorJuiz/thesis huggingface dataset:
Modulation of immune cell niches for therapeutics in cancer and inflammatory diseases
Keywords: Hematopoietic Stem cell transplant
tolerance
Interleukin 7
niche
Dendritic cell
IL-7
Sunitinib
KIT

Immune cell niches are microenvironments that support the survival of specific hematopoietic cells. The size of a given niche is dependent on survival and proliferation signals provided. Modulation of niche size can be a useful therapeutic tool, and a better understanding of the factors that control the size of immune cell niches can lead to more targeted therapies.
Here bone marrow and thymic niches were modulated with tyrosine kinase inhibition to achieve increased engraftment following stem cell transplantation (SCT). SCT resulting in mixed chimerism is curative for several benign blood diseases, but toxicities associated with myeloablative and cytotoxic conditioning regimens limit the application of SCT. Sunitinib inhibits multiple tyrosine kinases including KIT, an essential survival signal within the hematopoietic stem cell and thymic progenitor niches. Sunitinib therapy diminishes hematopoietic and thymic progenitor cells in mice and enhances accessibility of marrow and thymic niches to transplanted bone marrow. This provides a novel, non-cytotoxic approach to accomplish mixed hematopoietic chimerism.
The observation that T cells undergo increased proliferation and accumulate in IL-7R deficient mice compared to other lymphopenic hosts raised questions about the factors that control the size of the T cell niche. Understanding these factors is useful in designing therapeutics to increase T cell responses for treatment of many diseases including cancer. Dendritic cells (DCs) are well known for their ability to modulate T cell responses; however, very little is known about the role of IL-7R signaling on DCs. The data presented here show that bone marrow derived DCs treated with IL-7 were less able to induce T cell proliferation in coculture. In vivo systems using CD11cDTR mice showed a role for IL-7 signaling on CD11c+ cells in T cell homeostasis. Together these data suggest that IL-7R signaling on DCs is important for regulating the size of the T cell niche.
Droughts in future climate change in the UK
Keywords: climate change
model
droughts
UK

This thesis seeks to investigate the changes in the characteristics of 20th and 21st century meteorological droughts in the UK to address the following lines of inquiry: 1) How credible are rainfall-based indices in representing hydrological droughts, 2) How coherent are droughts?, 3) Can alternative method of analysis provide new (or additional) information on the uncertainties in climate models?, and 4) Will future drought characteristics change?. Key results, respectively, are summarized as follows:
• The drought severity index (DSI), can be considered a good proxy for assessing hydrological droughts as can be seen in its ability to capture the major hydrological events. The main caveat of the DSI is that there is often an underestimation of drought intensity and duration,
• Drought covariance is higher for the (i) wet season, (ii) moderate and (iii) shorter duration droughts,
• Evaluating climate models using drought statistics produces contrasting results compared with that using the model's precipitation fields. Drought statistics show biases which are largely negative, more intense, and have a greater spatial coverage.
• The projected ensemble-mean change is generally greater (and more widespread) for (i) moderate droughts and (ii) wet season compared with extreme droughts and the dry season, respectively with increases in drought intensity, drought covariance index, frequency of drought months and frequency of drought events for a given duration shown for England.
Models of primate supraretinal visual representations
Keywords: Neural Networks
Vision
Reference Frames
Computational Neuroscience

This thesis investigates a set of non-classical visual receptive field properties observed in the primate brain. Two main phenomena were explored. The first phenomenon was neurons with head-centered visual receptive fields, in which a neuron responds maximally to a visual stimulus in the same head-centered location across all eye positions. The second phenomenon was perisaccadic receptive field dynamics, which involves a range of experimentally observed response behaviours of an eye-centered neuron associated with the advent of a saccade that relocates the neuron's receptive field. For each of these two phenomena, a hypothesis was proposed for how a neural circuit with a suitable initial architecture and synaptic learning rules could, when subjected to visually-guided training, develop the receptive field properties in question. Corresponding neural network models were first trained as hypothesized, and subsequently tested in conditions similar to experimental tasks used to interrogate the physiology of the relevant primate neural circuits. The behaviour of the models was compared to neurophysiological observations as a metric for their explanatory power. In both cases the neural network models were in broad agreement with experimental observations, and the operation of these models was studied to shed light on the neural processing behind these neural phenomena in the brain.
The effect of interpersonal power on cognitive processing: a behavioural and neural perspective
Keywords: attention
social neuroscience
memory
power
EEG

Interpersonal power, defined as the asymmetrical control over valued outcomes, has important effects on the way cognitive processing unfolds. This work explores the effect of power on basic cognitive processes, in addition to broader processes that appear at the level of social behaviour. I begin this thesis with an introductory chapter, followed by a chapter describing the theory and practice behind electro-encephalogram recordings. In Chapter 3, I explore the effect of power on attention selection using a task that requires the ability to focus or divide attention in space, while varying the amount of distractors. The results suggest that low-power participants (subordinates) are more susceptible to the presence of distractors, regardless of whether the task necessitates focused or divided attention. In this context, inhibition accounts for the results to a greater extent than spatial orienting. In Chapter 4, I explore the effect of power on early inhibition processes in the context of executive control, in a task which allows participants to allegedly observe each others’ performance and receive feedback. The results show that high power is associated with reduced behavioural accuracy on trials that require executive control. Event-related potential analyses show that power-holders devote reduced motivational resources to their targets compared to subordinates, but do not differ at the level of early conflict detection. Their feedback potential results show a greater expectation of rewards, but reduced subjective magnitude attributed to losses. Subordinates, on the other hand, are asymmetrically sensitive to power-holders’ targets. They expect fewer rewards, but attribute greater significance to losses. In Chapter 5, I show that subordinates are asymmetrically competent at remembering diagnostic choices made by power-holders. In a final general discussion chapter, I integrate the findings of the experiments, which point to multi-layered effects of power, conferring those who possess it and those who lack it with distinct cognitive processing styles that suit their adaptive needs. The results are consistent with a hypothesized link between subordination and up-regulation of vigilance and environmental sensitivity. Limitations and future directions are discussed.
Structural and functional studies of the hedgehog signalling pathway 
Keywords: Hedgehog signalling
developmental biology
macromolecular crystallography
structural biology
smoothened
protein chemistry
structure
smoothened ectodomain

Hedgehog (Hh) morphogens play fundamental roles in development whilst dysregulation of Hh signalling leads to disease. Multiple receptors are involved in the modulation of Hh morphogens at the cell surface. Among these, the interactions of Hh ligands with glycosaminoglycan (GAG) (for example heparan or chondroitin sulphate) chains of proteoglycans in the extracellular matrix play a key role in shaping morphogen gradients and fulfil important functions in signal transduction. Several high resolution crystal structures of Sonic Hh (Shh)-GAG complexes have been determined. The interaction determinants, confirmed by binding studies and mutagenesis reveal a novel Hh site for GAG interactions, which appears to be common to all Hh proteins. This novel site is supported by a wealth of published functional data, and resides in a hot spot region previously found to be crucial for Hh receptor binding. Crystal packing analysis combined with analytical ultracentrifugation on Hh-GAG complexes suggest a potential mechanism for GAG-dependent multimerisation.
A key step in the Hh pathway is the transduction of the Hh signal into the receiving cell. The Hh signal transducer, Smoothened, is a key target drug target in the pathway with several modulators in clinical trials, despite an absence of structural data. Smoothened is required to activate all levels of Hh signalling. Recent evidence points to the conserved N-terminal ectodomain (ECD) in regulating Smo activity, from vertebrates to invertebrates. Despite the central importance of the ECD, its precise function remains elusive. A crystal structure of the ECD at 2.2 Å resolution is reported here. Structural analysis and biophysical experiments are discussed with reference to the potential function of this intriguing domain.
Political parties, irredentism and the Foreign Ministry: Greece and Macedonia, 1878-1910
Keywords: Greek politics.
Macedonia
Theotokis
Ottoman Empire
Trikoupis

The Macedonian Question has attracted much attention since the 1990s due to the emergence of the dispute over the name of Macedonia between Greece and the Republic of Macedonia. In Greece there is a prolific literature on this subject, but some basic questions remain unanswered. In particular, the role of the government, and of government institutions – especially the Ministry of Foreign Affairs – have attracted little or no attention: on the contrary, historians have focused on the 'heroes' of the conflict, the fighters themselves, the result being that the Macedonian Question is understood as a military fight of good versus evil. In this D.Phil. thesis, we examine how the government got involved with the Macedonian Question and second, in what ways it was involved, especially given that an official acknowledgement of the government's involvement with the paramilitary operations was diplomatically impossible. We approached these questions by examining the personal archives of Greek politicians and diplomats (most notably of the Dragoumis family) and the Archives of the Ministry of Foreign Affairs, especially the Archives of the Greek Embassies in London, Paris and Constantinople, which have only recently become available. The key finding is that the Greek government, despite its declarations to the opposite effect, was involved heavily with the paramilitary fighting in Macedonia, but also that the official involvement with Macedonia was constrained and influenced by electoral concerns and by the powerful Macedonian lobbies in Athens. Decisions were rarely made in a rational, bureaucratic way, but were more often reached after consultations with journalists, military officers and intellectuals and always bearing domestic political realities in mind. These findings suggest that future research should move away from understanding the 'Macedonian Struggle' solely as a military issue, and put it into the wider context of early twentieth-century Greek political and diplomatic history.
Determinants of medium-term blood pressure variability and the related risks of stroke and dementia
Keywords: Blood Pressure Variability
Meta-analysis
Dementia
Physiology
Hypertension
Stroke

Visit-to-visit variability in blood pressure (BP) increases stroke risk, independent of mean BP. However, its physiological validity, the ideal method of measurement and the mechanisms increasing cardiovascular risk are unclear.
In meta-analyses of individual patient data, I pooled associations between BP variability and risk of stroke, all cardiovascular events and death. I then determined antihypertensive drug-class differences in cardiovascular risk, intra-individual (I-VR) and inter-individual BP variability (M-VR). In 500 Oxford Vascular Study (OXVASC) patients undergoing thrice-daily home (HBPM) and awake ambulatory monitoring (ABPM), associations between mean, maximum or variability in BP (CV-BP) were determined with premorbid BP, hypertensive arteriopathy (creatinine, aortic stiffness, cognitive impairment, stroke versus TIA and leukoaraiosis) and cardiovascular events. In 200 patients, I determined associations with pulsatility or stiffness (pulse wave velocity) in cerebral and aortic vessels.
There was a 21% and 27% increased risk of stroke and myocardial infarction per standard deviation of CV-SBP in 318700 patients, independent of mean SBP. In 244,479 patients, SBP variability was reduced by CCBs and diuretics within (I-VR=0.89, 95% CI=0.82-0.96, p=0.0001) and between individuals (M-VR 0.83, 0.77-0.89, p<0.0001), especially in the first year of treatment, explaining drug class differences in stroke risk (OR=0.76, 0.68-0.87, p<0.0001). In OXVASC, drug class differences on day-to-day SBP variability were greatest immediately after waking.
Residual hypertension after treatment on HBPM but not ABPM (BP>135/85) predicted recurrent cardiovascular events (HR 2.82, 1.44-5.51, p=0.002 vs. 1.48, 0.68-3.23, p=0.33), reflecting stronger associations with premorbid BP and hypertensive arteriopathy, due largely to inaccuracy of ABPM in patients aged >65 years. Furthermore, day-to-day maximum and CV-SBP were associated with premorbid BP, hypertensive arteriopathy and cardiovascular events, with no additional predictive value of mean SBP when analysed with maximum SBP. Maximum SBP was greater in men and CV-SBP in women, whilst age and creatinine determined both. Increased stroke risk may partly be due to the association between BP variability and cerebral pulsatility, which was correlated with leukoaraiosis (p=0.01) and determined by aortic stiffness (p=0.016) and pulsatility (p<0.001).
BP variability is clinically significant and physiologically valid, and is treatable with CCBs and diuretics. After TIA or minor stroke, HBPM best identifies residual hypertension and demonstrates the predictive value of BP variability and maximum BP, but associated arterial changes might explain some of the increased stroke risk.
Clouds and hazes in Saturn's troposphere and stratosphere
Keywords: retrieval theory
saturn
giant planets
climatology

The cloud and haze properties in the troposphere and stratosphere of Saturn are investigated in this thesis by analysing Cassini/VIMS spectra at 0.8-3.5 μm and 4.5-5.1 μm. The aerosol properties are derived from VIMS data by using the retrieval tool NEMESIS developed at the University of Oxford. Near-infared VIMS data between 4.5 and 5.1 μm are mainly sensitive to deeper tropospheric levels down to approximately 5 bar. At such pressure levels, thermochemical models predict the formation of condensed clouds made of ammonia and ammonium hydrosulphide ices, although none of these species has been spectrally detected so far. In addition, phosphine and ammonia are responsible for most of the gaseous absorption at these wavelengths. Therefore, the cloud properties and gas distributions can be retrieved from VIMS near-infared spectra. In this thesis, the analysis of limb-darkening data at 4.5-5.1 μm is performed in order to constrain the aerosol properties in Saturn’s atmosphere. The best-fitting model consists of a scattering cloud between 2 and 3 bar, and a scattering haze layer which can be placed anywhere between 10 and 500 mbar. The composition is still poorly constrained for both the deep cloud and haze layer. The haze physical and optical properties can however be independently retrieved from VIMS near-infrared spectra at shorter wavelengths in the 0.8-3.5 μm spectral range. Saturn’s hazes in the troposphere and stratosphere reflect the sunlight at 0.8-3.5 μm. The properties and vertical structure of tropospheric and stratospheric hazes are then investigated from VIMS reflection spectra in the near-infared. The latitudinal variation of haze properties is compared to a thermal feature known as "the temperature knee", corresponding to a local increase of temperature right below the tropopause. The north-south temperature variations in the troposphere are obtained from the analysis of thermal infrared data measured with the Composite InfraRed Spectromete (CIRS) instrument on board Cassini. Finally, VIMS near-infrared data at 0.8-3.5 and 4.5-5.1 μm are combined in order to obtain a cloud and haze model coherent with both wavelength ranges.
The role of consumer leverage in financial crises
Keywords: Consumer Leverage
Financial Frictions
Chained Loan Contracts
Financial Institutions Leverage
Subprime Mortgage Crisis

This thesis demonstrates that consumer leverage can contribute to financial crises such as the subprime mortgage crisis characterised by increased bankruptcy prospects and tightened credit access. A recession may follow even when the leveraged sector is not a production sector and can be triggered by seeming positive events such as a technological innovation and a relaxation of borrowing conditions. The first preliminary chapter updates the Bernanke, Gertler and Gilchrist (1999) approach with financial frictions in the production sector to a two-sector model with consumption and housing. It shows that credit frictions in the capital financing decisions of housing firms are not sufficient to capture the negative consumer experience with falling housing prices and relaxed credit access during the recession. The second chapter brings the model closer to the subprime mortgage crisis by shifting credit constraints to the consumer mortgage market. Increased supply of houses lowers asset prices and reduces the value of the real estate collateral used in the mortgage which in turn worsens the leverage of indebted consumers. A relaxation of borrowing conditions turns credit-constrained households into a potential source of disturbances themselves when market optimism allows them to raise their leverage with little downpayment. Both cases demonstrate that although households are not production agents, their worsening debt levels can trigger a lasting financial downturn. The third chapter develops a chained mortgage contracts model where both homeowner consumers and the financial institutions that securitize their mortgage loan are credit-constrained. Adding credit constraints to the financial sector that provides housing mortgages creates opportunities for risk sharing where banks shift some of the downturn onto indebted consumers in order to hasten their own recovery. This consequence is especially evident in the case of relaxed credit access for banks. Financial institutions repair their debt position relatively fast at the expense of consumers whose borrowing ability is squeezed for a long period despite the fact that they may not be the source of the disturbance. The result mirrors the recent subprime mortgage crisis characterised by a sharp but brief decline for banks and a protracted recovery for mortgaged households.
Knowing and understanding
Keywords: Functions vs rogators
Synthetic necessary truth
Gottlob Frege
Immanuel Kant
Synthetic apriori knowledge

The avowed aim of the thesis is to show that there are some synthetic necessary truths, or that synthetic apriori knowledge is possible. This is really a pretext for an investigation into the general connection between meaning and truth, or between understanding and knowing, which, as pointed out in the preface, is really the first stage in a more general enquiry concerning meaning. (Not all kinds of meaning are concerned with truth.) After the preliminaries (chapter one), in which the problem is stated and some methodological remarks made, the investigation proceeds in two stages. First there is a detailed inquiry into the manner in which the meanings or functions of words occurring in a statement help to determine the conditions in which that statement would be true (or false). This prepares the way for the second stage, which is an inquiry concerning the connection between meaning and necessary truth (between understanding and knowing apriori).
The first stage occupies Part Two of the thesis, the second stage Part Three. In all this, only a restricted class of statements is discussed, namely those which contain nothing but logical words and descriptive words, such as "Not all round tables are scarlet" and "Every three-sided figure is three-angled". (The reasons for not discussing proper names and other singular definite referring expressions are given in Appendix I.)
A site-directed spin labelling study of the human alpha-lactalbumin molten globule
Keywords: nuclear magnetic resonance spectroscopy
paramagnetic relaxation enhancement
human alpha-lactalbumin
TEMPOL
molten globule
double electron-electron resonance
electron paramagnetic resonance spectroscopy
MTSL

The human α-lactalbumin (α-LA) molten globule formed at low pH is a model for the study of protein folding intermediates. The molten globule lacks native-like side-chain interactions, resulting in a fluctuating ensemble of tertiary structures, characterisation of which has been precluded by severe line-broadening in NMR spectra and a lack of long-range NOEs. Paramagnetic relaxation enhancements (PREs) have been measured in a variant of α-LA in which all native cysteines have been mutated to alanine (all-Ala α-LA). Cysteine residues have been mutated into regions of interest and spin labelled with MTSL. These measurements have confirmed that all-Ala α-LA forms a compact molten globule. Transient, long-range interactions that are stabilising the compact fold have also been identified using PREs measured in urea-denatured states. This has identified several interactions formed by hydrophobic residues from both the α- and β-domain, which could be important for initiating and driving folding. The molten globule’s 3D topology has been probed by measuring long-range distances between MTSL pairs using Double Electron-Electron Resonance (DEER). Broad distance distributions have been identified between elements of secondary structure, indicative of a fluctuating but compact fold. By contrast, a narrower distance distribution has been measured within one of the major helices, indicative of native-like secondary structure. The surface accessibility of all-Ala α-LA and that of two other variants ([28-111] α-LA and 4SS α-LA) has been probed using solvent PREs obtained using TEMPOL, a paramagnetic co-solute. This has revealed differences in the solvent-exposure of hydrophobic residues due to the removal of disulphide bonds. This method has also identified buried hydrophobic residues that contribute to forming the molten globule’s stable, native-like core.