VictorJuiz/thesis huggingface dataset:
Exploiting sulfinylamines in synthesis

In the following thesis, new methodologies which exploit sulfinylamine reagents to enable one-pot syntheses of a range of nitrogen-containing sulfur(VI) functional groups are documented. The union of sulfinylamines with widely available organometallic reagents and amines allows the rapid construction of complex, medicinally relevant sulfoximine, sulfonimidamide and primary sulfonamide products.
Chapter 1 is a literature review covering the properties, applications and synthesis of sulfonimidamides and sulfoximines.
Chapter 2 describes the development of a new strategy for the preparation of sulfonimidamides. A remarkably stable sulfinylamine reagent, N-sulfinyltritylamine (TrNSO), is identified and used in a one-pot, three component synthesis of N-H sulfonimidamides. Analogues of the anti-arthritis drug Celecoxib are prepared using the method and subjected to biological assays by collaborators at UCB Biopharma.
Chapter 3 documents the discovery of a new class of sulfinylamines, O-aryl-Nsulfinylhydroxylamines, that enable the preparation of sulfoximines by the sequential addition of two Grignard reagents, or sulfonimidamides by the sequential addition of a Grignard reagent and an amine. Two possible mechanistic pathways are discussed and evaluated.
Chapter 4 details the serendipitous discovery of a one-pot synthesis of primary sulfonamides from the novel reagent O-tert-butyl-N-sulfinylhydroxylamine. Preliminary mechanistic studies are presented.
Chapter 5 discusses the conclusion of the research and the potential for future work.
Chapter 6 presents the experimental data.

Advisor: Willis, M
The Oseen-Frank theory of liquid crystals

This thesis concerns the minimization of the Oseen-Frank bulk free energy. The structure is as following: in Chapter 1, we will give a brief introduction to the Oseen-Frank theory and the Landau-de Gennes theory. Also we will introduce some established results related to the two theories. In Chapter 2, we define first in Section 2.1 the degree for a vector field n ∈ H1/2(𝕊1; 𝕊1); and then in Section 2.2 the degree for an H1/2 vector field from a Lipschitz boundary ∂w to 𝕊1: In Section 2.3, we prove the fact that vector fields subject to some given boundary conditions and degree constraints in a given exterior N-connected domain can be written explicitly, and the result is stated in Proposition 2.3.6. We began in Chapter 3 by focusing on the existence and uniqueness of minimizers for a modified one-constant Oseen-Frank energy subject to some prescribed boundary conditions in a 2D circular domain Ω = {x ∈ &Ropf;2 | 0 < a < |x| < ∞} and derive some ‘nice’ asymptotic behaviour at ∞ of the minimizer. In Chapter 4, we make the problem studied in Chapter 3 more complicated by adding more ‘holes’ in the domain. Then by introducing the homotopy classes for vector fields subject to prescribed boundary conditions, we prove that there exists a unique minimizer for a modified oneconstant Oseen-Frank energy in each homotopy class and we still have the ‘nice’ asymptotic behaviour of the minimizer in each homotopy class. Also, there exists a minimizer in the union of these homotopy classes, although this minimizer may not be unique. Then in Chapter 5, we work with line fields on the boundary in the given exterior N-connected Lipschitz domain. By introducing an auxiliary vector field and modifying the definition of homotopy classes in Chapter 4, we prove the uniqueness of the minimizing line field in each homotopy class. Also the result proved in Chapter 5 applies to both orientable and non-orientable line fields on the boundaries, and when the given boundary line field is orientable, it is equivalent to our result proved in Chapter 4. Finally, in Chapter 6, we study the 2D non-equal constant case (i.e. without assuming k1 = k2 = k3, and k4 = 0) in a one-circular domain. In particular, in Section 6.1 we assume the vector fields are radius-independent and derive the minimizers to the Oseen-Frank bulk free energy subject to prescribed degree constraint on the circular boundary. Then in Section 6.2 we show that the result proved in Section 6.1 will also hold when one of the Frank elastic constant is zero (degenerate case), but will be in a different function space W1,1(Ω;𝕊1). At last in Section 6.3 we will show that the minimizers derived in Section 6.1 and Section 6.2 are in general not minimizers for the radius-dependent case.

Keywords: Line field models
Liquid Crystal
Oseen-Frank
Homotopy Classes
Advisor: Ball, J
Objects from motion

This thesis tackles the challenge of learning the abstract structure of object categories without manual supervision. We show that we can learn useful representations based on the motion of objects in videos and even from collections of static images through the use of synthetic warps. An important contribution of this work is the notion of an Object Frame, an object-centric frame of reference which can be learned from motion. Objects that appear in images can be affected by complex nuisance factors such as viewpoint changes and deformations, yet our method manages to factorize out these variations and semantically map objects to a common coordinate frame. Importantly, this mapping also works across different object instances despite only being trained on instance-specific correspondences. Two implementations of the Object Frame idea are presented. The first learns a sparse, landmark-based representation of structure, simultaneously discovering which landmarks are useful and learning to predict their locations consistently across instances. The second is a dense approach which maps image pixels to a canonical spherical coordinate frame in a semantically consistent manner. We show that the latter formulation has applications in discovering the symmetries of deformable objects, and also explore the relationship between our Object Frame and generic, higher dimensional feature descriptors. We also present a trainable method to compute dense matches, and a state of the art self-supervised learning method using optical flow similarity to compute pixel embeddings.

Advisor: Vedaldi, A
The protective function of the oxidation resistance 1 gene in ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by the selective degeneration of motor neurons in the brain and spinal cord, resulting in muscle wasting, paralysis and eventually death usually within 2-5 years of symptom onset. Despite decades of intense research to ultimately find a cure, there are still only a few treatments available to patients, none of which are effective in slowing disease progression. Therefore, novel therapeutic strategies will be increasingly important to alleviate this health burden. While the underlying pathogenic mechanisms remain unclear, increasing evidence suggests that oxidative stress (OS) is a key contributory factor early in ALS pathology. Therefore, understanding the role of proteins involved in antioxidant defence networks will facilitate the development of new therapeutic approaches. Oxidation resistance 1 (OXR1) has emerged as an essential antioxidant protein that regulates neuronal survival in response to OS, however its precise molecular functions remain unclear.
Thus, the overall aim of this thesis was to investigate the neuroprotective function of Oxr1 in motor neurons, particularly focusing on its role in modulating disease-relevant phenotypes observed in ALS. To ascertain the importance of Oxr1 to motor neuron function and survival, mice in which Oxr1 was conditionally deleted in motor neurons were behaviourally and pathologically characterised. My data indicates that loss of Oxr1 specifically in motor neurons does not increase their susceptibility to degeneration or cause motor dysfunction in aged mice, but can induce a local neuroinflammatory response in the spinal cord. Next, to investigate the neuroprotective function of Oxr1 in ALS caused by mutations in TAR DNA-binding protein 43 (TDP-43), longitudinal behavioural and pathological analysis was carried out on a novel mutant TDP-43 mouse model of ALS in the presence or absence of increased Oxr1 expression. I demonstrate that neuronal overexpression of Oxr1 protects against motor dysfunction and neuromuscular defects in TDP-43 mutant mice. Furthermore, using primary motor neurons from TDP-43 mutant mice, I show that overexpression of Oxr1 can reduce the mislocalisation of TDP-43 protein, which is a characteristic feature in more than 95% of ALS cases. Finally, in order to begin to determine whether endogenous Oxr1 expression can be manipulated as a therapeutic strategy, I investigated its transcriptional regulation by characterizing Oxr1 promoter regions. I identified a highly conserved functional promoter region of Oxr1 that was subsequently used in establishing a new cell-based luciferase reporter assay that can be employed to identify compounds that upregulate Oxr1. Taken together, these studies deepen our understanding of Oxr1 as a neuroprotective antioxidant protein and offers new insights into its potential use as a future therapeutic target for the treatment of ALS.

Advisor: Davies, K
Oliver, P
Investigating the role of RAD51 phosphorylation during the cell cycle

The RAD51 recombinase safeguards genomic integrity by promoting double-strand break repair and replication fork protection. PLK1-dependent RAD51 phosphorylation contributes to RAD51 recruitment at DNA double strand breaks and stalled replication forks. During an unperturbed cell cycle, RAD51 phosphorylation peaks in late G2 phase and mitosis, suggesting a role for (phosphorylated) RAD51 during the later stages of the cell cycle.
In this thesis, CRISPR/Cas9 RAD51 phospho-mutants were generated to assess the importance of RAD51 phosphorylation during the cell cycle. Consistent with previous research, I present data which suggest that RAD51 phosphorylation contributes to RAD51 recruitment at stressed DNA. I further demonstrate that RAD51 phosphorylation protects against the detrimental consequences of replication stress and that RAD51 phosphorylation may influence replication rate and mitotic duration in unperturbed conditions.
I present evidence for the role of RAD51 in mitotic DNA synthesis (MiDAS), as well as the contribution of RAD51 phosphorylation in this process. Based on the data presented here, I hypothesize that RAD51 phosphorylation enables the recruitment of RAD51 to mitotic chromatin to promote MiDAS. Break-dependent and break-independent mechanisms of MiDAS are proposed and the potential roles of RAD51 are discussed in each. The interplay between MiDAS and mitotic duration is explored. Anaphase onset is found to be delayed upon RAD51 inhibition, while polymerase inhibition decreases mitotic duration. A model is proposed in which the presence of mitotic DNA breaks and active replication intermediates in mitosis prevent SAC silencing, thereby ensuring enough time for the completion of replication prior to anaphase.

Advisor: Esashi, F
Systematic studies of the sweet potato and its wild relatives

Phylogenetic studies on the genus Ipomoea, and specifically on the species closely related to the sweet potato, have been hindered by limited taxon and character sampling. Any study that aims to investigate the phylogenetic relationships within a megadiverse genus such as Ipomoea, with an estimated 800 species, must rely on a comprehensive data set that covers as much diversity as possible, in order to provide accurate and robust phylogenetic inference.
In this thesis, I present a comprehensive phylogenetic study of the genus Ipomoea and of the group of species closely related to the sweet potato using genomic-scale data. The aim of this study was to provide a phylogenetic framework with which to understand the diversity existing within the genus and to inform taxonomic decisions. The phylogenies presented here identify several recurrent patterns in the evolution of Ipomoea, for instance the multiple origin of storage roots and the existence of multiple episodes of long-distance dispersal by natural means.
I also address several questions pertaining to the sweet potato that have been a matter of debate for decades but remained unanswered until recently. Our genome-scale data facilitated comprehensive phylogenies for all wild species that are most closely related to the sweet potato. Our phylogenies resolve that sweet potato is monophyletic and had a single origin, as well as identified the wild species that is its closest relative: Ipomoea trifida, with all other extant species more distantly related. In addition, our studies corroborate the existence of two sweet potato chloroplast lineages and infer that one of them resulted from a hybridisation between sweet potato and I. trifida following species divergence.
Finally, I also address a question that has been of interest for over two centuries: the presence of the sweet potato, an American crop, in Polynesia in pre-European times.

Keywords: sweet potato
systematics
morning glories
crop wild relatives
Ipomoea
phylogenetics
Polynesia
Advisor: Scotland, R
Development of a portable laser-cooled ytterbium ion microwave atomic clock

Portable microwave clocks that incorporate laser cooling promise to bring significantly improved performance compared to commercially available microwave clocks that are based on thermal atoms. This thesis reports on the development of a portable, laser-cooled ytterbium-171 trapped-ion microwave frequency standard from design to testing.

Keywords: ytterbium
Advisor: Baird, P
Gill, P
Rethinking thirteenth-century Byzantine historiography: a postmodern, narrativist, and narratological approach

In the study of thirteenth-century Byzantium, historiography (made up of linguistic, narrative, and ideological texts) and the past (constituted of things that happened before now) have been conflated. This conflation has proved highly problematic for the study of Byzantine historiography by modern scholars. To explain and describe the period between 1204 and 1261, modern historians have constructed a historiographical narrative that purports to present what happened in the past. This narrative, which I call the Nikaian narrative, constructs a simplistic and teleological story of ‘Byzantine reconquest’ that amongst other things privileges the so-called Nikaian ‘empire’, which conquered Constantinople in 1261. This modern narrative is founded on a problematic reading of the Chronike syngraphe of George Akropolites, a historiographical text, which has dominated the construction of the period.
In this thesis I deconstruct the Nikaian narrative, through the use of various postmodern, narrativist, and narratological tools. In the first three chapters, I deconstruct this narrative, at the macro-level of narrative (and metanarrative), and at the meso-levels of events and characters, exploring the construction five battle-events that structure the Nikaian narrative and the characters to which it attributes agency. In the fourth and final chapter, I extend the argument of the first three chapters to the micro-level through a case study drawn from four narrative historiographical texts, which have been assumed to narrate the ‘same events’ in the thirteenth-century past. I demonstrate the limitations of an approach to these texts focused on the ‘reconstruction’ of the past, offering instead an analysis of these texts based on their relationships to each other, not as ‘sources’ but as texts.

Advisor: Holmes, C
The construction and validation of the primary scientific reasoning test

A major task of science education is to foster scientific reasoning. Despite extensive research, it is still unclear how best to assess this cognitive proficiency; a limited consensus of its nature has arguably constrained the development of classroom assessments of scientific reasoning. Therefore, this research aimed to develop a valid and reliable test of scientific reasoning – the Primary Scientific Reasoning Test (PSRT) – for primary-aged pupils. Developments in science education, as well as emerging and novel insights across substantive literature, formed the theoretical framework underlying the PSRT.
A mixed methodology was used to develop and validate the PSRT over four phases. The first phase developed the theoretical framework and the draft items. In the next phase, an 18-member expert panel from Singapore and England evaluated and endorsed the conceptual validity of the construct and the content validity of the draft items. The third phase field-tested and refined the draft instrument with 138 Year 7 pupils from four Singapore secondary schools. In the fourth and last phase, 431 Year 6 pupils from six Singapore primary schools attempted the finalised 100-item PSRT. Results from psychometric analysis using Rasch modelling supported inferences of a unidimensional construct underlying the test, and examination of the item difficulty estimates produced evidence that the order of difficulties generally accorded with the framework of scientific reasoning.
Given that the explanatory concepts in the framework generally explained the pupils’ performance and drawing on the strength and scope of other evidence, the thesis concludes that the PSRT displayed reasonably strong construct validity. This conclusion supports the use of PSRT as a valid and reliable measure of scientific reasoning for primary-aged pupils. The theoretical basis of the PSRT and its construction procedures also bear lessons for test developers and researchers. Overall, the study contributes clarification and understanding about the nature and assessment of scientific reasoning, particularly for primary-aged pupils.

Keywords: Scientific Reasoning
Test of Scientific Reasoning
Primary School Science
Scientific Thinking
Construct Validation
Advisor: Baird, J
McGrane, J
The evolution of Leszek Kołakowski’s religious thought

This thesis examines the entire work of the Polish philosopher Leszek Kołakowski (1927–2009), and argues that religious questions were at the heart of his thought from the very beginning of his intellectual career. Furthermore, it maintains that Kołakowski’s youthful engagement with Communism in Stalinist Poland, along with his later historical inquiries into various strands of modern philosophy were, in fact, phases in his development as a religious philosopher.
The thesis, which relies on a textual analysis of Kołakowski’s published and unpublished works, argues that the investigation of consecutive texts from the late 1940s to the late 1980s shows a gradual ‘evolution’ in Kołakowski’s attitude to religion – developing from a militant Stalinist to a conservative apologist for Christianity. To this effect, the thesis is structured chronologically. The methodology employed is that of ‘qualified contextualism’, which recognises the fundamental importance of historical context in investigating philosophical questions, yet acknowledges that traditional contextualism does not suffice in explaining the ideas from the past.
The entire intellectual trajectory of Kołakowski can be summarised as the quest for the most satisfactory formula for an Absolute being that not only serves as the source of ethical normativity but also endows human lives with a sense of meaningfulness. In his studies of secular philosophical systems, Kołakowski asserts that people cannot establish moral values for themselves and need a transcendent metaphysical reality. Although he was a sympathiser, Kołakowski never officially committed to any institutional form of religion. The apparent Christian synthesis between the concepts of a loving Person and an eternal Absolute seemed irreconcilable for him. It is on these grounds that this thesis concludes the mature Kołakowski can be called a religious thinker, but not a Christian thinker. ‘Kołakowski’s God’ is a being that is closer to the Neoplatonic Absolute, one that overcomes contingency of human life and makes it meaningful.

Keywords: Leszek Kołakowski
Leszek Kolakowski
Religious thought
Advisor: Ash, T
Zachhuber, J
Kunicki, M
Sex, signalling, and steroids: regulation of nuclear size and intracellular trafficking in secondary cells in the D. melanogaster male accessory gland

The fruit fly, Drosophila melanogaster, can be a useful in vivo model for understanding the biology of cells and the signalling pathways by which this biology is regulated. My Dissertation focuses on the accessory glands of male D. melanogaster, where two types of cells—main cells and secondary cells—are responsible for producing many seminal fluid proteins. The work presented in this Dissertation describes some of the aspects of secondary cell biology that are involved in controlling the growth and secretory activity of these cells.
Secondary cells are secretory cells, and they contain large intracellular compartments—some of which accumulate proteins destined for secretion. The BMP ligand, Decapentaplegic (Dpp), is one such protein, which can regulate secondary cell biology via an autocrine signalling mechanism. Previous work has shown that BMP signalling regulates a D. melanogaster steroid receptor—the ecdysone receptor (EcR)—to form a BMP/EcR signalling axis that controls secondary cell nuclear growth.
In this Dissertation, I show that the BMP/EcR signalling axis regulates the expression of the D. melanogaster initiator caspase, DRONC, and that this caspase and other related regulators control intracellular trafficking in secondary cells. I propose that this process might be orchestrated via non-apoptotic mobilisation of the cytoskeleton. In addition, I show that secondary cells produce the lipoprotein, Hedgehog, and that it is released into the seminal fluid. Like Dpp, Hedgehog seems to signal back into secondary cells to regulate their biology and nuclear growth. This growth is reduced when hedgehog (and its downstream signalling components) is knocked-down in secondary cells. Conversely, activating the Hedgehog-dependent transcription factor, Cubitus interruptus (Ci), promotes this growth. Like BMP signalling, autocrine Hedgehog signalling might play an important role in coordinating growth and secretion in secondary cells.
Previous studies have shown that secondary cell nuclei grow after mating. In an effort to understand how this growth is regulated, I identified the BMP/EcR signalling axis as a key regulator—alongside cell cycle regulators, like Cyclin D and Cyclin E. My work shows that secondary cell nuclei seem to grow after mating, partly as the result of BMP/EcR-dependent increases of the secondary cell DNA content—perhaps to increase the cells’ biosynthetic potential. This suggests that secondary cell nuclei can grow via two distinct mechanisms: one that is mating-dependent, and one that is not. Altogether, the work presented in this Dissertation describes important roles for steroid signalling and sexual activity in the regulation of secondary cell biology. This complex co-ordination of BMP- and steroid signalling might also be relevant to other organisms.

Keywords: nuclear growth
male accessory gland
steroid signalling
BMP signalling
Hedgehog signalling
Advisor: Wilson, C