VictorJuiz/thesis huggingface dataset:
Mathematical modelling of cell growth in tissue engineering bioreactors

Expanding cell populations extracted from patients or animals is essential to the process of tissue engineering and is commonly performed in laboratory incubation devices known as bioreactors. Bioreactors provide a means of controlling the chemical and mechanical environment experienced by cells to ensure growth of a functional population. However, maximising this growth requires detailed knowledge of how cell proliferation is affected by bioreactor operating conditions, such as the flow rate of culture medium into the bioreactor, and by the initial cell seeding distribution in the bioreactor. Mathematical modelling can provide insight into the effects of these factors on cell expansion by describing the chemical and physical processes that affect growth and how they interact over different length- and time-scales.
In this thesis we develop models to investigate how cell expansion in bioreactors is affected by fluid flow, solute transport and cell seeding. For this purpose, a perfused single-fibre hollow fibre bioreactor is used as a model system. We start by developing a model of the growth of a homogeneous cell layer on the outer surface of the hollow fibre in response to local nutrient and waste product concentrations and fluid shear stress. We use the model to simulate the cell layer growth with different flow configurations and operating conditions for cell types with different nutrient demands and responses to fluid shear stress. We then develop a 2D continuum model to investigate the influence of oxygen delivery, fluid shear stress and cell seeding on cell aggregate growth along the outer surface of the fibre. Using the model we predict operating conditions and initial aggregate distributions that maximise the rate of growth to confluence over the fibre surface for different cell types.
A potential limitation of these models is that they do not explicitly consider individual cell interaction, movement and growth. To address this, we conclude the thesis by assessing the suitability of a hybrid framework for modelling bioreactor cell aggregate growth, with a discrete cell model coupled to a continuum nutrient transport model. We consider a simple set-up with a 1D cell aggregate growing along the base of a 2D nutrient bath. Motivated by trying to reduce the high computational cost of simulating large numbers of cells with a cell-based model, and to assess the validity of our previous continuum description of cell aggregate growth, we derive a continuum approximation of the discrete model in the large cell number limit and determine whether it agrees with the discrete model via numerical simulations.

Keywords: mathematical modelling
Advisor: Waters, S
Byrne, H
Whiteley, J
Shipley, R
Machine learning to assess the fetal brain from ultrasound images

Obstetric care decisions fundamentally rely upon accurate estimation of gestational age (GA). Ultrasound- (US) based measurements provide reliable estimates of GA, if performed early in pregnancy. However, in low-income settings, the lack of appropriately trained sonographers and the tendency for women to present for care late in pregnancy are barriers to the use of US for dating purposes. In this thesis, we propose to exploit sonographic image patterns associated with dynamic fetal brain development to predict GA. We designed an algorithm which automatically estimates GA from an US scan collected from a single visit, thereby enabling clinically useful estimates of GA to be made even in the third trimester of pregnancy: a period complicated by biological variation and unreliable size-based estimates.
The presented model was conceived on the basis that fetal brain development follows a precise spatiotemporal pattern, with folds emerging and disappearing on the surface of the brain (cerebral cortex) at fixed time points during pregnancy. This timing is so precise that post-mortem neuroanatomical and MRI evidence suggest that the 'developmental maturation' of the fetal brain may be a better predictor for GA than traditional size-based estimates.
We capitalize on these age-related patterns to develop, for the first time, a unified model which combines sonographic image features and clinical measurements to predict GA and brain maturation. The framework benefits from a manifold surface representation of the fetal head which delineates the inner skull boundary and serves as a common coordinate system based on cranial position. This allows for fast and efficient sampling of anatomically-corresponding brain regions to achieve like-for-like structural comparison of different developmental stages. Bespoke features capture neurosonographic patterns in 3D images, and using a regression forest classifier, we characterize structural brain development both spatially and temporally to capture the natural variation existing in a healthy population (n=448) over an age range of active brain maturation (18 to 34 weeks).
Our GA prediction results on a high-risk clinical dataset (n=187) strongly correlate with true GA (r=0.98, accurate within ± 6.10 days), confirming the link between maturational progression and neurosonographic activity observable across gestation. Our model also outperforms current clinical methods, particularly in the third trimester. Through feature selection, the model successfully identified regional biomarkers of neurodevelopmental progression over gestation. Guided by these regions, we present a novel approach for defining and testing hypotheses associated with neuropathological deviations.

Keywords: Brain development
Ultrasound
Regression forests
Fetal brain
Gestational age
Advisor: Noble, J
Sandawe oral literature

The Sandawe of central Tanzania have a simpler material culture than their neighbours, but oral art is important and forms an indispensable part of their lives. They are a nation of singers rather than of poets; all poetry is minor verse but it is found everywhere: in story-telling , in dance, and in ritual. The study of oral literature provides historical detail, knowledge of manners and customs, religion, social values in the present and in the past; it helps to correct a possibly distorted image of the tribe, to remove prejudice, to give insight into different sets of values, and thereby to create respect and understanding.
Inhibition of [NiFe]-hydrogenases with pi-acid ligands: electrochemical and in situ infrared spectroelectrochemical studies

Hydrogenases are of great interest because they utilise abundant and inexpensive metals, Fe or Ni-Fe, in their active sites to catalyse hydrogen cycling – highly relevant to enzyme-based or bio-inspired technologies. The Fe in the active site is in a biologically unusual ligand environment coordinated by CO and CN-. These small molecule ligands have intense infrared absorption features and serve as good probes to monitor the coordination state and electronic environment of the active site. Infrared spectroscopy has therefore become a standard approach for characterising hydrogenases isolated from different organisms, but to date only few spectroscopic results have been correlated with states of the active site generated during catalysis. A new approach, PFIRE, which couples direct electrochemical control of hydrogenase, immobilised on a carbon particle electrode, and FTIR spectroscopy together is exploited in this Thesis to address this issue. This Thesis develops a surfactant-modified particle electrode to have a high loading of E. coli Hyd-2 (a standard [NiFe]-hydrogenase) for use in PFIRE for comparison with the O2-tolerant membrane-bound hydrogenase, E. coli Hyd-1, during catalytic turnover. A systematic study of how E. coli Hyd-1 and E. coli Hyd-2 respond to other Π-acid ligands is also reported in this Thesis. Cyanide was found to have unusual reactions with Hyd-1 and Hyd-2; it can promote the formation of the oxidised inactive state, Ni B. Isocyanides are shown for the first time as inhibitors of [NiFe]-hydrogenases.
The use of bulky isocyanides as probes in this Thesis reveals that the catalytic pocket of Hyd-1 is more spacious than previously thought, as even n-butyl isocyanide with a long tail is capable of getting in and out to react with the active site reversibly. Overall this Thesis provides a view of how pi-acid ligands react with a prototype O2-sensitive and O2-tolerant [NiFe]-hydrogenase.

Advisor: Vincent, K
Molecular markers of stress

Using data from the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE) Consortium study of major depressive disorder (MDD)on 11,670 Han Chinese women, this thesis describes an investigation on the etiology of MDD, a psychiatric disease that has eluded previous genetic studies as well as investigations of its mechanistic underpinnings. It asks: what happens during stress, how may it contribute to the risk of developing MDD, and why does it increase the risk of MDD in some people but not others. It presents three main findings.
First, a GWAS on MDD conducted on 10,640 samples (5,303 cases and 5,337 controls) in the CONVERGE dataset found two genome wide significant associations with MDD, one lying at the 5' side of SIRT1, and the other in an intron of LHPP. Both signals have been replicated in a completely independent cohort of severe MDD cases and matched controls from Northern China, making them the first replicated association loci for MDD to date. Second, I found there are more copies of mtDNA in cases of MDD than controls and while the increase can be induced by stress, it is contingent on the depressed state. Further analyses of results from animal experiments showed stress increases mtDNA levels in a dose-dependent, reversible and tissue specific way that is mediated partly by stress steroids. Third, the total amount of heteroplasmy was found to increase with increasing mtDNA levels, and therefore is higher in cases of MDD than controls, consistent with a change in mitochondrial function observed in animal models of chronic stress.
All three findings suggest stress causes changes in mtDNA, and this change may be larger in cases of MDD than controls. This difference between cases and controls may be due to differences in their regulation of mtDNA levels and sequence mutation during stress, and this may be genetically determined. This study provides a new perspective to the etiology of depression, suggesting it may have origins in metabolic regulation.

Advisor: Flint, J
The application of click reactions in the synthesis of modified oligonucleotides

'Click' chemistry has been widely applied in nucleic acid studies, the most common reactions being the copper-catalysed and strain promoted alkyne-azide cycloadditions (CuAAC and SPAAC respectively). This thesis describes the use of these complementary reactions in the synthesis of modified oligonucleotides. Both reactions are used to ligate alkyne and azide-modified oligonucleotides together to form larger strands on the solid phase. The CuAAC reaction can produce ODNs containing a biocompatible triazole linkage that mimics the DNA phosphodiester linkage, however its use in vivo is limited by the cytotoxicity of Cu(I). In contrast, the SPAAC reaction does not require catalysis, but more chemically complex cyclooctynes are needed. Multiple sequential ligations by the SPAAC reaction can be carried out on solid-phase without a template oligonucleotide, allowing the efficient synthesis of oligonucleotides up to ca. 190 bases in length, and greatly simplifying purification. Click chemistry was used to synthesize novel nucleic acid fluorescent probes. Using the SPAAC reaction, fluorescently labelled oligonucleotides were ligated to obtain permanently cross linked stable duplexes, which were evaluated for their FRET properties. A new nucleic acid probe system was developed containing thiazole orange (TO) or benzothiazole orange (BO), and a second fluorophore was directly attached to the same nucleobase by CuAAC. The thermal stability and steady state fluorescence of the oligonucleotides containing these modifications were studied. These probes can be multiplexed for detection of point mutations in DNA. This was exemplified by targeting R516G mutation in the CFTR gene by simultaneously monitoring two channels in real-time PCR.

Advisor: Brown, T
Defining the role of autoantibodies in paediatric immune-mediated encephalopathies

Autoimmune encephalopathies, mainly described in adults, are neurological syndromes characterized predominantly by impaired alertness usually with seizures, movement disorders, psychiatric features or autonomic instability. Well-characterised serum or cerebrospinal fluid (CSF) antibodies to neuronal surface proteins have been identified in these disorders. The aim was to define and extend the role of autoantibodies in paediatric encephalopathies. The clinical, paraclinical and immunological features of patients with autoimmune encephalopathies, acute encephalitis, N-methyl-D-aspartate receptor (NMDAR)-antibody and voltage gated potassium channel (VGKC)-complex antibodies, and in children with basal ganglia encephalitis were studied in detail.
In 48 children with a diagnosis of probable autoimmune encephalopathy, 21 (43% ) had CNS autoantibodies, principally to NMDAR and VGKC-complexes, but children without these antibodies could also respond well to immunotherapies. Immune-mediated/autoimmune encephalitis was also the largest subgroup (34% ) of encephalitis in an Australian paediatric encephalitis cohort. NMDAR-antibodies were found in children with well-defined encephalitis, but also in patients presenting without an encephalopathy, with distinct clinico-radiological white matter syndromes, or with a neurological relapse following herpes-simplex encephalitis. Children with VGKC-complex antibodies did not have autoantibodies to the complex associated proteins leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2) as frequently seen in adults, but were more likely to have a primary neuroinflammatory disease than in patients without these antibodies. Finally, despite a recent report, dopamine receptor antibodies or an alternative autoantibody were not found in children with basal ganglia encephalitis.
Novel clinical syndromes were identified with NMDAR-antibodies, raising important questions about the role of NMDARs in white matter, and the relationship with preceding infections. Patients with basal ganglia encephalitis may have an alternative pathobiology mediating their disease. Moreover, antibody positivity is not essential for the diagnosis of autoimmune encephalitis and children with or without detectable neuronal antibodies may respond to immunotherapy.

Advisor: vincent, A
Governing deceleration: the natures, times, and spaces of ecotourism in South Korea

This thesis explores the governmentalities of ecotourism in South Korea in relation to the specific historical-political experience of accelerated modernisation, focussing on three selected analytical themes of nature, time, and space. It develops a theoretical framework that combines Foucauldian governmentality analysis with concepts and insights related to nature, time and space developed in more-than-human and relational geographies and cognate social sciences. Drawing on three cases of tidal flat tourism, countryside walking, and whale tourism, it first examines the assemblages and technologies of ecotourism governance. It argues that ecotourism in South Korea is characterised by a decentralised mode of governance involving an array of political actors. This mode relies less on sovereign power and more on disciplinary and biopolitical techniques. Second, it examines the ways in which political technologies relating to nature, time, and space are engaged in the governmentalities of South Korean ecotourism. The analysis centres on: understandings of nature enacted through the discourse of saengmyeong [life] and therapeutic experiences; a discourse of slowness enacted through a paradoxical temporal organisation of accelerated slowness; and the multiple spatial relations entangled in the geographical-historical connections of South Korean modernisation. Together, these political technologies are deployed to create an ecotourism subject who cares about the self and the environment, which differs from the prevalent South Korean positions of the disciplined worker and the practical user of nature. This thesis argues that ecotourism in South Korea serves as a new biopolitical intervention to conduct the conduct of its human participants in ways that differ from those established through accelerated modernisation. By offering one of the first social science accounts of ecotourism in South Korea, it provides novel concepts and practices for the analysis of ecotourism. These differ from the mainstream approaches that deploy a political economy framework and focus largely on examples drawn from Sub-Saharan Africa, Latin America and Southeast Asia.

Keywords: Environmental politics
Governmentality
Human-nonhuman relationships
Advisor: Lorimer, J
The evolutionary dynamics of endogenous retroviruses

This thesis studies the evolution, influence, and proliferation of endogenous retroviruses (ERVs) within animal genomes. First, a simple mathematical model is constructed to address the question of whether retroviral endogenizations occur most often in male or female hosts. The result of applying the model to a diversity of genomes suggests that there may be female risk factors to endogenization, or that selection may be acting on full-length ERVs. Second, a study of the divergence of orthologous full-length ERVs from human and chimpanzee is performed. It is found that highly transcribed members of the HERV-H family have been under directional selection in the last six million years. Third, the insertion and deletion activity of the largest ERV families in five primate species is studied. Using a phylogenetic model it is demonstrated that ERVs are likely to be deleted early if they are to be deleted at all. Notably, it is also shown that HERV-H is an outlier family that is unusually slowly deleted. Fourth, the HERV-H loci in the human genome are studied on an individual basis. It is found that the long terminal repeats of HERV-H affect the magnitude and specificity of its transcription. Surprisingly, a region of the retroviral gag gene is positively associated with transcription and it is argued that this association is a partial explanation for the preferential maintenance of HERV-H in a full-length form. In conclusion, it is argued that researchers should take seriously the notion that many ERVs have not drifted to fixation. It is also argued that taking account of solo-LTR formation is important to accurately assessing the historical activity of ERVs. Finally, it is hypothesised that the application of bioinformatics techniques like those developed in this thesis may be sufficient to identify exaptation events in species quite distant from the primates that are studied here.

Advisor: Katzourakis, A
Hein, J
The revival of Sphoṭa in early modern Benares: Śeṣakṛṣṇa's Sphoṭatattvanirūpaṇa

This thesis examines the revival of the sphoṭa doctrine in early modern Benares and &Sacute;eṣakṛṣṇa's Sphoṭatattvanir&umacr;paṇa as an influential work in that revival. The sphoṭa doctrine is the richest contribution of the grammarians to the philosophy of language, but its semantic significance was not highlighted until late, because its theological implication was stronger. &Sacute;eṣakṛṣṇa was a renowned Sanskrit grammarian who flourished in sixteenth-century Benares. He also wrote poetry and Dharma&sacute;āstric works, and played an important role as a juridical authority. Despite his illustrious career, &Sacute;eṣakṛṣṇa encountered criticism for his works from contemporary critics. The only work he wrote solely on the philosophy of language was the Sphoṭatattvanir&umacr;paṇa. As the first discrete work on sphoṭa by a grammarian, the Sphoṭatattvanir&umacr;paṇa represented an important landmark in the later expositions of the doctrine of sphoṭa particularly because it renewed the later grammarians' interest in sphoṭa, which then resulted in a series of individual works of a similar sort. The revival of the sphoṭa doctrine in early modern Benares coincided with that of the philosophy of language, which was caused by a number of social and intellectual factors in different proportions and phases. &Sacute;eṣakṛṣṇa's Sphoṭatattvanir&umacr;paṇa emerged on the eve of that revival, and can be recognized as a pioneer work in terms of its revitalization of the grammarians' interpretation of sphoṭa after a period of dormancy, and its influence on later works on sphoṭa.

Keywords: Śeṣakṛṣṇa
Sphotatattvanirupana
Sphota
Sphoṭa
Sesakrsna
Sphoṭatattvanirūpaṇa
Early Modern India
Advisor: Benson, J
Rational Cherednik algebras and link invariants

Motivated by homological mirror symmetry, Smith and Thomas tried to construct a link invariant considering the derived category of coherent sheaves on the Hilbert scheme of n points on the minimal resolution of the Klenian singularity of type A, and an object ℒ(n) thereof. The braid group acts on this category by spherical twists, so one obtains a braid invariant by taking the Ext between ℒ(n) and its image under the braid group action. Smith and Thomas proved that taking the plat closure of the braid, this cohomology does not produce a link invariant but is close to doing so, and they conjectured that, in order to fix the one knot relation that is not satisfied, one has to consider a deformation of the Hilbert scheme.
In this thesis, we give a non-commutative approach to this problem: the commutative picture can be quantised by considering modules for the rational Cherednik algebra of cyclotomic type. This algebra gives a quantisation of the Hilbert scheme and there is a localisation theorem which allows one to work in the algebraic setting. In this context, the role of ℒ(n) turns out to be played by a certain module for the rational Cherednik algebra which we define for k=0. We then show that this module deforms to non-zero values of k. There is an action of the braid group on the derived category of category 𝒪 by twisting functors, which is defined at all deformation parameters, whereas the existence of the action on deformed Hilbert schemes in the commutative setting has not been rigorously established. We prove the analogue of the Smith-Thomas theorem, and conjecture that the braid invariant given by the algebraic analogue of the Smith-Thomas construction yields a link invariant for certain non-zero values of the deformation parameter.

Keywords: Non-commutative resolutions
Knot theory
Symplectic reflection algebras
Quantisation
Rational Cherednik algebras
D-modules
Advisor: Mcgerty, K