VictorJuiz/thesis huggingface dataset:
An integrative framework for computational modelling of cardiac electromechanics in the mouse
Keywords: genetically modified mice
computational biology
electromechanics
cardiac modellling

This thesis describes the development of a framework for computational modelling of electromechanics in the mouse, with the purpose of being able to integrate cellular and tissue scale observations in the mouse and investigate physiological hypotheses. Specifically, the framework is applied to interpret electromechanical coupling mechanisms and the progression of heart failure in genetically modified mice.
Chapter 1 introduces the field of computational biology and provides context for the topics to be investigated.
Chapter 2 reviews the biological background and mathematical bases for electromechanical models, as well as their limitations.
In Chapter 3, a set of efficient computational methods for coupled cardiac electromechanics was developed. Among these are a modified Newton method combined with a solution predictor which achieves a 98% reduction in computational time for mechanics problems.
In Chapter 4, this computational framework is extended to a multiscale electromechanical model of the mouse. This electromechanical model includes our novel cardiac cellular contraction model for mice, which is able to reproduce murine contraction dynamics at body temperature and high pacing frequencies, and provides a novel explanation for the biphasic force-calcium relation seen in cardiac myocytes. Furthermore, our electromechanical model of the left ventricle of the mouse makes novel predictions on the importance of strong velocity-dependent coupling mechanisms in generating a plateau phase of ventricular pressure transients during ejection.
In Chapter 5, the framework was applied to investigate the progression of heart failure in genetically modified 'Serca2 knockout' mice, which have a major disruption in mechanisms governing calcium regulation in cardiac myocytes. Our modelling framework was instrumental in showing for the first time the incompatibility between previously measured cellular calcium transients and ventricular ejection. We were then able to integrate new experimental data collected in response to these observations to show the importance of beta-adrenergic stimulation in the progression of heart failure in these knockout mice.
Chapter 6 presents the conclusions and discusses possibilities for future work.
KDM2B links recognition of CpG islands to polycomb domain formation in vivo
Keywords: gene transcription regulation
chromatin biology
epigenetics

Mammalian genomes are characterised by global and pervasive DNA methylation and this modification is generally thought to be inhibitory to transcription. An exception to this widespread DNA modification are genomic elements called CpG islands (CGI), contiguous regions of non-methylated DNA which encompass the transcription start site of two thirds of mammalian genes. Although CGIs represent the most prominent feature of mammalian promoters, the contribution of these elements to promoter function remains unclear. Work in this study shows that the histone lysine demethylase KDM2B (FBXL10/ JHDM1B) is a nuclear protein which binds specifically to non-methylated CpG dinucleotides and associates with CGI elements genome-wide through its zinc-finger CxxC (ZF-CxxC) DNA binding domain. Furthermore, in mouse embryonic stem cells, biochemical investigation revealed that KDM2B associates with Polycomb group E3 ubiquitin ligase RING1B to form a variant Polycomb repressive complex 1 (PRC1) characterized by the PCGF1 subunit.
Considering that KDM2B has clear DNA-binding activity and that CGIs were reported to function as nucleation sites for polycomb repressive complexes, a potential role for KDM2B in mediating PRC1 recruitment to target genes was investigated. Stable depletion studies indicated that KDM2B is required for the normal targeting of RING1B to CGIs and the regulation of expression of a subset of Polycomb-occupied genes. By taking advantage of a genetic ablation system in which the DNA binding domain of KDM2B can be conditionally deleted, results in this thesis reveal that the ability of KDM2B to recognize non-methylated DNA is essential for polycomb domain formation and normal embryonic development. Finally, through the use of a de novo targeting assay, an unexpected PRC2 recruitment pathway was discovered which is dependent on PRC1-mediated H2AK119ub1 deposition. Together this work uncovers a novel mechanism linking KDM2B-dependent recognition of non-methylated DNA with recruitment of Polycomb proteins and provides the framework on which to further investigate the contribution of CGIs to formation of polycomb domains.
Role of Tbr2 in intermediate progenitors during cortical neurogenesis
Keywords: cerebral cortex
IPC
intermediate progenitors
Tbr2
developmental neurobiology

During embryonic development neurons of the cerebral cortex are generated from various progenitor cells that have progressively restricted fate. Understanding the multiple regulatory pathways that regulate the cell cycle kinetics and the identity of neurons is crucial to comprehend the etiology of severe developmental defects such as microcephaly and polymicrogyria and also the evolutionary expansion of the mammalian cerebral cortex. Intermediate progenitors (IPCs) express the transcription factor Tbr2 (a T-box gene) and deletion of this gene causes a decrease in brain size and cortical thickness. However, little is known about the molecular mechanisms regulating behavior of IPCs.
In this thesis, I studied the molecular mechanisms regulating cell division and cell fate choices in IPCs using an overexpression system. I show that Tbr2 controls the expression of key genes such as Cdk4, Aspm and Wnt5a by directly binding to upstream regulatory sequences. These downstream targets could explain the role played by Tbr2 in cell cycle, spindle assembly and Wnt signaling in intermediate progenitors. The interaction with Aspm also suggests a possible mechanism of self-renewal of IPCs leading to an expanded generation of cortical neurons and ultimately an increased cortical size.
While the role of IPCs in cortical neurogenesis is undisputed, it is widely believed that they contribute only towards supragranular layers. Using a knock-in transgenic mouse line (Tbr2Cre), I show that IPCs provide glutamatergic neurons (but not GABAergic neurons or GFAP+ astrocytes) towards all cortical layers in a significant proportion (20-40%). I also show that clonally generated neurons disperse within tangential dimension across the cortex significantly closer (142.1 ± 76.8 µm) than unrelated ones (294.9 ± 105.4 µm) though within the confines of a cortical column (300-600 µm).
Finally, I describe the similarity in the germinal zones of a large-brained gyrencephalic rodent, agouti and a lissencephalic primate, marmoset. Both these species show similar germinal zone cytoarchitecture and distribution of various progenitors. Further, the number of IPCs is grossly expanded thus demonstrating the conserved role of IPCs in cortical expansion regardless of the folding status of the cortex in these two species.
Lo-Fi aesthetics in popular music discourse
Keywords: Recording
Aesthetics
Punk
Indie
DIY
Lo-Fi
Music
Folk
Popular Music

During the late twentieth and early twenty-first centuries, 'lo-fi,' a term suggesting poor sound quality, the opposite of 'hi-fi,' became a characteristic perceived in certain popular-music recordings and eventually emerged as a category within independent or 'indie' popular music. It is typically taken to express the technical and technological deficiencies associated with amateur or 'DIY' musical production, namely at home using cheap recording equipment. However, this thesis rejects the assumption that lo-fi equates to a mode of production and charts it as a construction and a certain aesthetics within popular music discourse, defined as 'a positive appreciation of what are perceived and/or considered normatively interpreted as imperfections in a recording.' I chart the development and manifestation of lo-fi aesthetics, and the ways it focuses on various 'lo-fi effects' such as noise, distortion ('phonographic imperfections') and performance imperfections, in several decades of newspapers, magazines and websites covering popular music in the English-speaking world.
I argue that lo-fi aesthetics is not merely the unmediated, realist authenticity that it is often claimed to be, but one that is also fascinated with the distance from perceived commercial norms of technique and technology (or 'technocracy') that lo-fi effects signify. Lo-fi aesthetics derives from aesthetics of primitivism and realism that extend back long before phonographic imperfections were positively received. I also differentiate between lo-fi aesthetics and aesthetics of noise music, distortion in rock, glitch, punk and cassette culture. An appreciation for recording imperfections and the development of 'lo-fi' as a construction and a category is charted since the 1950s and particularly in the 1980s, 1990s and in the twenty-first century, taking in the reception of artists such as the Velvet Underground, Bob Dylan, Hasil Adkins, the Shaggs, Jandek, Daniel Johnston, Beat Happening, Pavement, Sebadoh, Guided By Voices, Beck, Will Oldham, Ariel Pink and Willis Earl Beal.
Interactions of Neisseria meningitidis with the human immune system
Keywords: factor H
PilC
type IV pilus
FHbp
Neisseria meningitidis
ZapE
PilE

Neisseria meningitidis is an obligate human pathogen causing over 1000 cases of meningococcal disease within the U.K., 10 % of which result in long-term disability or fatality. 10-70 % of the population carry N. meningitidis in their nasopharynx, the natural reservoir of this bacterium, as a commensal. The host-pathogen interactions of this species are complex and a greater understanding of the molecular mechanisms involved in pathogenesis and immune evasion is required. Three aspects of N. meningitidis pathogenesis were explored in this study.
One mechanism of immune evasion which promotes serum resistance of N. meningitidis is recuitment of complement factor H through domains 6 and 7 (fH67) by factor H binding protein (fHbp). In this study, mouse fH67 was recombinantly expressed and purified. fHbp did not bind mouse fH67 at physiologically relevant protein concentrations. The structure of mouse fH67 was solved, showing differences in domain orientation and surface chemistry compared to the human version of this protein, potentially accounting for the host specificity of this interaction.
Type IV pili (T4P) are crucial adhesins of N. meningitidis, the fibre of which is composed of thousands of copies of PilE. A method was developed to recombinantly produce large quantities of this protein from a variety of meningococcal strains and the structure was solved of one PilE protein. Subsequent analysis was performed with the PilE proteins investigating their interaction with the putative pilus receptor CD46 and human epithelia as well as their immunogenicity. A method was also established to produce PilC, the proposed tip-assocoated adhesin of T4P.
ZapE has recently been identified as an important protein in pathogen colonisation, functioning as an ATPase linked to Z-ring formation in bacterial cell fission. Both N. meningitidis and E. coli ZapE were recombinantly produced. The domain boundaries were mapped and ATPase activity was confirmed. No interaction was seen with FtsZ but DNA binding and modulation was observed by shift assays, the exact function of which remains to be elucidated in future studies.
Innovating with technology in the classroom: experiences with developing a new tool in support of teaching and learning in A-level history
Keywords: concept mapping
A-level history
technology in education
wiki
classroom

This study investigates a process of technological innovation in the classroom, and a range of related issues. It discusses the development of a technology-assisted tool, ThinkSpace, combining computer-based concept mapping and a wiki, aimed at facilitating collaborative and critical engagement with complex study material.
The study adopts a design-based research approach in order to develop in tandem the technological implementation of the tool as well as the pedagogical practices for the use of the tool in the classroom. ThinkSpace was introduced into two schools where it was used by A-level history students. In close collaboration with the teachers practical uses for the tool were developed and implemented in the classroom. Data were collected through classroom observation, student and teacher interviews, as well as gathering evidence of students’ work with the tool.
The thesis engages with questions of developing pedagogical practice to incorporate technological tools. It provides insights into the processes of working with teachers and students on collaborative innovation projects and the ways in which technology and pedagogy can gradually be aligned to achieve shifts in classroom practice. The project also investigates opportunities for developing productive uses of wikis and concept mapping in the classroom.
The results of this study highlight the gradual and incremental nature of innovation in the classroom. The study concludes that innovation with tools such as ThinkSpace requires changes to deeply-seated learning practices, which are closely linked to student identity. If such practices are to be altered, it is necessary to think more carefully about supporting students through the pedagogical changes that some technological innovations endeavour to put into place. Possible ways of providing support in the processes of innovation were found in the present study through the scrutiny of the ways some students were beginning to appropriate the ThinkSpace tool. This suggested more targeted ways of encouraging conceptualisation and collaboration practices, which were the target of the innovation presented here.
The p53 response: a new mitochondrial role for cofactor strap
Keywords: strap
ATP synthase
mitochondria
p53
apoptosis

Strap is a DNA damage responsive p53 cofactor, reflecting its control by the DNA damage signalling pathway. This study identified Strap at the mitochondria where it is damage regulated and can augment p53-dependent cytochrome c release leading to apoptosis. Moreover, p53 and Strap facilitate each other’s localisation from the mitochondria to the nucleus during the DNA damage response. Two ATM/ATR phosphorylation consensus sites in Strap were identified by mass spectrometry and phosphorylation of all the ATM/ATR consensus sites resulted in mitochondrial localisation of Strap during DNA damage. Targeting Strap to the mitochondria depletes cellular ATP when cells favour energy production through oxidative phosphorylation and sensitises cells to p53-dependent damage-induced apoptosis. These results thus imply that Strap co-ordinates different arms of the p53 response, and might be responsible for integrating its mitochondrial and nuclear functions.
Constitutionalism under China: Strategic Interpretation of the Hong Kong Basic Law in Comparative Perspective
Keywords: Hong Kong
Constitutional Law
Judicial Review
China

The scholarly consensus on the political foundations of independent constitutional review – that it invariably stems from electoral and inter-branch competition – has been weakened by recent empirical discoveries which demonstrated that constitutional courts in a number of authoritarian states are actually more activist than previously assumed.
This dissertation examines this phenomenon using the case of Hong Kong, an authoritarian polity first under the sovereignty of Britain and then of China. It is widely believed that the competence of the Hong Kong Court of Final Appeal – a cosmopolitan common law final appellate court – to strike down legislative and executive acts, and its ability to induce the regime’s compliance with its rulings, is intrinsic to the Basic Law, just as it is in liberal democracies. Nevertheless, two interrelated anomalous phenomena – the Court’s repeated issuance of activist rulings with near-complete impunity, and the continuing forbearance of China’s foremost constitutional authority, the National People’s Congress Standing Committee (NPCSC), faced with the Court’s aggressive assertions – necessitates careful explanation.
This dissertation proposes an explanatory Constitutional Investment Theory, which highlights the similarities between “investment” in constitutional review and investment in financial assets, to explain the activation, consolidation, and ascendancy of independent constitutional review in authoritarian settings. It shows how strong incentives to signal its ideological commitment to the “One Country, Two Systems” scheme, both internationally and domestically, first drove the NPCSC to acquiesce in the Court’s self-aggrandisement; how internal divisions within and external opposition to the Hong Kong regime have rendered retaliation a costly option; and how the Court’s strategic resolution of the Basic Law’s ambiguities has encouraged continuous political investment in its jurisdiction and autonomy. Altogether, these have contributed to the formation of a dynamic equilibrium of constitution control, under which the Court and the NPCSC dynamically developed their own jurisprudence within their respective bailiwicks.
Characterisation of a novel tick-derived dendritic cell modulator: Japanin
Keywords: immunology
immune modulation
Ticks
Dendritic cells

Dendritic cells (DC) play a key role in immunity and represent a great target for modulation, because of their ability to prime T cells and direct their polarisation into effector subsets. Ticks release immunomodulatory compounds in their saliva, possibly in order to evade host immune responses during feeding. We have recently reported that Rhipicephalus appendiculatus ticks produce ‘Japanin’, a secretory lipocalin that arrests differentiation of monocytes into DC and reprogrammes maturation of DC in response to various stimuli towards a tolerogenic phenotype . Japanin was cloned and recombinantly expressed in a baculovirus system for subsequent immunological and biochemical analysis. This study was set out to further investigate the immunomodulatory activity of Japanin as well as the underlying mechanism of action. We have discovered that Japanin prevents DC-mediated proliferation and polarisation of allogeneic T cells. Experiments with labelled Japanin have demonstrated that it binds predominantly to ex vivo generated human monocyte-derived DC (moDC) and to a reduced degree to monocyte and DC populations in peripheral blood, yet to no other blood leucocytes. We have identified CD206, also known as the mannose receptor, as a Japanin-binding receptor on moDC. This identification has been achieved by crosslinking and subsequent pull-down of Japanin-receptor complexes from moDC. Affinity studies with recombinant CD206 constructs have confirmed the binding to Japanin. Moreover, the binding has been verified by specific siRNA knock-down of CD206 in moDC, which resulted in significantly decreased binding of Japanin. Unexpectedly, CD206 has appeared to be dispensable for at least most of the DC-modulatory activity of Japanin. Therefore, attempts were made to determine other factors in the mode of action of Japanin, through which we have found that IL-10 is not essentially involved. Further results have suggested that the activity of Japanin demands cell contact. Collectively, we have come to the conclusion that the mechanism of action of Japanin might require internalisation by DC, potentially enabling modulation of intracellular pathways involved in the regulation of DC maturation.
A taxonomy of tort law defences
Keywords: Tort law
defences

Tort law provides for a large number of defences to liability. While the circumstances in which some of these defences apply have been explored in detail, scant attention has been given to the theoretical foundations of defences. In particular, no serious attempt has been made to explain how defences relate to each other. This thesis seeks to reduce this gap in our understanding of tort law by proposing a system by which defences may be organised. It is argued that tort defences should be arranged into a threefold taxonomy consisting in (1) absent element defences; (2) justifications; and (3) public policy defences. These categories differentiate defences from each other on the basis of the story that they tell about the defendant’s practical reasoning. Absent element defences indicate that the defendant did not commit any wrong. Justifications reveal that the defendant acted wrongly but that his acts conformed to the balance of reasons. Public policy defences give no insight as to the quality of the defendant’s practical reasoning.
Impacts of development-induced displacement on urban locality and settlers: a case-study of the railway upgrading project in Metro Manila
Keywords: Metro Manila
urban livelihoods
urban socio-spatial change
development-induced displacement and resettlement
development impacts

Population displacement has long been a controversial companion of development. The central tension has been between the position challenging the kind of development that removes people from their homes, livelihoods and communities, and a managerial position that the impoverishment risks of displacement can be mitigated through an effective intervention. Whereas recent research has been devoted to unpacking a rather unsuccessful performance of involuntary resettlement as a mitigation measure, this study aims to question the assumption of mitigation itself by expanding the concept of development impacts beyond the realm of displacement. Through an empirical study of a railway project in Metro Manila, the Philippines, I examine how urban residents are affected by a large-scale demolition and displacement that took place in their locality. Semi-structured interviews were conducted along the railway tracks after the land was cleared of informal settlements since the study placed particular focus on residents who were not physically displaced. They are identified in my research as non-displaced people. Few studies have addressed the possibility that other people might have been adversely affected in situ and this is particularly so in urban areas.
Empirical findings reveal that the physical environment and socio-economic relationships in the locality were significantly transformed through the clearance; impacting the tenure status, livelihoods and social milieu of non-displaced people. Tenure security was important for avoiding displacement but was not a definitive factor as a number of people are still informal settlers who continue to be faced with other eviction threats. For the non-displaced, the physical change of the locality became relevant when their productive capital, notably, a second house or business space, was affected. The loss or erosion of physical capital had a secondary impact on livelihoods, which was compounded by the rupture in the local livelihood network following a mass population outflow. Whereas the income of locally-based businesses decreased substantially, livelihoods that operate beyond the locality remain relatively resilient. Differentiated experiences of a local change are also reflected in a range of evaluations that describe local social ambiance before and after the event. Diverse ways in which non-displaced people were affected underline that the current conceptualisation of impacts is limited to one dimension of displacement. This raises the need to adopt a more holistic and disaggregated approach to understanding the complexities of development impacts. A discussion on whether and how they can be mitigated would benefit further from such a comprehensive study.