VictorJuiz/thesis huggingface dataset:
Investigating the interplay between cellular mechanics and decision-making in the C. elegans germ line

The behaviour of individual cells must be carefully coordinated across a tissue to achieve correct function. In particular, proliferation and differentiation decisions must be precisely regulated throughout development, tissue maintenance, and repair. A better understanding of how these processes are controlled would have implications for human health; cancer is, after all, dysregulated proliferation, while regenerative medicine relies on being able to influence cell decisions accurately. To investigate such fundamental biological processes, it is common practice to use an experimentally tractable model organism. Here, we focus on the germ line of the nematode worm C. elegans, which provides opportunities to study organogenesis, tissue maintenance, and ageing effects. Despite the advantages of this organism as a biological model, certain questions about germ cell behaviour and coordination remain challenging to address in the lab. There is therefore a need for computational models of the germ line to complement experimental approaches.
In this thesis, we develop a new in silico model of the C. elegans germ line. Novel aspects include working in three dimensions, covering the late larval period, and integrating a logical model of germ cell behaviour into a wider cell mechanics simulation. Our model produces a reasonable fit to wild-type germline behaviour, and provides the first cell tracking and labelling predictions for the larval period. It also suggests two new biological hypotheses: 1) that “stretching” growth plays a significant role in gonadogenesis, and 2) that a feedback mechanism acts on the germ cell cycle to prevent overproliferation. Having introduced the full model, we address some technical questions arising from our work, namely: what is the effect of applying a more physically realistic force law?; and can simulation performance be improved by changing the numerical scheme? Finally, we use in silico modelling to compare a number of hypothesised germ line maintenance mechanisms. There, our results support a model with functionally equivalent germ cells undergoing at most infrequent, transient cell cycle arrests.

Keywords: stem cell
C. elegans
cell based modelling
numerical methods
simulation
Advisor: Baker, R
Gavaghan, D
Dunn, S
Osborne, J
Kugler, H
Characterisation of the development of cardiac lymphatic vessels and their response to myocardial infarction

The lymphatic vasculature is a blind-ended network, present in all mammals, which is responsible for immune surveillance, tissue fluid regulation and absorption of lipid-containing chylomicrons into the gut. During pathological conditions lymphatic vessels expand via the process of lymphangiogenesis in order to aid the clearance of inflammation and interstitial fluid. The systemic lymphatic vasculature begins to develop in the mouse embryo around E9-9.5. This process is initiated at three venous sites within the embryo where lymphatic endothelial cells (LECs) migrate away from veins to form lymphatic structures. Since the 17th century it has been known that the lymphatic vasculature is present in the heart, however, until recently little was known regarding its developmental origins or its function during cardiovascular disease. The aims of this thesis were to characterise the development of cardiac lymphatic vessels and their response to adult heart injury, as a means to identify whether the lymphatics reactivate embryonic programs during pathological insult and to establish a potential basis for future therapeutic targeting towards improved repair.
I have characterised the spatiotemporal development of the murine cardiac lymphatics and have performed lineage tracing to determine their cellular origins. This revealed that cardiac LECs are not solely derived from veins, which was confirmed by analysis of conditional PROX1 knockout mouse hearts. Collectively these data refute the previous dogma that all lymphatic vessels are venous-derived. I have also performed studies to assess the roles of lymphatic vessels following myocardial infarction (MI). This revealed that expression of the pro-lymphangiogenic growth factor VEGF-C is reactivated in the heart post-MI, driving cardiac lymphangiogenesis. Treatment with additional recombinant VEGF-C further enhanced the lymphangiogenic response and resulted in improvements in cardiac function. Furthermore, VEGF-C treatment resulted in reduced numbers of macrophages within the heart by day 7 post-MI. This suggests that enhancing lymphangiogenesis leads to increased clearance of the post-MI inflammatory cells, which may modulate levels of inflammation and fibrosis, resulting in an improved outcome. I have also utilised genetic mouse models (LYVE-1 knock-out and PROX1 heterozygous lines) with defects in their lymphatic vasculature. Following MI in LYVE-1 knockout animals, where transmigration of leucocytes into lymphatic vessels is impaired, neutrophils and macrophages were found to accumulate within the heart at day 7 post-injury. Together these data demonstrate that therapeutic targeting of the cardiac lymphatic vasculature may have a significant impact on the resolution of inflammation and the post-MI healing process.

Advisor: Riley, P
Manifestations of the dead: investigating ghost encounters among the Tsachila of western Ecuador

Focusing on the Tsachila, Amerindians of western Ecuador, this thesis examines how competing "common knowledge" accounts of the afterlife (conventional Tsachi, Catholic, and Protestant) are related to experiences of encounters with ghosts. Inspired by conversation analysis it advocates the study of these encounters through close attention to how accounts of them are constructed in conversation, from which they emerge as inherently disruptive and resistant to any definitive interpretation. From this starting point a descriptive account is given of the ways in which these anomalous experiences form the background to everyday life among the Tsachila. Experiential associations are identified linking ghosts with the circadian patterns of sound, light and sociality. Next the thesis examines and compares a selection of myths depicting the dead and animals and it is shown that the boundaries between myth and everyday life and between the living and the dead are uncertain and subject to revision in the light of experience. They cannot be taken for granted but must be constantly reinforced. An example of such reinforcement is provided by the Tsachi celebration of the Catholic Day of the Dead, and it is shown how this intersects with and is inflected by Tsachi attitudes to the dead and their disposal. In the final chapter a selection of accounts of personal encounters with ghosts is examined to reveal ways in which the common knowledge previously discussed is shaped, deployed and contested in the context of these accounts. It is suggested, in conclusion, that personal experience of this kind cannot be treated as simply a cultural expression, but that it exerts a motivating and disruptive force on thought and action.

Advisor: Hsu, E
Ewart, E
The role of CD1a and phospholipase A2 in psoriasis

Psoriasis is a chronic inflammatory skin disease associated with a T helper 17 (Th17) response, yet it has proved challenging to identify relevant peptide-based T cell antigens. Langerhans cells show a differential migration phenotype in psoriatic lesions and express constitutively high levels of CD1a, which presents lipid antigens to T cells. In addition, phospholipase A2 (PLA2) is highly expressed in psoriatic lesions and is known to generate neolipid skin antigens for recognition by CD1a-reactive T cells. Here we observed expression of a cytosolic PLA2 (PLA2G4D) in mast cells in psoriatic lesions but not in healthy skin, but unexpectedly also found the PLA2G4D activity to be extracellular. This could be explained by IFN-α-induced mast cell release of exosomes, which transferred cytosolic PLA2 activity to neighbouring CD1a-expressing cells. This led to the generation of neolipid antigens and subsequent recognition by lipid specific CD1a-reactive T cells inducing production of IL-22 and IL-17. Circulating and skin-resident T cells from patients with psoriasis showed elevated PLA2G4D responsiveness compared to healthy controls. Overall these data present an alternative model of psoriasis pathogenesis in which unconventional lipid-specific CD1a-reactive T cells contribute to psoriatic inflammation. The findings suggest that PLA2 inhibition may have therapeutic potential for psoriasis.

Advisor: Ogg, G
Joyce after Nietzsche: irony and the will to truth

This thesis explores and evaluates the work of James Joyce using the ideas of Friedrich Nietzsche. It does so not only by examining Joyce's knowledge of Nietzsche's writings, but also through demonstrating how effectively they can illuminate Joyce’s themes and techniques, and aid in a general reconceptualisation of his literary project.
My analysis draws on several of Nietzsche's key concepts – perspectivism, ressentiment, the will to power – and applies them to Joyce’s work. The main idea I use however is the will to truth. I argue that Joyce's primary concern as an artist was the depiction of what he saw as the truth of contemporary existence, in Dublin and more generally. This aim determines his techn&emacr;, the origin and form of his work of art. Various manifestations of irony, a key element of Joyce's technique, help illustrate the importance of this will to truth. This understanding of his work eliminates the false division between form and content and through an emphasis on Joyce's artistry and philosophy, rather than the historical context in which he wrote (that is, on the author rather than the man), allows for a truly critical assessment.
The five chapters that follow my introduction are chronologically ordered. They examine the early works, Dubliners, A Portrait of the Artist as a Young Man, and especially Ulysses, in considerable detail and from various angles. Though careful to respect the individuality of each, my analyses find a common thread of realism uniting the three major works of prose fiction; beginning with the French naturalism of the short stories, moving on to a new development of perspectival irony and a unique mode of allegory in his first novel, and ending in what Joyce called 'the new realism' of his epic. My study then explains how and why realism is problematised in the later chapters of Ulysses as the will to truth comes to question itself. The thesis concludes with an assessment of Finnegans Wake, considering how it marks a radical departure from Joyce’s earlier practice, and why I regard it a failure.

Advisor: O’Donoghue, B
The linguistic elements of Old Germanic metre: phonology, metrical theory, and the development of alliterative verse

I examine those linguistic features of Old English and Old Norse which serve as the basic elements for the metrical systems of those languages. I begin with a critical survey of recent work on Old English metrical theory in chapter 1, which suggests that the four-position and word-foot theories of metre are the most viable current frameworks. A further conclusion of this chapter is that stress is not, as is often claimed, a core element of the metre. In chapter 2, I reassess the phonological-metrical phenomenon of Kaluza's law, which I find to be much more regular and widely applicable within B&emacr;owulf than has previously been recognized. I further argue that the law provides evidence that Old English phonological foot structure is based on a preference for precise bimoraism. In chapter 3, I examine the role of syllables in the Norse Eddic metre fornyrðislag, which supports a view of resolution and phonological feet similar to that found in Old English, though Norse prosody is much more tolerant of degenerate, light feet. I reconsider the other major Eddic metre, ljóðaháttr, in chapter 4, integrating the insights of Andreas Heusler and Geoffrey Russom to propose a new system of scansion for this notoriously recalcitrant verse form. This scansion provides important support for the word-foot theory, and suggests that linguistic elements larger than syllables or phonological feet play a crucial role in early Germanic verse. In the final chapter, I give a diachronic account of Germanic metre and relevant linguistic structures, arguing that the word-foot theory provides the best metrical framework for understanding the development of Germanic alliterative verse. This metrical system is linguistically supported by Germanic word structures and compounding rules, and interacts with bimoraic phonological feet, all of which have a long history in Proto- and pre-Germanic.

Keywords: Alliterative verse
Beowulf
Phonology
Resolution
Metrics
Syllabification
Fornyrðislag
Edda
Ljóðaháttr
Kaluza's law
Proto-Germanic
Advisor: Lahiri, A
Social deprivation and criminal punishment

My aim in this thesis is to examine whether there are some mitigating factors, i.e. reasons to punish an offender less for his crime than an otherwise similar offender (other than that the offender suffered from mental disorder or disturbance or other forms of irrationality at the time of offence), that are more applicable to socially deprived offenders than to non-socially deprived offenders. I will answer the thesis question through a critical examination of twelve arguments for claiming that there is a mitigating factor that is more applicable to socially deprived offenders, each proposing a different mitigating factor.
My conclusions are as follows:
(1) Most of the arguments that I examine fail, i.e. they either fail to highlight a genuine mitigating factor, or we do not have much evidence that the mitigating factor highlighted by the argument has a greater applicability to socially deprived offenders than to non-socially deprived offenders.
(2) However, one argument, which can be called the no violation of natural duties argument, is successful.
(3) Moreover, the improvement of the worst off argument, an argument that is not often discussed in the literature, is particularly noteworthy. If my discussion about that argument is correct, then even if, as I will argue, the mitigating factor highlighted by that argument may not be more applicable to socially deprived offenders than to non-socially deprived offenders, the remaining parts of that argument would still have profound influence on punishment in our unjust societies.

Advisor: Gardner, J
McDermott, D
Enhancement and mapping of ultrasonic drug release from thermosensitive liposomes by acoustic cavitation

One of the major limiting factors of cancer therapy is the inability to deliver a sufficient dose of drugs to a target tumour without incurring significant side effects. Recent advances in nano-sized liposome formulations have enabled encapsulation of anti-cancer agents that simultaneously reduce off-target toxicity and allow increased accumulation in tumours due to the enhanced permeability and retention effect. Yet, a method for reliably releasing the drug from encapsulation has yet to be found. In this work, low-temperature sensitive liposomes, which release an encapsulated anti-cancer agent (doxorubicin) in the temperature range of 39-45±C, are combined with focused ultrasound-induced mild hyperthermia to deliver a predictable, site-specific, and high dose of anti-cancer agents that has the potential of overcoming the current limitations of targeted drug delivery for cancer.
To reach this aim, acoustic cavitation-enhanced heating was harnessed to produce rapid and efficient temperature rises that could be spatiotemporally monitored and eventually controlled. For this purpose, a reproducible, non-exothermic, cell-embedding tissue-mimicking model was first developed to have an attenuation coefficient, thermal response and cavitation threshold similar to liver. The phantom platform was then utilised to allow for high-throughput optimisation of ultrasound exposure parameters that efficiently and safely produced mild hyperthermia and drug release. Inertial cavitation-enhanced heating was successfully shown to enhance drug release from the liposomes and subsequent cancer cell death due to release of the encapsulated agents, using a 25% Duty Cycle, 1Hz PRF 6 s sonication sequence. The remotely detectable acoustic emissions associated with cavitation were then exploited to enable real-time monitoring and spatial mapping of drug release using a novel passive acoustic mapping method. Finally, these developments and techniques were combined to demonstrate the feasibility of cavitation enhanced drug release and delivery in a world-unique isolated normothermic liver perfusion model that provides blood-flow rates comparable to those encountered in humans.

Advisor: Coussios, C
Learning via automaton minimization and matrix factorization

This thesis focuses on weighted-automaton learning and minimization, matrix factorization, and the relationships between these areas.
The first part of the thesis studies minimization and learning of weighted automata with weights in a field, focusing on tree automata as representations of distributions over trees. We give a minimization algorithm that runs in polynomial time assuming unit-cost arithmetic, and show that a polynomial bound in the Turing model would require a breakthrough in the complexity of polynomial identity testing. We also improve the complexity of minimizing weighted word automata. Secondly, we look at learning minimal weighted automata in both active and passive learning frameworks, analysing both the computational and query complexity. For active learning, we give a new algorithm for learning weighted tree automata in Angluin's exact learning model that efficiently processes DAG counterexamples, and show a complexity lower bound in terms of polynomial identity testing. For passive learning, we characterise the complexity of finding a minimal weighted automaton that is consistent with a set of observations.
The second part of the thesis studies nonnegative matrix factorization (NMF), a powerful dimension-reduction and feature-extraction technique with numerous applications in machine learning and other scientific disciplines. Despite being an important technique in practice, there are a number of open questions about the theory of NMF---especially about its complexity and the existence of good heuristics. We answer a major open problem posed in 1993 by Cohen and Rothblum: the nonnegative ranks over the rationals and over the reals differ. We first tackle a variant of the problem, restricted NMF, which has applications in topic modelling and a geometric interpretation as the nested polytope problem. Lastly we show that NMF is polynomial-time reducible to automaton minimization, and then use our results on NMF to answer old open problems on minimizing labelled Markov chains and probabilistic automata.

Advisor: Worrell, J
Kiefer, S
Benedikt, M
Total synthesis and stereochemical reassignment of dehydromicrosclerodermin B and microsclerodermin J

This thesis describes research towards the total synthesis of two marine natural products, dehydromicrosclerodermin B and microsclerodermin J. The synthesis of the most complex subunit of these peptides, AMMTD, was accomplished in a longest linear sequence of 21 steps starting from (S)-Roche ester. Preliminary results conducted by other group members were improved; the key cuprate displacement reaction and the final steps of the synthetic sequence were developed. Subsequently, AMMTD-GABOB dipeptide was synthesised and coupled with the northern hemisphere. An appropriate protecting group strategy was developed such that macrolactamisation and subsequent protecting group removal could be achieved. This required the design of a new approach to the synthesis of the tryptophan-2-carboxylic acid. An "end-game" strategy, which had previously been developed on model substrates, failed on late-stage cyclic or linear hexapeptides. Because of this, studies turned to the completion of a synthesis of dehydromicrosclerodermin B. Comparison of the data for synthetic and natural dehydromicrosclerodermin B revealed a mistake in the assignment of the (45S)-configuration. The corresponding (45R)-epimer was synthesised and its data were in a good agreement with those of dehydromicrosclerodermin B. Based on the reassignment of the C45 stereocentre of dehydromicrosclerodermin B, the total synthesis of microsclerodermin J containing a reassigned (R)-configured pyrrolidinone unit was accomplished. NMR data for synthetic and natural microsclerodermin J were in complete agreement, confirming that the initial stereochemical assignment of this natural product was incorrect.

Advisor: Donohoe, T
Ultrafast indoor optical wireless communications

Traffic from wireless and mobile devices is predicted to increase 10-fold between 2014 and 2019, surpassing wired data traffic by 2016. Given the expected radio frequency (RF) capacity crunch, this growing wireless demand will have to be met using a variety of new technologies exploiting other parts of the electromagnetic spectrum. Promising research areas include the Millimetre Band as well as Optical Wireless Communications (OWC).
Millimetre Band demonstrations have accomplished ultrafast multi-Gigabit links, making use of state-of-the-art fibre transmission systems. However, complex opto-electronic (OE) interfaces are required to convert the optical carrier into Millimetre wireless signals. To avoid these interfaces, an all-optical transparent network is proposed here, spanning over both the fibre and OWC domains, in order to deliver ultrahigh data rates to mobile end-users in indoor environments. This is supported by the recent deployment of fibre-to-the-home (FTTH) networks creating the potential for Terabit aggregate connections at the user’s doorstep.
Therefore, infrared fibre-wireless-fibre (FWF) links are studied to support data rates over 100 Gb/s in nomadic applications. The link coverage is achieved via narrow beam beamsteering over a wide field-of-view (FOV) using suitable localization and tracking techniques. The proposed model is inherently bidirectional and transparent, i.e. independent of the data rate and modulation format.
In this thesis, the potential for ultrafast wide coverage OWCs using SMF-based transceivers and coherent transmission is demonstrated. A record data rate of 418 Gb/s and 209 Gb/s with a wide FOV of θFOV=±30° and θFOV=±20°, respectively, is shown at a free space range of 3 m. To the best of our knowledge, this is the fastest demonstration of an indoor wireless link that offers practical room-scale coverage. The automated alignment of this FWF link is also demonstrated with the design and implementation a mm-accurate localization and tracking system. Finally, architectures for point-to-multipoint communications are explored in order to adapt the system to multiple users.

Keywords: Beamsteering
Optical Wireless Communications
Ultrafast wireless communications
Adaptive optics
Localization and tracking systems
indoor wireless coverage
Spatial Light Modulators
Advisor: O’Brien, D