VictorJuiz/thesis huggingface dataset:
Computer simulation of phosphate ester hydrolysis reactions

Phosphate esters and their hydrolysis reactions underpin many of the most important reactions in biology and have therefore been the focus of continued research.
In this thesis, a range of theoretical studies on two phosphate ester hydrolysis reactions is presented. Particular attention is paid to the role of solvent in these reactions. The first reaction studied is the hydrolysis of dimethyl phosphate. A study using density functional theory examines three possible mechanisms for this reaction in the gas phase and the presence of solvent is also considered through the use of reaction field methods. The base-catalysed mechanism for this reaction receives further attention and the reaction energy profile in solution is adiabatically mapped using two different hybrid QM/MM potentials. The use of a QM/MM potential facilitates an atomistic representation of the solvent. Another study determines the potential of mean force for this reaction by simulating the reaction using QM/MM molecular dynamics simulations in conjunction with umbrella sampling methods. Both QM/MM studies demonstrate that, in solution, the rate-determining step for the base-catalysed reaction is the cleavage of the bond between the phosphorous and the leaving group. The QM/MM studies also established that the reaction proceeds via the formation of a short-lived pentacoordinated intermediate species.
The second reaction studied was the base-catalysed hydrolysis of methyl ribose phosphate, a realistic model of the nonenzymatic hydrolysis of RNA. Since the hydrolysis of thio-substituted analogues of RNA have been the study of many experimental studies probing the mechanism of RNA hydrolysis, theoretical studies of the hydrolysis of two thio analogues of methyl ribose phosphate are also presented. The results of these studies provide valuable insight into the mechanism of RNA hydrolysis and concludes that the cleavage of P-O5' bond corresponds to the reaction transition state.

Advisor: Richards, W
Richards, G
A marine geophysical study of the Wilkes Land rifted continental margin, Antarctica

The Wilkes Land margin of East Antarctica, conjugate to the southern Australian margin, is a non-volcanic rifted margin that formed during the Late Cretaceous. During 2000-01 and 2001-02, Geoscience Australia (GA) acquired ~10,000 line km of seismic reflection, magnetic anomaly, and gravity anomaly data, on the Wilkes Land margin. Seismic reflection and sonobuoy refraction data provide the first constraints on sediment thickness and images of the deep crustal structure for the extent of the Wilkes Land margin. Two major post-rift seismic-stratigraphic sequences are recognised, separated by a regionally correlatable unconformity. The unconformity is interpreted as Early- to Middle-Eocene (~50 Ma). This unconformity has previously been interpreted to represent the onset of continent-wide glaciation at ~34 Ma. A major unconformity at the base of post-rift sediments is interpreted as a breakup unconformity, of approximately Turonian (85-90 Ma) age. Timing the onset of seafloor spreading using lineated magnetic anomalies within the Australia-Antarctic Basin (AAB) is extremely difficult due to uncertainties in correlating anomalies to the geomagnetic reversal time scale. Modelling indicates that the anomaly commonly correlated to Chron 34y may, in some cases, be associated with high level intrusions and/or serpentinisation of exhumed upper-mantle peridotites. Process-oriented gravity modelling indicates that the Wilkes Land margin lithosphere is characterised by a relatively high effective elastic thickness (Te). Isostatic anomalies are most effectively reduced for models utilising Te = 30 km. Although the margin is broadly characterised by a high Te, zones of low Te are inferred from modelling. Spectral analysis of isostatic anomalies indicates that the power of the flexural isostatic anomalies is lower than the free air gravity anomalies. The margin does not appear to be segmented, at least in regard to its long-term strength. However, a change in initial, zero-elevation crustal thickness (Tc) is inferred from west to east. A Tc of ~35 km is inferred for western Wilkes Land, whereas eastern Wilkes Land is characterised by Tc = 29 to 31 km. Limited seismic refraction data from the conjugate margin indicates a similar trend from southwest to southeast Australia.

Keywords: sedimentology
Antarctica
flexure
subsidence
Wilkes Land
geophysics
Advisor: Watts, A
Computational modelling of structure and dynamics in lightweight hydrides

Hydrogen storage in lightweight hydrides continues to attract significant interest as the lack of a safe and efficient storage of hydrogen remains the major technological barrier to the widespread use of hydrogen as a fuel. The metal borohydrides Ca(BH₄)₂ and LiBH₄ form the subject of this thesis; three aspects of considerable academic interest were investigated by density functional theory (DFT) and molecular dynamics (MD) modelling. (i) High-pressure crystal structures of Ca(BH₄)₂ were predicted from a structural analogy between metal borohydrides and isoelectronic metal oxides. The structural stability of hydrogen storage materials under high pressure is an important aspect, as high-pressure polymorphs may provide structures with better hydrogen desorption properties. The isoelectronic analogue of Ca(BH₄)₂ is TiO₂, and structural equivalents of Ca(BH₄)₂ in the baddeleyite, columbite and cotunnite structures of TiO₂ were found to be stable at elevated pressure. Thermodynamic stability was evaluated by computing the Gibbs energy with respect to pressure and temperature. The pressure-dependence of the Helmholtz energy was determined to described a third-order Birch-Murnaghan equation of state, and the harmonic approximation was used to compute the vibrational energy levels and the Helmholtz energy as a function of temperature. The proposed structures are consistent with reports of two hitherto unidentified high-pressure phases observed experimentally. (ii) The disordered structure of the high-temperature phase of LiBH4 was studied by ab initio molecular dynamics (MD) at temperatures ranging from 200-535 K. It was found that the model emerging from analysis of the MD simulations properly accounts for dynamical disorder and fundamentally differs from the published experimental and theoretical structures. The validity of the MD model was corroborated by comparison of calculated pair distribution functions, vibrational spectra and a crystallographic model with neutron diffraction data; good agreement was found. A reassignment of the space group from P63mc to P63/mmc is proposed based on evidence for additional symmetry from MD simulations. (iii) Finally, a new MD-based method was developed to simulate fast ionic diffusion in LiBH₄. The colour diffusion algorithm - a nonequilibrium molecular dynamics method originally developed for the study of model fluids - was adapted and applied to self-diffusion of atoms in a solid for the first time. Calculated diffusion coefficients agreed very well with published measurements, and diffusion pathways that include collective particle effects were determined directly from the simulation results, thereby opening up a promising and efficient new method for the study of phenomena such as superionic conduction.

Keywords: fuel cell
renewable energy
materials modelling
hydrogen storage
computational chemistry
Advisor: David, WIF
Edwards, PP
Behaviour of corrosion-protection coatings in light alloys

Anionic chromate (VI) compounds are inhibitive pigments and have been effectively incorporated into organic coatings to protect metal surfaces from aggressive ions, but their risk as a human carcinogen and being harmful to the environment has led to the search of suitable alternatives. Aluminium alloy, AA2024-T3, is the substrate metal alloy used in the experiments and can be found in aircraft fuselage structures due to their high strength-to-weight ratio. However, the presence of intermetallic particles increases susceptibility to localised corrosion.
To investigate the protection mechanisms of primers on light alloys, many different factors must be taken into account; from aluminium alloy corrosion processes, the effects of intermetallic additions to coating chemistry, morphology and inhibitive pigments. The chemical environment in which the samples are tested in will also affect the corrosion mechanisms of the alloy as well as the performance of the coatings and release of pigments. It will be important to consider which factors are operating under particular conditions so that experimental results can then be best interpreted.
As part of this project, potentiodynamic polarisation, electrochemical impedance spectroscopy and electrochemical noise analysis have been used to investigate the protective mechanisms in which chromate-based paints protect against corrosion and UV-Visible spectroscopy, scanning acoustic microscopy and optical microscopy have been used to investigate pigment release mechanism to identify what characteristics are important when developing new primers.

Keywords: Aluminium
Corrosion
Coatings
Advisor: Sykes, J
Assender, H
Vagueness, inconsistency, and semantic competence

I defend Cognitive Inconsistentism, a novel explanation of vagueness qua susceptibility to sorites paradoxes. The view is contrasted with the Inconsistency Theories of Michael Dummett and Matti Eklund. I argue that these latter views are committed to unattractive theories of linguistic understanding. I propose an alternative Chomskyan, cognitive theory of linguistic understanding. I employ this cognitive framework to argue that speakers mentally represent a similarity constraint on conceptual classification, which is causally and explanatorily implicated in language acquisition and use. This cognitive similarity constraint causally explains our linguistic intuitions with respect to sorites paradoxes.

Keywords: understanding
vagueness
inconsistency
semantics
Advisor: Williamson, T
Studying centrosome formation and the consequences of centrosome loss in Drosophila melanogaster

Centrioles are conserved microtubule-based structures that are required for the formation of two important cellular organelles, centrosomes and cilia. Centrosomes form the poles of the mitotic spindle and consist of a pair of centrioles surrounded by a matrix of pericentriolar material (PCM) that has the ability to nucleate and organise microtubules. Centrosome defects are implicated into a variety of human diseases including cancer, microcephaly, and ciliopathies. Therefore it is of great interest to understand the mechanisms that lead to centrosome formation and the consequences that centrosome defects have in cells.
I have analysed the roles of several centrosomal proteins in centrosome assembly in Drosophila. My results indicate that Sak/PLK4 is only required for the initial step of centriole duplication, but has no further role in recruitment of PCM. I show that two proteins important for PCM recruitment, Asterless (Asl) and Spd-2, are preferentially phosphorylated when they are integrated into the centrosome and I identified these phosphorylation sites using a phosphoproteomic screen. A phosphorylation site in Asl is specifically phosphorylated in mitosis, and the phosphorylation state of Spd-2 regulates its maintenance at the centrosome, suggesting that phosphorylation of PCM proteins is an important mechanism to ensure PCM assembly specifically at the centrosome and in mitosis.
I have performed a global transcriptional analysis of flies lacking centrosomes or having extra centrosomes to investigate the effects of centrosomal defects on a cellular level. Surprisingly, my results indicate that centrosome defects per se do not dramatically alter cellular physiology. Finally, I demonstrate that in the absence of centrioles acentrosomal microtubule-organising centres (aMTOCs) are formed in an Asl- and Cnn-dependent fashion, and I show that these aMTOCs can contribute to spindle focusing in acentrosomal cells.

Keywords: centrioles
mitotic spindle assembly
centrosomes
Advisor: Raff, J
Prediction of homing pigeon flight paths using Gaussian processes

Studies of avian navigation are making increasing use of miniature Global Positioning Satellite devices, to regularly record the position of birds in flight with high spatial and temporal resolution. I suggest a novel approach to analysing the data sets pro- duced in these experiments, focussing on studies of the domesticated homing pigeon (Columba Livia) in the local, familiar area. Using Gaussian processes and Bayesian inference as a mathematical foundation I develop and apply a statistical model to make quantitative predictions of homing pigeon flight paths. Using this model I show that pigeons, when released repeatedly from the same site, learn and follow a habitual route back to their home loft. The model reveals the rate of route learning and provides a quantitative estimate of the habitual route complete with associated spatio-temporal covariance. Furthermore I show that this habitual route is best described by a sequence of isolated waypoints rather than as a continuous path, and that these waypoints are preferentially found in certain terrain types, being especially rare within urban and forested environments. As a corollary I demonstrate an extension of the flight path model to simulate ex- periments where pigeons are released in pairs, and show that this can account for observed large scale patterns in such experiments based only on the individual birds’ previous behaviour in solo flights, making a successful quantitative prediction of the critical value associated with a non-linear behavioural transition.

Keywords: bird
behaviour
navigation
probability
pigeon
avian
gaussian process
Advisor: Roberts, S
Guilford, T
The influence of selected sulphur containing compounds on retinal cell death: neuroprotective effects of hydrogen sulphide in a glaucoma model

Ganglion cell death in glaucoma is caused by a variety of insults that include ischemia, insufficient neurotrophic support and oxidative stress. Experimental studies were therefore conducted on cell cultures to determine how serum deprivation (to mimic insufficient neurotrophic support) or oxidative glutamate toxicity (GB), cause oxidative stress and induce retinal cell death. Moreover, studies were carried out to deduce whether selected sulphur containing compounds can blunt any negative influences to cells in culture and/or a defined ischaemic insult to the rat retina in situ, as this might suggest their use for the treatment of glaucoma.
Serum deprivation and GB caused generation of reactive oxygen species (ROS) and apoptosis-like death to transformed retinal ganglion cells (RGC-5 cells). RGC-5 cells were more susceptible to the detrimental effects of GB than serum deprivation. RGC-5 cells subjected to serum deprivation appear to die by mechanisms that resemble classical apoptosis more closely than that caused by GB and the phase between the maximal generation of ROS and cell death were different. Cell death caused by serum deprivation was caspase-dependent but this was not the case for GB. Moreover, of the two sulphur compounds sulbutiamine and N-acetyl cysteine (NAC), sulbutiamine blunts the effect of serum deprivation more effectively. In addition, the pan caspase inhibitor z-VAD-fmk attenuated the negative effect of serum deprivation to RGC-5 cells while the necroptosis inhibitor (necrostsatin-1) counteracted solely the insult of GB.
The sulphur containing compounds, ACS1 and ACS 67 which release hydrogen sulphide (H2S) slowly and NAC (a pro-cysteine GSH precursor) attenuated GB-induced cell death of RGC-5 cells. In contrast, sulbutiamine (a lipophilic thiolic thiamine derivative) was particularly effective in protecting RGC-5 cells from an insult of serum deprivation. Moreover, all of the sulphur compounds directly sequestered different types of ROS but with varying efficiency.
Common features by which all tested sulphur containing agents seem to elicit a mode of action include the stimulation of GSH and the antioxidant enzyme glutathione-S-transferase (GST) as well as to scavenge excess free radicals. Moreover, the slow release of H2S from the ACS compounds appears to protect cells from oxidative stress through increasing the level of GSH, modulation of the cystine uptake transporter xCT, stimulation of the oxidative stress related transcription factor Nrf2 and the stimulation of pro-survival signalling pathways.
The slow releasing H2S sulphur compound ACS67 also counteracts a number of detrimental influences to the rat retina in situ because of ischemia/reperfusion that includes damage to their ganglion cells. This suggests that such sulphur compounds might find a use in the treatment of glaucoma where ischemia probably plays a part in the disease process.

Keywords: apoptosis
neuroprotection
free radical damage
oxidative stress
hydrogen sulphide
Advisor: Osborne, N
A clinicopathological study of inclusion body myositis

Sporadic inclusion body myositis (IBM) is the commonest acquired myopathy in individuals aged over 50 years. Currently, diagnosis is based largely upon specific muscle biopsy findings, though these are thought to lack sensitivity. More recently, many abnormal protein aggregates have been described in IBM and some have been proposed as diagnostic markers. However, their diagnostic utility is untested and how they relate to the pathogenesis is uncertain.
The clinical characteristics, pathological findings and disease course in 67 patients with histopathologically diagnosed and clinically diagnosed IBM were compared and revealed that patients with IBM have a characteristic pattern of weakness at presentation that is independent of the pathological findings. Current diagnostic pathological features are more common in older patients and therefore may be linked to disease duration.
The pathology of IBM and the diagnostic utility of protein aggregates in IBM were studied in six clinicopathologically typical cases of IBM. Protein aggregates immunoreactive for p62, TDP-43, myotilin, α B-crystallin and ubiquitin were more abundant than the current diagnostic pathological features. The diagnostic potential of these pathological features was then assessed in pathologically typical and atypical IBM and controls. This revealed that staining for p62, MHC Class I, CD8 positive lymphocytes and mitochondrial abnormalities could support the diagnosis and should be included in diagnostic criteria for IBM.
Laser microdissection and label-free mass spectrometry were used to validate the histological findings. The presence of nuclear and aggresomal proteins in rimmed vacuoles indicated that they are derived from myonuclei. Increased protein synthesis and ER stress suggest that abnormal protein aggregates may be the result of abnormal protein production.
In conclusion, this thesis emphasises that a diagnosis of IBM can be confidently made on clinical grounds, with a supportive muscle biopsy. The histological and proteomic findings reveal that there is a spectrum of pathological features most likely associated with the disease duration and that adherence to the current pathological based diagnostic criteria may have led to some erroneous conclusions about the pathogenesis of this enigmatic disease.

Keywords: Inclusion Body Myositis
Muscle
Myositis
Advisor: Hilton-Jones, D
Holton, J
Squier, W
Ideology and dramatic form in the plays of Sean O'Casey, 1922-49

Sean O'Casey was a writer much involved in both social and theatrical politics. He was, by turns, a Communist, nationalist, pacifist, feminist and Christian-humanist, and one of the early concerns of the thesis is to clarify his political position vis a vis leading socialists of his time, and to explore the extent to which his politics took overt shape as an ideology within his plays.
A second and central concern is to explore the aesthetics of the less definite 'political' form of carnivalism within O'Casey's work, and to examine in the plays the relations between this form of anti-rationalist and anti-bourgeois comedy and a parallel mood of increasing despair and 'nihilism' which I believe to be related to O'Casey's frustration at finding so few of his political ambitions and values fulfilled in the Ireland of his time.
At its best, his carnivalism expresses a deeply dialogical grasp of metaphysical issues. At its worst, it twists into an entropic nihilism under the pressure of its own anti-idealistic materialism. In the later plays (1927-49), an attempt is made to balance the earlier nihilism with a stress upon carnivalistic elements of dance, song and play, but the later work is flawed at those moments where metaphysical expressions become detached from social and self-consciously discursive processes and become merely an expression of romantic vitalism.
Finally, one can theorise O'Casey's carnivalism as a response to the efforts of some contemporary writers to detach their literary language from ordinary social processes in the at tempt to create a 'mythological' and nationally pure form of drama which had shed signs of its contemporaneity. I have chosen the example of W. B. Yeats to illustrate this point. O'Casey's carnivalism produces a hybrid form of Irish drama which is, by contrast. unashamed of its precipitation from the heteroglossic literary and social discourses of its time. Ultimately, however, O'Casey shares much of Yeats's suspicion of English empiricism and utilitarianism and his work can be seen as complementary to Yeats's own post-colonial development.

Keywords: Sean O'Casey
Advisor: Eagleton, T
The image of Christ in Late Antiquity

This dissertation focuses on images of Christ that date from the first half of Late Antiquity, defined as the three centuries between AD 200 and 500.
The cultural dynamics of this period left a distinct impression on Christian art, and this dissertation traces that impact. Unlike other studies that attempt to resolve ambiguity within the corpus of Christ images, the argument here maintains that ambiguity was a key component in the creation and subsequent interpretation of the Late Antique Christian iconography.
The dissertation proceeds in three parts, each comprising two chapters. In the first section, the history and historiography of the image of Christ is explored, and a methodology capable of accommodating the diverse meanings assigned to the Christ’s discrepant and ambiguous iconographies is developed.
In order to better understand the socio-religious environment in which the first images of Christ were produced and interpreted, the second section of the dissertation moves away from material culture and towards method and theory. The notion that interpretation is a group level phenomenon is critiqued, and a model explaining how individuals in Late Antiquity could have made sense of ambiguous images of Christ is advanced.
The final section turns back to the material culture and applies the framework developed in the second section to two artworks: (1) the sarcophagus of Junius Bassus and (2) the floor mosaic from the Hinton St. Mary Roman Villa now in the British Museum. By complementing the standard analyses of Christian art with interpretations grounded in the diverse interactions viewers had with artworks, new perspectives will emerge that provide a fuller picture of Late Antique Christianity and the iconography of its godhead alike.

Keywords: Late Antiquity
Image of Christ
Christianity
Advisor: Elsner, J
Rosser, G