VictorJuiz/thesis huggingface dataset:
The development and applications of the Lewis acid-mediated osmium-catalysed oxidative cyclisation
Keywords: oxidative cyclisation
Pectenotoxin-4
osmium cyclisation
Neodysiherbaine A
Tetrahydrofuran synthesis

The acid-mediated osmium-catalysed oxidative cyclisation of 1,2-diols bearing a pendent alkene has been shown to be a powerful method for the formation of cis-2,5-disubstituted tetrahydrofurans. This thesis describes the development of this methodology to broaden the scope of the general reaction, followed by applying the oxidative cyclisation to the synthesis of tetrahydrofuran containing natural products.
Introduction: This section reports a range of ractions that osmium oxo-species will facilitate, namely the formation of carbon-oxygen and carbon-nitrogen bonds in a selective manner. In addition to this a variety of similar metal-mediated oxidative cyclisations are discussed.
Results and Discussion: The process for optimising the oxidative cyclisation is documented, along with examples which directly compare newly developed methodology with existing methodology. The incorporation of a catalytic amount of a Lewis acid is shown to be more effective than using an excess of a Brønsted acid, with osmium catalyst loading being reduced to 0.2 mol%. Subsequently, this methodology is shown to facilitate the successful oxidative cyclisation of vinyl silanes to form silyl-substituted tetrahydrofurans, along with methodology to “unmask” the silane, as a potential route to lactols. Finally, the application of this methodology to synthesis is demonstrated, with the successful synthesis of neodysiherbaine A being achieved in 7 steps and the C21-30 fragment of pectenotoxin-4 in 12 steps.
Charge transport dynamics in electrochemistry
Keywords: electrochemistry
charge transport
double layer
Nernst-Planck-Poisson equations
migration
computational chemistry
electroneutrality
diffusion
charge separation
mass transport

Electrolytic solutions contain mobile ions that can pass current, and are essential components of any solution-phase electrochemical system. The Nernst–Planck–Poisson equations describe the electrodynamics and transport dynamics of electrolytic solutions.
This thesis applies modern numerical and mathematical techniques in order to solve these equations, and hence determine the behaviour of electrochemical systems involving charge transport. The following systems are studied: a liquid junction where a concentration gradient causes charge transport; an ideally polarisable electrode where an applied potential difference causes charge transport; and an electrochemical cell where electrolysis causes charge transport.
The nanometre Debye length and nanosecond Debye time scales are shown to control charge separation in electrolytic solutions. At equilibrium, charge separation is confined to within a Debye length scale of a charged electrode surface. Non-equilibrium charge separation is compensated in solution on a Debye time scale following a perturbation, whereafter electroneutrality dictates charge transport. The mechanism for the recovery of electroneutrality involves both migration and diffusion, and is non-linear for larger electrical potentials.
Charge separation is an extremely important consideration on length scales comparable to the Debye length. The predicted features of capacitive charging and electrolysis at nanoelectrodes are shown to differ qualitatively from the behaviour of larger electrodes. Nanoscale charge separation can influence the behaviour of a larger system if it limits the overall rate of mass transport or electron transfer.
This thesis advocates the use of numerical methods to solve the Nernst–Planck–Poisson equations, in order to avoid the simplifying approximations required by traditional analytical methods. As this thesis demonstrates, this methodology can reveal the behaviour of increasingly elaborate electrochemical systems, while illustrating the self-consistency and generality of fundamental theories concerning charge transport.
The role of Notch and GATA3 in postnatal and adult haematopoiesis
Keywords: Rbp-Jk
Notch
haematopoietic stem cell
GATA3
T cell progenitor
myeloid

The role of Notch in cell fate determination and lineage restriction in the bone marrow (BM) is controversial in the field. Recent studies have convincingly shown that Notch is dispensable for haematopoietic stem cell (HSC) regulation in adult haematopoiesis (Maillard et al., 2008). In contrast, Notch signaling has been proposed to be of importance in the regulation of BM megakaryocyte progenitor differentiation, based on dominant negative genetic approaches, identifying a potentially distinct role for Notch in adult BM haematopoiesis (Mercher et al., 2008). Here, I found that by selectively ablating the gene coding the transcription factor recombination signal-binding protein J kappa (RBP-Jk), to which all canonical Notch signaling converges, canonical Notch signaling does not mediate HSC maintenance, neither in steady state nor in conditions of stress. Furthermore, I propose, in contrast with previous studies (Mercher et al., 2008), that canonical Notch signaling plays no role in myeloerythropoiesis cell lineage commitment in the BM. My data also show that key Notch target genes are suppressed by RBP-Jk, as their expression is unaffected in Notch1-deficient BM progenitors, while target genes are upregulated in Rbp-Jk-deleted megakaryocyte and erythroid progenitors. This establishes for the first time in mammalian cells in vivo, that Notch target genes are kept in a suppressed state by RBP-Jk, potentially restricting T cell commitment to the thymus and not to the BM, at the expense of myeloerythropoiesis.
Notch signaling and GATA3 are two master regulators in T cell commitment (Han et al., 2002; Ho et al., 2009; Pui et al., 1999; Radtke et al., 1999; Zhu et al., 2004). However, although very well established as being involved in the thymic stages of T cell restriction, there is little evidence of Notch and GATA3 being involved in the migration of a thymus settling progenitor (TSP) from the BM to the thymus or in the establishment of the earliest thymic progenitor (ETP) in the thymus. From this thesis work, I conclude that Notch signaling is essential for the emergence of ETPs in the thymus in a NOTCH1-independent manner. Moreover, I demonstrate, as supported by a very recent published study (Hosoya et al., 2009), that GATA3 is important for the development of the earliest T cell progenitor.
GATA1 and GATA2 mediate haematopoietic stem cell maintenance in the BM. GATA1 is required for erythropoiesis, megakaryocytes and eosinophils while GATA2 is important for the proliferation and survival of HSCs. In contrast, a role for GATA3 in the BM has never been established. By using a Gata3-conditional knockout mouse model, I demonstrate that GATA3 is dispensable for HSC maintenance in steady state and following active haematopoietic regeneration as well as for HSC self-renewal in the BM.
Methods and models for acute hypotensive episode prediction
Keywords: prediction
hypotensive episode
hypotension
biomedical engineering
modeling

Hypotension is both a dangerous condition and a critical marker for the progression of certain conditions and diseases.Additional research has shown that the more quickly a hypotensive state is predicted, the better the probability of survival.
This thesis explores the creation of models to predict an acute hypotensive episode at a minimum of one hour before occurrence. Models were based on data acquired from MIMIC II, a large-scale ICU database. A variety of techniques including Parzen models of normality, logistic regression, and neural networks are used to analyse the relationship between vital signs and the occurrence of hypotension in the general ICU population.
Both univariate and multivariate models were evaluated, and multi-variate neural network models were found to be the best predictors of hypotension in our dataset. The best model was a multi-layer perceptron constructed using values and first-order statistical functions of a patient's mean arterial blood pressure, respiration rate, blood oxygenation level, and heart rate. Best performance occurred at a time of 60 minutes prior to the onset of a patient's first recorded hypotensive episode, and yielded an AUC of 0.84. This corresponded to a classification accuracy of 82% in a balanced dataset and 84% in an unbalanced dataset which more closely rejects the prevalence of hypotensive data in an ICU. These results indicate that there are early patterns underlying general hypotension detectable in patient physiology.
Perceptions of public opinion. British foreign policy decisions about Nazi Germany, 1933-1938
Keywords: Jews
Nazi Germany
interwar-period
mass opinion
Cabinet
foreign policy
diplomatic crises
decision-making
public opinion

This thesis examines the historical problem of determining the relationship between a government's perception of public opinion and the decisions it takes. We introduce evidence for the social habits of the Cabinet in order to suggest new formulations of 'élite' and 'mass' public opinion. We argue that parliamentary opinion was generally more important in decision-making for the Cabinet, except at moments of extreme crisis when a conception of 'mass' opinion became equally significant. These characterization of mass opinion were drawn from a set of stereotypes about public opinion which academic and political theorization had produced. It is argued that this theorization was stimulated by ongoing debates about mass communication, the importance of the ordinary man in democracy and the outbreak of the first world war during the inter-war period.
The thesis begins with an introduction to the methodological problems involved, followed by one chapter on theorization about public opinion in the inter-war period. Three diplomatic crises are considered in the case study chapters: the withdrawal of Germany from the Disarmament Conference in 1933, the German reoccuption of the Rhineland in 1936 and the threat of invasion of the Sudetenland in 1938. Two further chapters examine the role of public opinion in protests to Germany about the treatment of the Jews in 1933 and in 1938. It is argued that perceptions of public opinion played a much more important role in decision-making than has hiterto been thought. The most significant argument posits that perceptions of public opinion were equally as important as military considerations in the decision to refuse the Godesberg terms in 1938. More generally, the way in which politicians used public opinion rhetorically is described and the limits of the usefulness of the term for historians are suggested.
The development of executive function in childhood
Keywords: task-switching
development
cognitive control
inhibition
executive function
working memory
children

The experiments in this thesis explored the development of executive function in 5- to 11-year-old children. Developmentally-appropriate versions of the task-switching paradigm, go/no-go task and self-ordered pointing test were used to measure shifting, inhibition and working memory respectively. These executive skills were examined independently and within-task experimental manipulations were used to explore both the executive and non-executive processes that influenced children’s performance. These allowed the investigation of not only when, but also how executive function develops. It was found that shifting development, as measured by the task-switching paradigm was highly influenced by the specific tasks switched between and the conflict created by the overlap of the tasks, as well as by previous task experience. Working memory for pictures was also influenced by previous experience and task difficulty, however the predicted relationship between memory for nameable objects and language ability was not found. Inhibition on the go/no-go paradigm appeared to be driven by an improvement in the efficiency of response inhibition enabling older children to inhibit a response at an earlier stage during the movement. Shifting, inhibition and working memory all showed developmental improvements during mid-childhood, demonstrating the protracted development of executive function. Shifting and working memory showed a similar pattern of development whereas inhibition reached a stable level of performance at an earlier age. There were no correlations between the three executive skills studied in this thesis, supporting the fractionation of executive function.
Government beyond law: exploring charity regulation and spaces of order in China
Keywords: non-governmental organisations
regulation
China
orphan and child welfare

This thesis examines the regulatory landscape relating to private orphanages, both foreign and domestically run, in China, and the formal and informal relationships between such homes and government which structure this space of order. Part A introduces the contextual factors shaping the gradual socialisation and privatisation of charitable activity generally, and the child welfare-specific social, economic and cultural dynamics influencing the emergence of private orphanages. Parts B and C set out the ethnographic findings of field-work examining the practical operations of private orphanages, and a theoretical analysis of the various interactions occurring with government orphanages, and local and central officials. It is shown that the ostensible government monopoly on institutional care of orphans, established in law and policy and consistent with the objective of maintaining tight control over civic organisations and religious-based and foreign-led activities, is belied by a proliferation of private orphanages emerging to address gaps in state welfare provision. This has led to the emergence of a delicate balance between top-down official discourse, rhetoric and law, and bottom-up pragmatic considerations. Further, the prima facie 'missing role' of the state in law, regulation and policy-making is contradicted in practice by evidence of a complexity of highly paternalistic state-orphanage relationships occurring beyond the normative framework of official laws and policies. Such extra-legal state-society interaction is characterised by informal, flexible and paternalistic negotiations with local officials, and mediated by structures of power and capacity. 'Law beyond government' and 'government beyond law' are central features of the multidimensional maintenance of this space of order, and point to several defining points of distinction of law as a cultural notion in the Chinese context, including a marked preoccupation with legitimacy over legality and paternalistic discipline and discretion over impartial adjudication.
Cardiovascular manifestations of Marfan syndrome: insights from advanced cardiovascular magnetic resonance
Keywords: Marfan syndrome
cardiovascular magnetic resonance

Marfan syndrome (MFS) is the commonest inherited disorder of connective tissue and is associated with a high risk of potentially life-threatening complications, including aortic aneurysm, dissection and rupture, and, perhaps, ventricular disease. This work describes the prospective application of advanced cardiovascular magnetic resonance techniques to the aorta and heart of consecutive, unselected subjects with MFS, and to appropriately matched control populations.
Comprehensive 3D visualisation of blood flow in the entire thoracic aorta of subjects with MFS was achieved using a time-resolved phase-contrast magnetic resonance technique with 3-directional velocity encoding (4D flow), demonstrating a high prevalence of major flow disturbance (87 ± 12%), compared to controls (28 ±18%), localising to those regions of the aorta known to be most prone to aortic dissection (sinuses of Valsalva and proximal descending aorta). Wall shear stress, recently identified as a potentially important determinant of aneurysm progression and rupture, was interrogated in these datasets at the sinuses of Valsalva (SOV), ascending aorta (AA), arch, and proximal (PDA) and distal descending aorta (DDA), using the 4D flow datasets, and was shown to be significantly reduced at each location (SOV -15%; AA -12%; Arch -17%; PDA -18%; and DDA -14%, p<0.05 for each), in subjects with MFS compared to healthy subjects.
4D flow datasets were used to generate relative pressure maps in healthy subjects and in subjects with several aortic diseases. A novel method for the separate evaluation of the components of relative pressure was applied, revealing marked differences in the relative contribution of the components of pressure (unsteady > convective >> viscous), and characteristic differences between subjects in overall relative pressure, and its components. Left ventricular volumes and function were evaluated in subjects with MFS, and did not differ significantly from healthy subjects in the absence of significant valvular regurgitation and / or shunt. Left ventricular end-diastolic volume varied markedly with degree of regurgitation (r=0.75, p=0.0001). The mechanistic implications of these findings, and the potential role of these techniques in the evaluation of cardiovascular disease, are discussed.
Byzantium and the Bosporus: regionality, identity, institutions
Keywords: Numismatics
Byzantium
Epigraphy
Regional History
Athenian Empire
Thrace
Byzantion
Ancient History
Greek History

This thesis presents a historical study of the relationship between the city of ancient Byzantium and the Thracian Bosporus. Structured around the themes of regional particularity and identity, it shows that local studies can be used to gain fresh insights into more general topics. Viewed through the lens of the relationship between strait and city, the history of the Bosporus sheds light on the nature of economic exploitation and ancient imperialism, and on the nature of ancient communities’ local identities.
Chapter 1 explores regionally specific geographical features in the strait, which directed and determined responses to life in the area, around which the regional economy revolved, and in response to which the identities of the local communities were created. Chapters 2 and 3 examine the history of economic exploitation of the region, exploring the attitude of the Athenian Empire toward the Bosporus, and the attempt by the local communities of the Bosporus to create a controlled monetary system in the third century BC. These efforts to exploit local opportunities and commodities, I show, transformed the Bosporus into an attractive economic resource. Chapter 4 examines the local fishing industries of the strait, and demonstrates that the extraordinary availability of fish in the region provoked responses which could not be emulated precisely elsewhere.
The thesis also shows that the cultural identity of a Greek city could be intensely local. Byzantium, a Greek colony typically characterized by its relationship to its mother-city, had a series of important local identities, explored in chapter 1. From this perspective, chapter 5 re-examines the difficult relationship between Greeks and Thracians in the region, and chapter 6 questions the validity of the traditional view of the relationship between a colony and its mother-city.
Statistical challenges in the detection of mutation and variation using high throughput sequencing
Keywords: high throughput sequencing
genome-wide sequence variation
mutation rate
long-term balancing selection
nucleotide diversity

The aim of this thesis is to obtain a better understanding of mutation rates within as well as between the genomes of humans and chimpanzees using data generated by high throughput sequencers. I will start with a review of the field and an overview of the technologies and protocols used to generate and analyse high throughput sequencing data. I apply some of the discussed techniques to show that there is evidence of a selective advantage of pathogenic de novo mutations in the Fibroblast Growth Factor Receptor 3 gene in the male germ line of humans. Furthermore, I use some of the methods to generate a map of genome-wide sequence variation in Western chimpanzees. Ever since Darwin [Darwin, 1871] and Huxley [Huxley, 1863] postulated more than a century ago that African great apes are our closest living evolutionary relatives, the study of chimpanzee individuals is of great scientific interest from an evolutionary point of view, as comparisons between the genomes of human and chimpanzee offer the potential to help to understand the molecular basis for similarities and differences between the two species. I use the generated data to explore the breadth of the nucleotide diversity in the chimpanzee genome in order to shed light on whether or not the local variation in mutation rate has been conserved since the divergence of the two species and to place human nucleotide diversity into perspective with an evolutionary closely related species. I explore the relationship of nucleotide diversity in chimpanzees with specific large-scale genome features to reveal a number of highly significant correlations which explain over 40% of the observed variation. I use data from the 1000 Genomes Project to examine the occurrence of ancestral polymorphisms shared between human and chimpanzee on a genome-wide scale. These ancestral polymorphisms do not only influence fine-scale divergence rates across the genome in very closely related species, they are also good candidates for regions under balancing selection and thus, they are a useful tool to study long-time population demographics and speciation. Using these variants, I postulate that long-term balancing selection may be more common than previously believed. I conclude with a discussion of the results contained in the body of the thesis and suggest a number of areas for future research.
Genetic and environmental factors influencing susceptibility to the complex disease multiple sclerosis
Keywords: Multiple sclerosis
Epstein-Barr virus
genetics
vitamin D
risk factors

Multiple sclerosis is a complex immune mediated condition of the central nervous system characterized by myelin loss and progressive neurodegeneration. The risk of developing MS is influenced by both genetic and environmental agents and, among them, several lines of evidence support a role for vitamin D deficiency, Epstein-Barr virus (EBV) infection and smoking in the aetiology of this disease. The aim of this work was to further elucidate how nature and nurture act in the causal cascade leading to MS. In chapter 1, I show that the main genetic factor in adult MS (the HLA-DRB1*1501 allele) plays an equally important role in paediatric cases of MS (PMS) and that EBV negative PMS patients represent a separate entity characterized by lower age at disease onset, lower female to male ratio and a trend towards a lower frequency of the HLA-DRB1*1501 allele. In chapter 2, I provide evidence in support of month of birth having a role on MS risk and T cell production and that vitamin D may underlie this effect. In chapter 3 I demonstrate the presence of a link between vitamin D deficiency and the immune response against EBV, whereby the proportion of EBV seropositive MS patients and controls increases with increasing latitude and high dose vitamin D supplementation appears to reduce the level of antibodies against this virus. In chapter 4, I show that MS associated genetic variants are located in genomic regions that exert a regulatory function and are active in immune cell types. In chapter 5, I illustrate how vitamin D receptor binding is also located within active regulatory regions in immune cells and that this is particularly evident near MS associated genes. Finally, in chapter 6, I use chromatin data on more than 100 different cell types and conclude that MS associated genetic variants are particularly active in T helper, T cytotoxic and B cells. Further work is needed to elucidate how genetic and environmental agents play a role in the cause of MS and to develop effective strategies for disease treatment and prevention.