VictorJuiz/thesis huggingface dataset:
Enantiopure lithium amides in asymmetric synthesis

This thesis is concerned with the application of the conjugate addition of enantiopure secondary lithium amides to α,β-unsaturated esters for the asymmetric synthesis of fluorinated β-amino acids, (–)-(R)-sitagliptin, and amino sugars.
Chapter 1 focuses on the asymmetric synthesis of compounds containing halogens, chalcogens and pnictogens via conjugate addition of enantiomerically pure lithium amides. The projective can be, achieved in two ways: incorporation of halogens, chalcogens and pnictogens in the α,β-unsaturated ester substrates (Class I), and electrophilic enolate functionalisation (Class II).
Chapter 2 details a full investigation into the conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to a range of β-fluoroaryl-α,β-unsaturated esters giving the corresponding β-fluoroaryl-β-amino esters. Subsequent efficient global N-deprotection was facilitated by hydrogenolysis without formation of products arising from defluorination being observed. Finally, hydrolysis of the resultant primary β-fluoroaryl-β-amino esters gave a range of β-fluoroaryl-β-amino acids in excellent yield. The power and generality of this conjugate addition methodology developed by Davies at al. to produce fluorinated β-amino acids was demonstrated well.
Chapter 3 describes two successful, efficient and concise asymmetric syntheses of (–)-(R)-sitagliptin, which is an effective treatment for type 2 diabetes, employing lithium amide conjugate addition methodology as the key stereodefining step.
Chapter 4 describes the successful and concise asymmetric syntheses of 5- or 6-membered ring amino sugars via cyclization of “alkene-masked” ω-aldehyde β-amino esters or “acetal-masked” ω-aldehyde β-amino esters derived from lithium amide conjugate addition methodology to the corresponding α,β-unsaturated ester.
Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3 and 4.

Advisor: Davies, SG
The Early English Text Society in the nineteenth century

Despite the importance of the subject to the discipline of Middle English studies, little research has been published on the history of the editing of Middle English texts. This thesis supplies a small, but essential portion of that history by examining the editorial practices that were used to produce the editions of Middle English texts published by the Early English Text Society in the nineteenth century. Then the dominant publisher in its field, EETS identified and printed almost the entire Middle English canon during a crucial time in the development of English studies the period in which it moved from being an almost exclusively amateur pursuit to one accepted and practiced by professional academics in the universities.
To provide a context for my examination of EETS editions, I first investigate the financial and material conditions under which EETS' publications were produced and examine the ideas which guided EETS' editorial policy in the light of contemporary theories about the editing of Middle English texts. I then examine nine editions in detail, analysing the various methods by which the text is established and formal manuscript detail is represented in print. The analysis contained in these nine studies is based on the evidence I compiled by comparing sample extracts of the printed text and associated paratext of each edition with the manuscript evidence originally available to the editor. I then use the information gathered about these individual editions as part of an assessment of the editorial practices that define the nature of EETS' nineteenth-century editorial output as a whole. I find that a conservative editorial approach that valorises the evidence of individual manuscripts characterises the majority of EETS' publications, but that the Society also produced a great variety of editions that diverge from this approach, including several of the earliest applications of recension to Middle English texts published in England.

Advisor: Hudson, A
Opening the black box: the politics of allocating public resources for health in Barbados

Within the field of public health, there has been increasing interest in the factors that influence national priorities in health in low- and middle-income countries (LMICs), where resources are often particularly scarce and decision-making processes are often ad- hoc. Understanding how priorities are set in these countries necessitates a look at the process concealed in the black box that transforms policy inputs into outputs. However, rigorous health policy analysis of macro-level priority setting in LMICs is rare.
Using a case study approach, this thesis explores the drivers of priority for primary health care, sanitation and HIV/AIDS over the past five decades in Barbados. To do this I use process tracing techniques, drawing on analysis of public expenditure on health from 1960 to 2010, in-depth interviews with key policy actors, non-participant observation, archives, media reports, parliamentary records and other documents.
I argue that powerful individual policy actors or 'policy entrepreneurs' act as necessary drivers of macro-level priority setting in Barbados, although they do not single- handedly determine the outcomes. In particular, I find that these actors are successful in generating priority when they are able to propagate powerful framing ideas and can effectively navigate the policy context by seizing windows of opportunity and managing negative constraints. Moreover, because resources are scarce, their ability to mobilize external financial support is also important.
In particular, this thesis stresses the fact that allocating public resources for health is a political process and suggests that it is best explained by considering a set of interrelated factors. In doing so, it illustrates the utility of health policy analysis in helping to open the black box of macro-level priority setting in LMICs more broadly.

Keywords: Barbados
Caribbean
Sanitation
Primary Health Care
Advisor: Sanchez-Ancochea, D
Wolstenholme, J
Transcutaneous delivery of T Cell-inducing viral vector Malaria vaccines by microneedle patches

There is an urgent need for improvements to existing vaccine delivery technologies to run parallel with the development of new-generation vaccines. The burdens of needle-based immunisation strategies are exacerbated by poor resource provision in such areas as sub-Saharan Africa, where annual malaria mortality stands at 860,000. Needle-free delivery of vaccine to the skin holds promise for improved immunogenicity with lower doses of vaccine, in addition to significant logistical advantages. Various methods have been described for the transcutaneous delivery of vaccines, including the use of microneedles to overcome the outer stratum corneum of the skin for efficient delivery of liquid or solid, microneedle-coated vaccines into underlying strata rich in antigen-presenting cells. This thesis aims to evaluate two transcutaneous silicon microneedle and microprojection patch technologies for the delivery of live recombinant Adenovirus and Modified Vaccinia Ankara-vectored vaccines encoding pre-erythrocytic malaria antigens in mice. Cellular immunogenicity directed against a well-documented epitope of the Plasmodium berghei circumsporozoite protein is evaluated, as is protection against lethal P. berghei sporozoite challenge. Immunological and logistical benefits of each technology are assessed, as well as mechanisms underlying differences in the generation of a patch-induced immune response to vaccination. These data inform the future development of transcutaneous microneedle patches for the delivery of live vaccine.

Keywords: immunology
skin
vaccine
malaria
microneedles
cutaneous
Advisor: Hill, A
Reyes-Sandoval, A
Robust indoor positioning with lifelong learning

Indoor tracking and navigation is a fundamental need for pervasive and context-aware applications. However, no practical and reliable indoor positioning solution is available at present. The major challenge of a practical solution lies in the fact that only the existing devices and infrastructure can be utilized to achieve high positioning accuracy.
This thesis presents a robust indoor positioning system with the lifelong learning ability. The typical features of the proposed solution is low-cost, accurate, robust, and scalable. This system only takes the floor plan and the existing devices, e.g. phones, pads, etc. and infrastructure such as WiFi/BLE access points for the sake of practicality. This system has four closely correlated components including, non-line-of-sight identification and mitigation (NIMIT), robust pedestrian dead reckoning (R-PDR), lightweight map matching (MapCraft), and lifelong learning. NIMIT projects the received signal strength (RSS) from WiFi/BLE to locations. The R-PDR component converts the data from inertial measurement unit (IMU) sensors ubiquitous in mobile devices and wearables to the trajectories of the user. Then MapCraft fuses trajectories estimated from the R-PDR and the coarse location information from NIMIT with the floor plan and provides accurate location estimations. The lifelong learning component then learns the various parameters used in all other three components in an unsupervised manner, which continuously improves the the positioning accuracy of the system.
Extensive real world experiments in multiple sites show how the proposed system outperforms state-of-the art approaches, demonstrating excellent sub-meter positioning accuracy and accurate reconstruction of tortuous trajectories with zero training effort. As proof of its robustness, we also demonstrate how it is able to accurately track the position regardless of the users, devices, attachments, and environments. We believe that such an accurate and robust approach will enable always-on background localization, enabling a new era of location-aware applications to be developed.

Keywords: lifelong learning
pattern matching
dead reckoning
positioning
Advisor: Trigoni, N
Single-molecule fluorescence studies of KirBac1.1

Inwardly rectifying potassium (Kir) channels are essential for controlling the excitability of eukaryotic cells, forming a key part of the inter-cellular signalling system in multi-cellular organisms. However, as prokaryotic (KirBac) channels are less technically challenging to study in vitro and have been shown to be directly homologous to eukaryotic channels, they are often studied in lieu of their mammalian counterparts. A vital feature of Kir and KirBac channels is their mechanism for opening and closing, or their gating: this study predominantly features observations of open and/or closed channel populations. A well-characterised member of the KirBac family, KirBac1.1, has been successfully expressed, purified into detergent micelles, and doubly labelled with fluorescent maleimide dyes in order to enable observation of confocal-in-solution Förster Resonance Energy Transfer (FRET) at the single molecule level. Results demonstrate single-molecule FRET signals from KirBac1.1 and therefore represent the first single-molecule FRET observations from a KirBac channel. Perturbation of the open-closed dynamic equilibrium was performed via activatory point mutations, changes in pH, and ligand binding. A protocol for reconstitution into nanodiscs was optimised in order to more closely approximate native conditions, and the single-molecule FRET observations repeated. This thesis presents a comparison between measurements made using the detergent solubilisation system and those made using nanodiscs.

Keywords: Kir
KirBac
single-molecule
potassium channels
FRET
confocal
dynamic equilibrium
excitable membranes
nanodiscs
detergent
Advisor: Tucker, S
Kapanidis, A
The priesthood in Anglo-Saxon England

The Priesthood in Anglo-Saxon England explores the life and work of priests in England between the arrival of St. Augustine in 597 and the reforming Council of Clofesho of 747. It seeks to reposition priests within the consciousness of Anglo-Saxon historians by demonstrating the essential role which they played first in the conversion of the English, and then in the pastoral care which the English people received up to the reforms instigated by Archbishop Cuthbert at the 747 Council of Clofesho. The thesis draws on several trends in recent Anglo-Saxon historiography, notably focus in recent years on the role and function of monasteria. Sarah Foot’s work, Monastic Life in Anglo-Saxon England, c. 600 – 900, is the primary study in this area. Many historians working in this area have read Bede’s Historia Ecclesiastica, the main narrative source for our period, in a predominantly monastic light. Close attention to the text of this and other works of Bede’s however demonstrates that priests were indispensable in the initial conversion and continued care of the people, particularly because of their ability to celebrate the sacraments.
This thesis contends that monasteria increasingly gained control over pastoral care through their continued endowment and royal privilege. This effectively removed the cura animarum from the bishops, to whom it was theoretically entrusted. Following the example of Theodore and Bede, and on the prompting of his contemporary Boniface, in 747 Archbishop Cuthbert recognised the need to reform the structure of the church in Southumbria, particularly the relationship between the episcopate and the monasteria, and so restore the cure to its rightful place. He and his fellow bishops achieved this by redefining pastoral care along sacramental grounds, thereby excluding monks from its exercise, and putting the priest back at the heart of the church’s mission to the people of England.

Keywords: priesthood
church
priest
Anglo-Saxon
Advisor: Foot, S
The poems of William Herbert, Third Earl of Pembroke

Writing in 1912, Sir Herbert Grierson, who had frequently encountered the poems of Pembroke while working on his edition of Donne, pointed out the need for a reliable edition of Pembroke’s poetry:
"A scholarly edition of the poems of Pembroke and Rudyard would be a boon. Many ascribed to them by the younger Donne in his edition of 1660 could be removed and others added from manuscript sources."
An attempt was made to fulfil this need in 1935 in a B.Litt thesis prepared by Miss Margaret A. Beese. At that time, however, the necessary manuscripts for such a study had not come to light , and Miss Beese was therefore able to attribute with certainty only three poems to Pembroke. Basing my study in part upon other sources, I have included twenty-four poems by him in the present edition.
The main problem of my study, as these statements imply, is to determine the canon of Pembroke’s poems. The only printed edition of his poems, which appeared thirty years after his death, was notoriously unreliable: over one-fourth of its poems were by other, well known seventeenth century poets. It could not be ignored however, and my approach to the canon has essentially been to attempt to ascertain where the attributions of the printed text might be accepted. This I have sought to do by determining the manuscript sources from which the edition derived.
[Please see pdf. for full preface.]

Keywords: poetry
William Herbert
canon
Advisor: Gardner, H
Buxton, J
High fidelity readout and protection of a 43Ca+ trapped ion qubit

This thesis describes theoretical and experimental work whose main aim is the development of techniques for using trapped 43Ca⁺ ions for quantum information processing. I present a rate equations model of 43Ca⁺, and compare it with experimental data. The model is then used to investigate and optimise an electron-shelving readout method from a ground-level hyperfine qubit. The process is robust against common experimental imperfections. A shelving fidelity of up to 99.97% is theoretically possible, taking 100 μs. The laser pulse sequence can be greatly simplified for only a small reduction in the fidelity. The simplified method is tested experimentally with fidelities up to 99.8%. The shelving procedure could be applied to other commonly-used species of ion qubit. An entangling two-qubit quantum controlled-phase gate was attempted between a 40Ca⁺ and a 43Ca⁺ ion. The experiment did not succeed due to frequent decrystallisation of the ion pair, and strong motional decoherence. The source of the problems was never identified despite significant experimental effort, and the decision was made to suspend the experiments and continue them in an improved ion trap which is under construction. A sequence of pi-pulses, inspired by the Hahn spin-echo, was derived that is capable of greatly reducing dephasing of any qubit. If the qubit precession frequency varies with time as an nth-order polynomial, an (n+1) pulse sequence is theoretically capable of perfectly cancelling the resulting phase error. The sequence is used on a 43Ca+ magnetic-field-sensitive hyperfine qubit, with 20 pulses increasing the coherence time by a factor of 75 compared to an experiment without any spin-echo. In our ambient noise environment the well-known Carr-Purcell-Meiboom-Gill dynamic-decoupling method was found to be comparably effective.

Keywords: measurement
dephasing
CPMG
hyperfine
shelving
qubit
UDD
Uhrig
readout
decoherence
quantum computing
dynamical decoupling
rate equation
ion trap
quantum computation
Advisor: Lucas, D
Computational studies of protein helix kinks

Kinks are functionally important structural features found in the alpha-helices of many proteins, particularly membrane proteins. Structurally, they are points at which a helix abruptly changes direction. Previous kink definition and identification methods often disagree with one another.
Here I describe three novel methods to characterise kinks, which improve on existing approaches. First, Kink Finder, a computational method that consistently locates kinks and estimates the error in the kink angle. Second the B statistic, a statistically robust method for identifying kinks. Third, Alpha Helices Assessed by Humans, a crowdsourcing approach that provided a gold-standard data set on which to train and compare existing kink identification methods.
In this thesis, I show that kinks are a feature of long -helices in both soluble and membrane proteins, rather than just transmembrane -helices. Characteristics of kinks in the two types of proteins are similar, with Proline being the dominant feature in both types of protein. In soluble proteins, kinked helices also have a clear structural preference in that they typically point into the solvent.
I also explored the conservation of kinks in homologous proteins. I found examples of conserved and non-conserved kinks in both the helix pairs and the helix families. Helix pairs with non-conserved kinks generally have less similar sequences than helix pairs with conserved kinks. I identified helix families that show highly conserved kinks, and families that contain non-conserved kinks, suggesting that some kinks may be flexible points in protein structures.

Keywords: Kink
Structural biology
Protein
protein structure prediction
Helix
Secondary structure
crowdsourcing
Advisor: Deane, C
Shi, J
Type 1 insulin-like growth factor receptor inhibition as treatment for urological cancer

The type 1 insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase that mediates diverse cellular functions including growth, differentiation, migration and apoptosis protection. IGF-1R signalling has been implicated in tumorigenesis in a variety of cancers, and IGF-1R inhibitory drugs are currently undergoing clinical evaluation. Previous work in our laboratory has shown IGF-1R over-expression in urological cancers at both the mRNA and protein level, thus making it a potential therapeutic target. The first aim of this project was to develop a protocol for IGF-1R immunohistochemistry, investigate the expression and cellular distribution of the IGF-1R receptor in clear cell renal cell carcinomas (ccRCC), and assess correlation with clinical parameters. In tissue microarray analysis, IGF-1R was detected in ~90% of 195 ccRCCs, with signal in the plasma membrane, cytoplasm and also in the nucleus. The presence of nuclear IGF-1R in up to 50% of ccRCCs and its association with adverse prognosis was a novel finding, and suggests that nuclear IGF-1R may influence ccRCC biology. Further investigations will clarify its role in the nucleus and its potential as a prognostic biomarker. The second aim was to investigate effects of IGF-1R inhibition on radiosensitivity and DNA repair, following previous work in our laboratory showing that IGF-1R depletion enhances chemo- and radio-sensitivity, delays double strand break (DSB) resolution, and may play a role in the homologous recombination (HR) pathway of DNA DSB repair. However, the repair defect seen in these early experiments was larger than could be entirely explained by a defect in HR. The current project used a small molecule IGF-1R tyrosine kinase inhibitor AZ12253801 (AstraZeneca), which blocked IGF-1 induced IGF-1R activation and inhibited cell survival. AZ12253801 enhanced the radiosensitivity of prostate cancer cells, which appeared to be independent of effects of IGF-1R inhibition on cell cycle distribution and apoptosis induction. IGF-1R inhibition delayed the resolution of γH2AX foci, supporting a potential role for the IGF-1R in DSB repair. This delay in focus resolution was apparent at early time-points (less than 4 hr), and was epistatic with DNA dependent protein kinase (DNAPK) inhibition in prostate cancer cells and DNAPK deficiency in glioblastoma cells. These results suggest a role for the IGF-1R in the non-homologous end-joining (NHEJ) pathway of DNA DSB repair. A cell-based reporter assay in HEK-293 cells confirmed that IGF-1R inhibition suppressed DSB repair by NHEJ, helping to explain the radiosensitization demonstrated upon IGF-1R inhibition. There was lack of support for a transcriptional effect, with no significant change observed in gene expression on microarray analysis. Although the mechanism of this effect remains unclear, the observed inhibition of NHEJ has implications for the use of IGF-1R inhibitors in combination with DNA damaging agents in cancer treatment.

Keywords: IGF-1R
DNA repair
non-homologous end-joining
urological cancer
Advisor: Macaulay, V
Composite materials for microwave frequency agile planar devices

The potential of Calcium-Vanadium garnet loaded binary composites for use in the production of planar frequency agile microwave devices has been investigated. A WR90 rectangular waveguide system using the transmission/reflection technique has been used to compare effective medium theory predicted permittivities and permeabilities for unmagnetised and transversely magnetised composites with actual measured composite properties. Use of the the Bruggeman effective medium theory with manufacturer supplied garnet permittivity and values of garnet permeability calculated using simple empirical models were demonstrated to be as accurate as predictions made using the measured properties of the composites' individual constituents. Errors in predicted material properties for unmagnetised and transversely magnetised samples relative to measured data were less than 5% across almost half of the 8.2 -12.4GHz measurement band and within a worst-case error of 15% across the whole band. A series of end-coupled linear microstrip resonators using garnet-loaded composite substrates has been fabricated and tested. Tunabilities in resonance of up to 3.9% at 9.2GHz have been demonstrated for DC magnetic bias fields applied transverse to the microwave magnetic field component. An entirely new and previously unpublished broadband microstrip technique for the measurement of the effective permittivity and permeability of bulk gyromagnetic and gyromagnetic material loaded composite substrates subject to transverse DC magnetic bias fields is presented. This will have wide application in the design of frequency agile microwave integrated circuits.

Keywords: composite materials
microwave
permittivity
permeability
Advisor: Edwards, D
Stevens, C
Dew-Hughes, D