VictorJuiz/thesis huggingface dataset:
Disorder and defects in functional molecular frameworks
Keywords: metal-organic frameworks
molecular frameworks
defects
crystallography
disorder

This Thesis explores the role of structural defects and disorder and their relationship to experimental data, with a particular emphasis on molecular framework materials. The question of how we can build atomistic models of amorphous materials from experimental data without needing to make system-specific assumptions is addressed. The role of 'structural invariance', i.e. the limited range of distinct local atomic environments within a material, as a restraint within reverse Monte Carlo refinement (RMC) is investigated. The operation of these invariance restraints operate is shown to be system-dependent and the challenges associated with effective refinement, e.g. configurational 'jamming', are also investigated. A generalisation to the 'structural simplicity', i.e. the simplest model, holding all else constant, is most likely to be correct. Three new metrics of structural simplicity are proposed: two intrinsically three-dimensional measures of local geometric invariance and one measure of local symmetry. These metrics are shown to robustly quantify the configurational quality. The ability of these metrics to act as effective restraints for the RMC refinement of amorphous materials is demonstrated by the construction of the first data-driven tetrahedral models of amorphous silicon. The role of defects and disorder within metal–organic frameworks (MOFs) is investigated through the canonical MOF UiO-66(Hf). Through a combination of techniques, including X-ray diffuse scattering, anomalous diffraction, total scattering and electron diffraction measurements, the existence of correlated metal-cluster absences in UiO-66(Hf) is demonstrated. Furthermore the ability to synthetically tune both the interactions and concentration of defects is shown. The thermomechanical properties of defective UiO-66(Hf) are also examined. UiO-66(Hf) is shown to rapidly densify by up to 5% (ΔV/V ) on ligand elimination. The resultant densified phase exhibits colossal (≥100MK-1) volumetric negative thermal expansion (NTE); the largest reported value for any MOF. Finally, the capability to tune the physical properties of MOFs through defect incorporation is demonstrated through the defect-dependence of both the densification and the NTE.
Tractable query answering for description logics via query rewriting
Keywords: Query Rewriting
OWL
Query Answering
Description Logics

We consider the problem of answering conjunctive queries over description logic knowledge bases via query rewriting. Given a conjunctive query Q and a TBox T, we compute a new query Q′ that incorporates the semantic consequences of T such that, for any ABox A, evaluating Q over T and A can be done by evaluating the new query Q′ over A alone. We present RQR—a novel resolution-based rewriting algorithm for the description logic ELHIO¬ that generalizes and extends existing approaches. RQR not only handles a spectrum of logics ranging from DL-Lite_core up to ELHIO¬, but it is worst-case optimal with respect to data complexity for all of these logics; moreover, given the form of the rewritten queries, their evaluation can be delegated to off-the-shelf (deductive) database systems. We use RQR to derive the novel complexity results that conjunctive query answering for ELHIO¬ and DL-Lite+ are, respectively, PTime and NLogSpace complete with respect to data complexity. In order to show the practicality of our approach, we present the results of an empirical evaluation. Our evaluation suggests that RQR, enhanced with various straightforward optimizations, can be successfully used in conjunction with a (deductive) database system in order to answer queries over knowledge bases in practice. Moreover, in spite of being a more general procedure, RQR will often produce significantly smaller rewritings than the standard query rewriting algorithm for the DL-Lite family of logics.
In aid of conflict: a study of citizen activism and American medical relief to Spain and China
Keywords: medical relief
Second Sino-Japanese War
humanitarianism
medical activism
Spanish Civil War
medical volunteer
American Red Cross
international aid

The outbreak of the Spanish Civil War in 1936 and the Second Sino-Japanese War in 1937 triggered many responses amongst the American public, including a number of private initiatives in medical aid that occupied a borderland between traditional humanitarian relief and political activism. This study is interested in the stories of three organisations arising in this tradition: the American Medical Bureau to Aid Spanish Democracy (AMBASD), the American Bureau for Medical Aid to China (ABMAC), and the China Aid Council (CAC). While three separate initiatives in terms of who was responsible for their creation in the United States, and the communities they sought to help abroad, all three demonstrate parallels in their foundation and development that merit a joint historical consideration.
Emerging from the backdrop of isolationism in U.S. foreign policy, the AMBASD, ABMAC, and CAC became a means of voicing both political and humanitarian ideals through the medium of medicine. In many ways, this thesis becomes a study of lost causes. As political campaigns, none of the organisations in this study succeeded in changing U.S. policy, although the ABMAC and CAC benefitted from interests that overlapped with larger changes in U.S. military alliances. As humanitarian organisations, only one (the ABMAC) lived past the conflict to which it owed its foundation. Their story, however, retains its historical interest in challenging both the way in which we examine the mythology of humanitarian idealism, and our understanding of the balance between internationalism and isolationism in the 1930’s United States. For the medical activists of these organizations, medical aid offered both a tangible outlet for personal ethical and political beliefs, but also promised an alternative means of diplomacy that brought greater agency to more popular levels.
Stochastic models of ion channel dynamics and their role in short-term repolarisation variability in cardiac cells
Keywords: cardiac electrophysiology
ion channels
Langevin equation
stochastic

Sudden cardiac death due to the development of lethal arrhythmias is the dominant cause of mortality in the UK, yet the mechanisms underlying their onset, maintenance and termination are still poorly understood. Therefore biomarkers are used to determine arrhythmic risk within patients and of new drug compounds. In recent years, the magnitude of variations in the length of successive beats, measured over a short period of time, has been shown to be a powerful predictor of arrhythmic risk. This beat-to-beat variability is thought to be the manifestation of the random opening and closing dynamics of individual ion channels that lie within the membrane of cardiac cells. Computational models have become an important tool in understanding the electrophysiology of the heart. However, current state-of-the-art electrophysiology models do not incorporate this intrinsic stochastic behaviour of ion channels. Those that do use computationally costly methods, restricting their use in complex tissue scale simulations, or employ stochastic simulation methods that result in negative numbers of channels and so are inaccurate. Therefore, using current stochastic modelling techniques to investigate the role of stochastic ion channel behaviour in beat-to-beat variability presents difficulties.
In this thesis we take a mathematically rigorous and novel approach to develop accurate and computationally efficient models of stochastic ion channel dynamics that can be incorporated into existing electrophysiology models. Two different models of stochastic ion channel behaviour, both based on a system of stochastic differential equations (SDEs), are developed and compared. The first model is based on an existing SDE model from population dynamics called the Wright-Fisher model. The second approach incorporates boundary conditions into the SDE model of ion channel dynamics that is obtained in the limit from the discrete-state Markov chain model, and is called a reflected SDE. Of these two methods, the reflected SDE is found to more accurately capture the stochastic dynamics of the discrete-stateMarkov chain, seen as the ‘gold-standard’ model and also provides substantial computational speed up. Thus the reflected SDE is an accurate and efficient model of stochastic ion channel dynamics and so allows for detailed investigation into beat-to-beat variability using complex computational electrophysiology models. We illustrate the potential power of this method by incorporating it into a state-of-the-art canine cardiac cell electrophsyiology model so as to explore the effects of stochastic ion channel behaviour on beat-to-beat variability. The stochastic models presented in this thesis fulfil an important role in elucidating the effects of stochastic ion channel behaviour on beat-to-beat variability, a potentially important biomarker of arrhythmic risk.
The development of functional hyaluronan hydrogels for neural tissue engineering
Keywords: biomimetics
trauma
hydrogel
stem cell
hyaluronan
hyaluronic acid
SANS
traumatic
neural
regenerative medicine
neuronal
neural network
tissue engineering
brain injury

Tissue engineers – in order to develop therapies for the treatment of complex neurological injuries and diseases – attempt to recreate elaborate developmental mechanisms in vitro. Neuronal precursor cells are excellent candidates for the study of developmental operations such as cell adhesion, differentiation, and axonal pathfinding. Hyaluronan (HA) is a common polysaccharide that is found extensively throughout the neuronal extracellular matrix (ECM), and can be functionalised and crosslinked to form stable hydrogels that support growing neuronal cells. Hyaluronan hydrogels can be modified chemically and mechanically to mimic the ECM of the developing brain, awarding control over mechanisms such as differentiation and axonal pathfinding. This thesis is concerned with the functionalisation and characterisation of HA hydrogels, ultimately in order to simulate vital properties of the developing brain. Here we show that HA hydrogels can be finely tuned mechanically (by modulating stiffness and viscosity), and chemically, by the conjugation of peptides that mimic the neural cell adhesion molecule (NCAM). NCAM mimics and novel mimics of sialylated NCAM significantly influence the differentiation of NSPCs in 2D and 3D. HA hydrogels successfully support long term culture of neural cells in 3D, and encourage the formation and extension of neurites of several cell types including human, mouse and rat neuronal precursor and stem cells. These results demonstrate for the first time that novel NCAM mimicking peptides can be conjugated to well defined hydrogel matrices that influence intricate developmental behaviours in 3D. Understanding how neural cells form functional networks is essential for the development of clinical approaches that attempt to address the injuries and diseases that affect these systems.
Engineering carboxymethylproline synthases towards the biosynthetic productions of carbapenem antibiotics
Keywords: carbapenems
combinatorial biosynthesis
carboxymethylproline synthases

Mechanistic and biocatalytic studies of two carboxymethylproline synthases (CMPSs), CarB and ThnE, members of the crotonase superfamily of enzymes, both in isolation and in conjunction with the activity of the crotonyl-CoA carboxylase/reductase (Ccr) the malonyl-CoA synthetase (MatB) and the methylmalonyl-CoA epimerase (MCE) are presented.
Protein engineering studies on carboxymethylproline synthases aimed at enabling stereoselective C–C bond formation leading to N-heterocycles via control of trisubstituted enolate intermediates were carried out. Active site substitutions, including at the oxyanion binding site, enabled the production of substituted N-heterocycles in high diastereomeric excesses via stereocontrolled enolate formation and reaction.
The biocatalytic promiscuity of malonyl-CoA ligase and the stereoselectivity of crotonyl–CoA carboxylase/reductase were successfully coupled to the selective tri- substituted enolate forming capacity of engineered carboxymethylproline synthases for the preparation of functionalized 5- and 6-membered N-heterocycles substituted with a variety of alkyl side chains at the C-5/C-6 positions at high diastereomeric excess. The effect of methylmalonyl-CoA epimerase on the diastereoselectivity of the carboxymethylproline synthase-catalysed enolated alkylation was also demonstrated.
The results illustrate the utility of the crotonase superfamily of enzymes for stereoselective biocatalysis and demonstrate the power of coupled enzyme systems to enhance diastereoselectivity and to expand the range of accepted substrates.
The theological dimensions of F.W.J. Schelling's theory of symbolic language
Keywords: symbol
Romanticism
Schelling
Goethe
reference

In this thesis I examine Schelling’s construction of symbolic language in §73 of his Philosophie der Kunst. I approach this construction in three ways. First, I compare Schellingian symbolic language to other contemporary theories of the symbol and language (in particular, those of Goethe, Kant and A.W. Schlegel). While Schelling’s theory of symbolic language possesses properties similar to these other theories (the identity of being and meaning, organic wholeness, the co-existence of opposites), I show that it differs in how they are interpreted.
Second, I excavate the metaphysical and epistemological principles from Schelling’s philosophy of the period which underlie this theory of language. Three tenets from the Identitätssystem (as it is called) are crucial: formation, quantitative differentiation and construction. They illuminate why Schelling interprets symbolic language very differently to his contemporaries.
Third, I consider the theological significance of Schellingian symbolic language. This significance is twofold. First, his theory gives rise to a conception of discourse without reference, and so to the notion of a theology without reference. On this basis, Schelling criticises Christian theology for remaining too concerned with referring to God, when what is at stake is rather the degree of intensity to which it produces God. Theology therefore stands in need of reformation. Second, the way in which theology is utilised by Schelling in order to construct symbolic language in §73 of the Philosophie der Kunst itself provides a model for reformed theological practice. I argue that Schelling conceives of traditional theology as material for intensifying the production of God. In this way, an ‘absolute theology’ is engendered which has no concern for reference or for the integrity of the theological tradition.
'The most affecting eloquence': Wordsworth and silence
Keywords: monasticism
silence
Wordsworth
Coleorton
pastoral

This thesis is the first close study of Wordsworth and silence. It uncovers the comprehensive investigation into monastic history and hagiography (with special emphasis on St Basil) that Wordsworth engaged in between 1807 and 1810, showing that the type of silence he valued came from the monastic tradition. I trace Wordsworth’s material commitment to the power of silence through his use of hermit figures and his habit of visiting ruined monasteries. I concentrate on the poetry he composed from 1807 onwards and mark his eight-month residence in 1806-7 at the home of Sir George and Lady Beaumont as the locus at which his intensive interest in monasticism germinated. I thus reveal a new dimension to this important patronal relationship, while additionally offering an analysis of a previously unstudied manuscript pamphlet ('An account of an English Hermit' by Thomas Barnard) which Lady Beaumont sent to the Wordsworths in 1809. I show how Wordsworth’s fascination with monastic sites and silence influenced his understanding of linguistic and political representation, inheritance, community, and pastoral retreat. At the same time, this critical attention to silence aids a revaluation of the religious vision of his work.
The thesis uses this historical and biographical information as a means of closely reassessing formal, linguistic, and generic features of Wordsworth's poetry. At its root, my work is about the natures of language, poetic representation, and readerly experience. How does Wordsworth communicate via silence? How does he use silence to 'create the taste' for his poetry? Where does silence impact on his renovation of genre and conceptions of form? I conclude that, for Wordsworth, silence is a positive gathering of stillness from within that is nourished by patterns of repeated activity and community. It is one of his most profound heuristic tools.
Mathematical modelling of oncolytic virotherapy
Keywords: travelling waves
reaction-diffusion
tumour
delay differential equations
oncolytic virotherapy
modelling
stochastic simulation algorithm

This thesis is concerned with mathematical modelling of oncolytic virotherapy: the use of genetically modified viruses to selectively spread, replicate and destroy cancerous cells in solid tumours. Traditional spatially-dependent modelling approaches have previously assumed that virus spread is due to viral diffusion in solid tumours, and also neglect the time delay introduced by the lytic cycle for viral replication within host cells.
A deterministic, age-structured reaction-diffusion model is developed for the spatially-dependent interactions of uninfected cells, infected cells and virus particles, with the spread of virus particles facilitated by infected cell motility and delay. Evidence of travelling wave behaviour is shown, and an asymptotic approximation for the wave speed is derived as a function of key parameters.
Next, the same physical assumptions as in the continuum model are used to develop an equivalent discrete, probabilistic model for that is valid in the limit of low particle concentrations. This mesoscopic, compartment-based model is then validated against known test cases, and it is shown that the localised nature of infected cell bursts leads to inconsistencies between the discrete and continuum models.
The qualitative behaviour of this stochastic model is then analysed for a range of key experimentally-controllable parameters. Two-dimensional simulations of in vivo and in vitro therapies are then analysed to determine the effects of virus burst size, length of lytic cycle, infected cell motility, and initial viral distribution on the wave speed, consistency of results and overall success of therapy.
Finally, the experimental difficulty of measuring the effective motility of cells is addressed by considering effective medium approximations of diffusion through heterogeneous tumours. Considering an idealised tumour consisting of periodic obstacles in free space, a two-scale homogenisation technique is used to show the effects of obstacle shape on the effective diffusivity. A novel method for calculating the effective continuum behaviour of random walks on lattices is then developed for the limiting case where microscopic interactions are discrete.
Mechanistic and inhibition studies on gamma-butyrobetaine hydroxylase
Keywords: gamma-butyrobetaine hydroxylase
carnitine

Carnitine is an essential metabolite in the human body. It carries out several roles in human metabolism, including that in fatty acid metabolism. γ-Butyrobetaine hydroxylase (BBOX) is an Fe(II) and 2-oxoglutarate dependent oxygenase, which catalyses the final step of carnitine biosynthesis, i.e. hydroxylation of γ-butyrobetaine (GBB) to carnitine. Inhibition of BBOX has potential in the treatment for cardiovascular diseases.
The work described in this thesis focussed on mechanistic and inhibition aspects of BBOX catalysis. Firstly, a set of analytical tools for BBOX activity measurements was developed. The synthesis of fluorinated substrate analogues provided the basis for development of two assays for use in vitro with the isolated protein and in lysates, with detection by fluorescence or 19F NMR, respectively. Furthermore, the use of 19F NMR to monitor protein-ligand interactions was exemplified with the work on metallo-β-lactamases.
The developed fluoride-release assay was then used to screen a library of small molecules and led to recognition of scaffolds with potential applications as inhibitors. Further structure-activity relationship studies led to the identification of potent BBOX inhibitors, which were then evaluated for their activity in cells. The crystal structure of human BBOX with one of the lead inhibitors revealed that BBOX can undergo significant conformational changes, involving a movement of an active site loop. BBOX conformational flexibility may have a role in the GBB mediated substrate inhibition observed both with isolated protein and in cells.
In addition to the mechanistic and functional studies, the potential of BBOX as a biocatalytic tool was examined. BBOX has been shown to catalyse a hydroxylation of the symmetrical dialkyl piperidine carboxylic acids, leading to formation of up to three stereocentres in one reaction.
In the last part of this work properties of human BBOX were compared to BBOX from Pseudomonas sp. AK1, revealing differences in kinetic behaviour and substrate specificity. Novel substrates for bacterial BBOX were identified. Pseudomonas sp AK1 BBOX was shown to hydroxylate amino acid analogues leading to formation of 1,2-amino alcohols.
Stepping dynamics of the bacterial flagellar motor and F1-ATPase
Keywords: Bacterial Flagellar Motor
F1-ATPase
Molecular Motor
Microscopy

Rotary molecular motors are protein complexes which convert chemical or electrochemical energy from the environment into mechanical work in the form of rotary motion. The work in this thesis examines two of these motors: the F1 portion of F1FO- ATP synthase, which is responsible for ATP production in bacteria and eukaryotes, and the bacterial flagellar motor (BFM), which rotates the flagella of a bacterium, enabling locomotion. The aim of these investigations was to measure the stepping dynamics of these motors, in order to further elucidate details of the stepping mechanism, the mechanism of rotation, and the mechanochemical cycle. A back-scattering laser dark field microscope of unprecedented resolution was designed and constructed to observe the rotation of gold nanoparticles attached to fixed motors. This micro- scope is capable of sub-nanometer and 20μs resolution.
The protocols and algorithms to collect and analyze high resolution rotational data developed for these experiments have yielded novel discoveries for both F1 and the BFM. While most of the previous single-molecule work has been done on F1 from the thermophilic Bacilus PS3 (TF1), only mitochondrial F1 has been well characterized by high-resolution crystal structures, and single-molecule studies of mesophilic F1 are lacking. This thesis presents evidence that mesophilic F1 from E. coli and wild type yeast F1 from S. cerevisiae are governed by the same mechanism as TF1 under laboratory conditions. Experiments with yeast F1 mutants allow a direct comparison between single-molecule rotation studies and high resolution crystal structures. A data set of unprecedented size and resolution was acquired of high speed, low load BFM rotation, enabling the first observation of steps in the BFM under physiological conditions. Preliminary results from this analysis question previously published results of the dependence of speed on stator number at low load and provide novel hypotheses necessitating new models of BFM rotation.