VictorJuiz/thesis huggingface dataset:
Analogues of Antibacterial Natural Products 
Keywords: Lemonomycin
Antibiotic
Oxazolomycin
Natural Product
16-Methyloxazolomycin
Synthesis
Antibacterial

Analogues of Antibacterial Natural Products Elizabeth Anne Heaviside, St Catherine’s College, University of Oxford DPhil Thesis, Trinity Term 2012 This thesis is concerned with the synthesis and biological evaluation of structural mimics for the natural products 16-methyloxazolomycin and lemonomycin which display potent biological activity including antibacterial and antitumour activity. Chapter 1 explores methods and approaches to the discovery of new antibacterial drugs and the challenges faced in this respect. It also gives an overview of the properties of the natural products investigated in the following chapters and summarises previous synthetic approaches to these molecules published in the scientific literature. Chapter 2 describes the work carried out towards the synthesis of the diazabicyclo[3.2.1]octane unit of the tetrahydroisoquinoline antitumour antibiotic lemonomycin. The intended retrosynthesis of the natural product led to a 2,5-disubstituted pyrrolidine bearing a 1ʹ-amino functional group; a series of routes were explored for the synthesis of this unit. Using (S)-pyroglutamic acid, strategies using Eschenmoser and thiolactim ether coupling reactions were investigated. A sequence based on the formation of a pyrrolidine ring from the cyclisation of an appropriately substituted oxime ether derived from L-phenylalanine was then implemented but a competing Beckmann rearrangement/Grob fragmentation prevented access to the desired heterocycle. Preliminary investigations were also carried out on the modification of cyclic imines derived from oxime ethers which did not undergo Beckmann rearrangement. Chapter 3 describes the synthesis of a library of densely functionalised tetramic acid and pyroglutamate mimics for the right-hand fragment of 16-methyloxazolomycin, and their coupling with a gem-dimethylamide unit mimicking the middle fragment of the natural product. Tetramates were accessed through the Dieckmann cyclisation of N-acyloxazolidines and were derivatised with various alkyl halides. The pyroglutamates were accessed via the highly diastereoselective aldol cyclisation of N-acyloxazolidines formed by the amide coupling of a threonine derived oxazolidine and β-keto-acids. A series of β-keto-acids were synthesised through the acylation and subsequent ring-opening/decarboxylation reaction of Meldrum’s acid. The formation of right-hand/middle fragment adducts was explored using cycloaddition, alkylation and Sonogashira chemistry before a Wittig protocol led to the formation of adducts (E)- and (Z)- 402 and 403. Biological evaluation of the compounds synthesised in this chapter was carried out using both broth and hole-plate bioassays and active compounds were identified. Of particular note was that the Wittig adducts displayed a higher level of activity against Gram-negative E. coli than either the pyroglutamate or amide motifs alone.
Orthogonal tight binding model for silicon carbide
Keywords: Carbon
Silicon carbide
Bond-order potentials
Model development
Orthogonal tight binding
Materials modelling

A new orthogonal tight binding (OTB) model for the silicon carbide (Si-C) system is presented. The model is parameterized in the reduced TB form which provides a critical step towards the development of an analytic bond-order potential (BOP) for Si-C. Coarse-grained from density functional theory (DFT), through TB, analytic BOPs address a number of the deficiencies of current interatomic potentials for Si-C including the neglect of explicit π-bonding and more accurate σ-bond contributions. Furthermore, the new reduced OTB model is important within TB in its own right as the first simple, selfconsistent OTB model parameterized specifically for SiC without the use of any averaging of elemental interactions. Selfconsistency is achieved through local charge neutrality (LCN). The distance-dependent functions used to define the Hamiltonian matrix elements in the two-centre approximation were obtained directly from given DFT-projected data, and repulsive parameters were fit to DFT binding energies. The electronic structure, binding energies, and heat of formation for the groundstate structures are reproduced well with no spurious groundstate structures found in a database of over 200 unique crystal structures. The significant improvements over existing OTB models for elemental Si and C and the binary SiC results show good promise for further applicability in modelling a wide range of phenomena in Si-C such as thin film growth or interfaces in general.
High resolution structural studies of membrane proteins using solid state NMR
Keywords: solid state nmr
membrane proteins

NMR crystallography is a new and developing area. Unlike solution state NMR, solid state NMR has the potential for structural studies of large, motionally restricted biological macromolecules, such as proteins in crystals which may, or may not, diffract. However, finding the best and the most useful sample form and geometry is still a major obstacle to rapid progress. Little has been reported about protein sample preparation for any class of protein for NMR crystallography, mainly since the availability of NMR labelled proteins is still not routine, especially for eukaryotic membrane proteins. The amino acid L-glutamate is the major excitatory neurotransmitter in the brain. Details of glutamate binding to any of its main brain or sensory receptors are not well resolved at the atomic level. In an effort to resolve the glutamate binding mechanism by solid state NMR methods, full-length taste and brain mGluR4 were expressed in E. coli, but proved to be toxic for the cells. The ligand-binding domains (LBD) of mGluR4, with various fusions for the periplasmic expression and with various fusions for expression in the cytoplasm therefore, were used. Solubilisation and then purification of the LBD from inclusion bodies is still under way, no crystals of mGluR4 for NMR were, therefore, grown. Initial NMR spectra of labelled 13C, 15N and 17O glutamate have been recorded to verify sensitivity requirements. Using homology modelling, a model for the truncated version of the ligand binding domain of mGluR4 has been constructed as a basis for designing solid state NMR experiments to probe the ligand binding site in the receptor. Bacteriorhodopsin is a large membrane protein and a model for G-protein coupled receptors (GPCRs). Spectra of bacteriorhodopsin produced in H. salinarium in purple membrane are reported here and compared to spectra of the protein crystallised from bicelles. Optimal conditions for producing spectra suitable for spectral assignment are reported as an initial step towards spectral resolution. Three differently labelled samples of bacteriorhodopsin were prepared to test the applicability of the various assignment strategies and the effects of deuteration on quality of solid state NMR spectra of a large, crystalline membrane protein.
Rethinking the bronze-iron transition in Iran: copper and iron metallurgy before the Achaemenid Period
Keywords: copper
iron
archaeometallurgy
Iran

Iran, a country rich in mineral resources, has a long history of metal working. Copper objects first appeared in the 7th millennium BC and in the following millennia, copper became the material of choice for the production of many objects. Artefacts of iron began to appear in the mid 2nd millennium BC and by the mid 1st, iron had replaced bronze for most uses, but the reasons for this change remain unclear.
This thesis seeks to examine the transition from bronze to iron metallurgy from a new angle. By looking at changes in copper-based metallurgy between the Bronze Age and the Iron Age, it attempts to better understand the context in which iron metallurgy developed. To that end, the results of previously published chemical analyses of over 5000 copper-based objects from Iran and neighbouring regions and the lead isotope analyses of about 380 objects were assembled in a database.
The tin, arsenic, nickel, antimony and silver concentrations in particular are studied. The data is divided into 16 metal groups based on the absence or presence of the latter four elements. The study of the main groups allows us to describe interesting new patterns of metal movement and recycling. It appears that before the end of the Bronze Age, a number of copper sources and/or trade routes from both east and west declined, leading to a reliance on more local sources for copper and tin in the Iron Age. The practice of recycling from the 3rd millennium BC onward is also evidenced.
Overall, it seems that iron appeared within a thriving bronze industry, with a good access to metal resources and a developed understanding of the possibilities offered by copper (alloying, recycling, mixing…). Was it then the more ‘permanent’ nature of iron that attracted the ancient metal-workers and led to its advent?
Quantification of microscopic brain structures using diffusion magnetic resonance
Keywords: diffusion MRI
extracellular space
extra-axonal space
intra-axonal space
hindered diffusion
diffusion spectrum
magnetic resonance imaging
restricted diffusion
intracellular space

Diffusion-weighted magnetic resonance imaging can be used to estimate microstructural parameters of white matter in the brain. Two complementary techniques are investigated: the use of the temporal diffusion spectrum to explore small length scales and the STEAM technique to probe larger features.
The diffusion spectrum has the potential to be more sensitive to small pores compared to conventional time-dependent diffusion. However, analytical expressions for the diffusion spectrum of particles only exist for simple geometries such as cylinders, which are often used as a model for intra-axonal diffusion. We propose a mathematical model for the extra-axonal space with parameters that are related to the microstructural properties of pore size, tortuosity, and surface-to-volume ratio. Measurements were made with an extra-axonal space phantom to validate the model. Fitted values for the phantom pore size match those from simulation.
We extend the model to include the intra-axonal signal contribution. However, the parameters used to describe the intra- and extra-axonal spaces are related and it is important to remove redundant parameters to avoid overparameterization, which would make the model less robust. We propose analytical expressions to simplify the model. The model was then applied to measurements on fixed corpus callosum, which is a model system consisting of parallel axons. The estimated values of the axon volume fraction and mean and standard deviation of the axon radius distribution are comparable to those found in literature.
Temporal diffusion spectra are useful for measuring the geometric properties of small spaces such as axon radii. However, longer diffusion times accessible using the STEAM sequence are necessary to probe structures with longer diffusion distances such as those parallel to the direction of axons. We used a model from the literature originally developed for use with animal magnetic resonance scanners and simplified it to quantify axial hindrance from data acquired on healthy volunteers in a clinical scanner. The interpretation of axial hindrance, which is a largely unexplored area of research, is discussed.
Pipe dreams; explaining the energy security policies of Poland, 1990-2007
Keywords: energy security
state-business relations
Polish-Russian relations
Poland
political economy of energy

This thesis seeks to explain Poland’s energy security policies towards Russia in the period from 1990-2007. It is inspired by the puzzle that Poland’s commitments to reduce its dependence on imported oil and gas from Russia have varied considerably during this period. Numerous large-scale projects to enhance energy security have been proposed, abandoned and revisited, all in the absence of a significant change to Poland’s level of dependence on Russia or its exposure to supply risks. This puzzle poses a challenge to conventional approaches to energy security, which tend to explain policies as a function of ‘material’ shifts in the price, supply or demand for fossil fuels. Though these factors are undoubtedly important it is argued that, in the case of Poland, energy security is more affected by domestic decision-making processes than by such material shifts. In particular, the degree and form of intervention in the energy sector by the political executive in Poland is highlighted as a key factor explaining energy security policy output. These interventions in Poland are classified and distinguished according to three types of ‘policy network’ – statist, corporatist and liberal, each of which represented a different outlook on the optimal means for ensuring energy security. These policy networks were embedded within different governments, and their preferences fashioned Poland’s responses to energy security challenges occurring under similar material conditions.
HSV-1 amplicon system for human artificial chromosome formation in human ES/iPS cells and pluripotency induction
Keywords: Human embryonic stem cells (hESc)
induced pluripotent stem cells (iPS)
Herpes Simplex Virus (HSV)-1 amplicon system
Human artificial chromosomes (HAC)
gene therapy
gene delivery

Development of safe and efficient approaches for gene delivery in human embryonic stem cells (hESc) and particularly in human induced pluripotent stem (hiPS) cells, which can be derived in a person-specific manner, is considered to be imperative for harnessing their full potential in both the basic and applied research. The aim of this study was to evaluate the potential of human artificial chromosome (HAC) for gene delivery and expression in hESc and hiPS cells. HAC offers many potential advantages including the provision for carrying large genes with corresponding regulatory elements to obtain long-term regulated gene expression. In addition, they can replicate and segregate independently without integration into the host cell genome. To develop HAC in hiPS cells, the first part of the study was aimed at generating hiPS cells utilising the Herpes Simplex Virus (HSV)-1 amplicon system. With the use of EBNA-1/OriP retention elements incorporated into the HSV-1 amplicon vectors, hiPS cells completely free of vector and transgenes sequences were successfully derived from human embryonic fibroblasts. The hiPS cells exhibited proliferation and differentiation potential similar to that of hESc. In the second part of the study, development of HAC in hESc and hiPS cells was assessed by utilising the HSV-1 amplicon system to deliver the HAC DNA. Analysis of the hESc confirmed the presence of functional HAC which replicated the behaviour of the host chromosomes. Additionally, HAC generation did not lead to impairment in the developmental potential and pluripotency of hESc. The hiPS cells supported HAC at low frequency but DNA also integrated into the host chromosomes. The HAC system, therefore, needs further refinements to improve the frequency of HAC formation and reduce the chromosomal integration of HAC constructs in hiPS cells. Overall, these findings provide a simple and safe way of pluripotency induction and genetic modification of pluripotent stem cells using the HSV-1 amplicon system and represent an important advance towards patient specific gene and cell therapy.
Mapping and understanding the distributions of potential vector mosquitoes in the UK: New methods and applications
Keywords: Bayesian
presence-only
Emerging infectious diseases
ecology
Community ecology
West Nile fever
Gaussian process
species distribution modles
statistics
mosquito

A number of emerging vector-borne diseases have the potential to be transmitted in the UK by native mosquitoes. Human infection by some of these diseases requires the presence of communities of multiple vector mosquito species. Mitigating the risk posed by these diseases requires an understanding of the spatial distributions of the UK mosquito fauna. Little empirical data is available from which to determine the distributions of mosquito species in the UK. Identifying areas at risk from mosquito-borne disease therefore requires statistical modelling to investigate and predict mosquito distributions.
This thesis investigates the distributions of potential vector mosquitoes in the UK at landscape to national scales. A number of new methodological approaches for species distri- bution modelling are developed. These methods are then used to map and understand the distributions of mosquito communities with the potential to transmit diseases to humans.
Chapter 2 reports the establishment of substantial populations of the West Nile virus (WNV) vector mosquito Culex modestus in wetlands in southern England. This represents a drastic shift in the species’ known range and an increase in the risk of WNV transmission where Cx. modestus is present.
Chapter 3 develops and applies a new species interaction distribution model which identifies fish and ditch shrimp of the genus Palaemonetes as predators which may restrict the distribution of the potential WNV vector community in these wetlands.
Chapter 4 develops a number of methods to make robust predictions of the probability of presence of a species from presence-only data, by eliciting and applying estimates of the species’ prevalence.
Chapter 5 introduces a new Bayesian species distribution modelling approach which outperforms existing methods and has number of useful features for dealing with poor- quality data.
Chapter 6 applies methods developed in the previous two chapters to produce the first high-resolution distribution maps of potential vector mosquitoes in the UK. These maps identify several wetland areas where vector communities exist which could maintain WNV transmission in birds and transmit it to humans.
This thesis makes significant contributions to our understanding of the distributions of UK mosquito species. It also provides methods for species distribution modelling which could be widely applied in ecology and epidemiology.
Quantum models of space-time based on recoupling theory
Keywords: penrose
racah
spin networks
quantum
relativity
groups
geometry
poincare group
regge
ponzano
recoupling

Models of geometry that are intrinsically quantum-mechanical in nature arise from the recoupling theory of space-time symmetry groups. Roger Penrose constructed such a model from SU(2) recoupling in his theory of spin networks; he showed that spin measurements in a classical limit are necessarily consistent with a three-dimensional Euclidian vector space. T. Regge and G. Ponzano expressed the semi-classical limit of this spin model in a form resembling a path integral of the Einstein-Hilbert action in three Euclidian dimensions. This thesis gives new proofs of the Penrose spin geometry theorem and of the Regge-Ponzano decomposition theorem. We then consider how to generalize these two approaches to other groups that give rise to new models of quantum geometries. In particular, we show how to construct quantum models of four-dimensional relativistic space-time from the re-coupling theory of the Poincare group.
Model free optimisation in risk management
Keywords: Model Free Option Pricing
Quantitative Risk Management
Infinite Dimensional Optimisation
Model Free Optimisation

Following the financial crisis of 2008, the need for more robust techniques to quantify the capital charge for risk management has become a pressing problem. Under Basel II/III, banks are allowed to calculate the capital charge using internally developed models subject to regulatory approval. An interesting problem for the regulator is to compare the resulting figures against the required capital under worst case scenarios. The existing literature on the latter problem, which is based on the marginal problem, assumes that no a-priori information is known about the dependencies of contributing risks. These problems are linear optimisation problems over a constrained set of probability measures, discretisation of which leads to large scale LPs. But this approach is very conservative and cannot be implemented robustly in practice, due to the scarcity of historical data. In our approach, we take a less conservative strategy by incorporating dependence information contained in the data in a form that still leads to LPs, an important feature of such problems due to their high dimensionality. Conceptually, our model is the discretisation of an infinite dimensional linear optimisation problem over a set of probability measures. For some specific cases we can prove strong duality, opening up the approach of discretising the dual instead of the primal. This approach is preferable, as it yields better numerical results. In this work we also apply our model to model-free path-dependent option pricing. Use of delayed column generation techniques allows us to solve problems several orders of magnitude larger than via the standard simplex algorithm. For high-dimensional LPs we also implement Nesterov's smoothing technique to solve the problems.
The facultative endosymbionts of grain aphids and the horizontal transfer of ecologically important traits
Keywords: parasitoid
facultative endosymbiotic bacteria
insect
aphid
symbiosis
mutualism

Insects are often infected with facultative endosymbiotic bacteria, which can have a range of important ecological effects. The grain aphid, Sitobion avenae, harbours diverse facultative symbionts, which suggests their importance in grain aphid biology.
This thesis attempts to explain the ecological roles of the facultative endosymbionts in S. avenae. It also examines the question of whether the horizontal transmission of symbionts between aphid clones and species can be important for shaping the ecology and evolution of multi-species aphid communities. Novel techniques developed for research with the grain aphid study system are presented.
Grain aphid clones vary in their tolerance to low temperatures, but this trait is not affected by their facultative endosymbionts.
Strains of a symbiont Hamiltonella defensa do not protect grain aphids from hymenopterous parasitoids, regardless of the host genotype. However, experienced parasitoid females preferentially oviposit in aphids which do not harbour symbionts.
Comparison of the fitness consequences of infection with the same Hamiltonella strains in their original and in novel grain aphid host clones reveal no consistent differences.
Symbiont strains establish easily following artificial transfer between clones of the grain aphid, but the symbionts transferred from other aphid species form less stable infections. Hamiltonella strains do not affect the fecundity of their grain aphid host clones regardless of their host species of origin, but also do not generally confer protection against parasitoids.
There are no clear patterns in the distribution of parasitoid-resistant phenotypes across phylogenetic trees of Hamiltonella and its bacteriophage APSE.
Strains of four unrelated species of endosymbionts, Rickettsia, Spiroplasma, Rickettsiella and Regiella, confer the same pathogen-resistant phenotype to a single pea aphid clone. The same symbiont strains can confer resistance to clones of two different aphid species. Some strains in multiple infections may compensate for the costs of infections with other symbionts.
The importance of these results for understanding the ecological and evolutionary role of facultative endosymbionts in aphids and other insects are discussed, and directions for further research are proposed.