VictorJuiz/thesis huggingface dataset:
Structural and biochemical studies of cysteine-rich domains in morphogen signalling

Cell-to-cell communication is vital to the morphogenesis and homeostasis of multicellular organisms and is linked to a variety of diseases. Extracellular Cysteine-Rich Domains (CRDs) are involved in the control of fundamental signalling pathways, mediating crucial interactions with protein and small molecule ligands. The localisation of extracellular ligands and receptors is regulated by the cell surface glycosaminoglycan (GAG) layer. In this thesis, structural and biochemical methods have been used to characterise two multi-domain proteins containing CRDs – HHIP and ROR2.
In Chapter 3, the process of structure solution of the HHIP N-terminal CRD (HHIP-N) by Sulphur-SAD phasing techniques is described. HHIP-N is a novel CRD, with implications for small molecule binding present. Chapter 4 concerns the study of the regulation of HHIP secretion and its interaction with GAGs. Discrete GAG-binding motifs are found on the surfaces of HHIP-N and the C-terminal region of HHIP (HHIP-C). Structural studies with GAGs enabled snapshots of cell surface-bound states. Interactions were dissected using cellular assays and GAG-binding experiments. In addition, the dynamics of HHIP oligomerisation were analysed using solution scattering and ultracentrifugation techniques. Work in this chapter represents a complex mode of HHIP assembly regulated by GAGs.
In chapter 5, structural and biophysical studies of ROR2 were performed. A structure of the ROR2 CRD with its C-terminal Kringle domain was determined. The structure forms a potentially stable structural unit with a marked inter-domain interface. The CRD structure is distinct from related CRDs and suggests that it cannot directly bind Wnt proteins. This was complemented by biophysical and cellular assays.
In summary, the CRD is a fold found in two unrelated signalling pathways tied to a number of diseases and its role in multi-domain protein architectures has been characterised within this thesis. CRDs are involved in a wide range of interactions and these are essential for the precise regulation of signalling pathway activation.

Advisor: Siebold, C
Truth, paradoxes, and partiality

This work is an investigation into the notion of truth. More specifically, this thesis deals with how to account for the main features of truth, with the interaction between truth and fundamental linguistic elements such as connectives and quantifiers, and with the analysis and the solution of truth-theoretic paradoxes.
In the introductory Chapter 1, I describe and justify the approach to truth I adopt here, giving some general coordinates to contextualize my work.
In Part I, I examine some theories of truth that fall under the chosen approach. In Chapter 2, I discuss a famous theory of truth developed by Saul Kripke. Some difficulties of Kripke's theory led several authors, notably Hartry Field, to emphasize the importance of a well-behaved conditional connective in conjunction with a Kripkean treatment of truth. I articulate this idea in a research agenda, which I call Field's program, giving some conditions for its realizability. In Chapter 3, I analyze the main theory of truth proposed by Field to equip Kripke’s theory with a well-behaved conditional, and I give a novel analysis of its shortcomings. Field's theory is remarkably successful but is technically and intuitively very complex, and it is unclear whether Field’s conditional is a plausible candidate for a philosophically useful conditional. Moreover, Field’s treatment of "determinate truth" and his handling of many kinds of paradoxes is not fully satisfactory.
In Part II, I develop some new theories that capture the main aspects of the notion of truth and, at the same time, give a philosophically interesting meaning to connectives and quantifiers – in particular, they yield a strong and conceptually significant conditional. The theory proposed in Chapter 4 extends the inductive methods employed in Kripke’s theory, showing how to adapt them to non-monotonic connectives as well. There, I also develop and defend a new, theoretically fruitful notion of gappiness. The theory proposed in Chapter 5 (and discussed further in Chapter 6), instead, employs some graph-theoretic intuitions and tools to provide a new model-theoretic construction. The resulting theory, I argue, provides a nice framework to account for the interaction between truth, connectives, and quantifiers, and it is flexible enough to be applicable to several interpretations of the logical vocabulary. Some new technical results are established with this theory as well, concerning the interplay between every Łukasiewicz semantics and some interpretations of the truth predicate, and concerning the handling of determinate truth. Finally, the theory developed in Chapter 5 provides articulate and telling solutions to truth-theoretical paradoxes.

Advisor: Halbach, V
Williamson, T
Understanding human mononuclear phagocyte ontogeny using human induced pluripotent stem cells (iPSCs)

Tissue-resident macrophages (MΦ) such as microglia, Kupffer and Langerhans cells derive from Myb-independent yolk sac (YS) progenitors generated before the emergence of hematopoietic stem cells (HSCs). Myb-independent YS-derived resident MΦ self-renew locally, independently of circulating adult monocytes and HSCs. In contrast, adult blood monocytes as well as infiltrating, gut and dermal MΦ derive from Myb-dependent HSCs and are less proliferative. These findings are derived from the mouse, using gene knock-outs and lineage tracing, but their applicability to human development has not been formally demonstrated. Here I use a human pluripotent stem cell (hPSC) differentiation model of hematopoiesis, capable of monocyte/MΦ production over prolonged periods of time, as a tool to investigate human mononuclear phagocyte ontogeny. Using a transcriptomic approach I showed that hiPSC-derived monocytes/MΦ (iPS-Mo/MΦ) produced early in differentiation (first weeks) are more proliferative and less immunologically mature than iPS-Mo/MΦ produced at a later time point. I therefore hypothesised either that iPS-Mo/MΦ only become fully mature after several weeks of differentiation or that there are two developmentally distinct waves of MΦ produced over time. By comparing the transcription profile of iPS-Mo/MΦs to that of primary adult blood monocytes and fetal microglia I then showed that early and late iPS-Mo/MΦs were transcriptionally closer to fetal microglia than to adult blood monocytes. To further investigate if iPS-Mo/MΦs are indeed of the same developmental origin as MYB-independent MΦ such as microglia, I used a CRISPR-Cas9 knock-out strategy to show for the first time, that human iPS-Mo/MΦs develop in a MYB-independent, RUNX1 and SPI1 (PU.1)-dependent fashion. This result makes human iPS-Mo/MΦs developmentally related to, and a good model for, MYB-independent tissue-resident \Macros such as alveolar and kidney MΦs, microglia, Kupffer and Langerhans cells. Interestingly, while MYB was not required for the generation of iPS-Mo/MΦs, its knock-out resulted in an increase in iPS-Mo/MΦ production. To investigate this increase I developed two methods for quantifying the differentiation bottleneck occurring during hiPSC differentiation to iPS-Mo/MΦs. Those techniques highlighted a potential increase in progenitor cell generation in MYB KO cells and thus lay foundation to improve our technical understanding of EB differentiation and will enable enhanced manipulation of the EB model.

Keywords: Macrophage
SPI1
Primitive hematopoiesis
RUNX1
MYB
Advisor: James, W
Subjects of justice: social institutions and the basic structure

I explore how justice can be said to apply to different subjects through an examination of the work of John Rawls. I first offer an interpretation of Rawls’s idea of a social institution, and explain how Rawls is able to avoid a well-known objection put forward by Hayek. I then raise a puzzle about how the justice of institutions is supposed to fit with the justice of the basic structure of society. Rawls asserts that justice is the first virtue of social institutions, but it is not clear whether this means that institutions must be just in isolation or in terms of the role they play in the basic structure. I examine two possible solutions to the puzzle, derived from the work of David Miller and Jon Elster, but find that neither is compatible with Rawls's theory. I illustrate the ambiguity by reference to the family, drawing a distinction between the family as a social institution and families as associations. I conclude from this example that institutions must be just in terms of the basic structure, but argue that Rawls's hierarchical account of domestic and local justice – applying to the basic structure and to families within it respectively – is underdeveloped and unconvincing. Turning to the basic structure itself, I argue that the language of 'subjects' of justice is insufficiently precise, and we should distinguish between a site and an agent of justice. I illustrate this distinction with reference to recent work by Miriam Ronzoni. Rawls originally saw the basic structure of society as the site of social justice, but moved in his later work towards a more agent-orientated conception. This difference, I suggest, has significant implications for the meaning of the highly influential thesis that the basic structure of society is the primary subject of justice.

Keywords: justice
Rawls
Advisor: Gardner, J
Hebrew borrowings in the Arabic speech of Palestinians in three refugee camps in the West Bank, occupied Palestinian territories

This thesis on Hebrew borrowings in Palestinian Arabic provides detailed casework from an understudied linguistic situation. It is firmly anchored in empirical results from fieldwork in three refugee camps in the Occupied Palestinian Territories. The results are presented and analysed with reference to speech's immediate interpersonal surroundings and the wider social, political and economic situation. Several aspects of the political economy of Israel and the Occupied Palestinian Territories are seen to affect borrowing from Hebrew: firstly, the formation of a Palestinian economy dependent on the capitalist Israeli core, a dependency exacerbated in the refugee camps by the refugees' sudden loss of their traditional livelihood in the peasant economy of pre-1948 Palestine; secondly, the existence at present of a customs union between Israel and the Occupied Palestinian Territories which opens the Palestinian consumer marker to Israeli goods; thirdly, the provision of some state services to Palestinian holders of Jerusalem residency cards; and fourthly, the functioning of the military occupation which imposes closures and other military restrictions on Palestinians. This context provides the setting for power relations between Israelis and Palestinians which give rise to a variety of practices of borrowing, including the use of Hebrew to demarcate in-groups, signal aspirations to a modern lifestyle, and give a political edge to humour. On the basis of this analysis, an explanatory model is proposed that seeks a non-deterministic link, termed "articulation", between the structure of the context and the speakers' agency manifested in the linguistic practice. This explanatory model moves away from the notions of conflict and national identity often submitted as explanations in sociolinguistics of the Middle East, but rather gives prominence to Palestinian and Israeli ideologies that inform the conceptual experience of Palestinians. These ideologies are identified as Palestinian nationalism, Palestinian pragmatism, Israeli securitism and Israeli consumerism. The analysis is sensitive to gendered patterns of behaviour as well as inter-generational differences.

Keywords: language contact
Palestinians
Hebrew
refugees
Arabic
sociolinguistics
language
migrant workers
anthropology
Israel
Israeli-Palestinian conflict
borrowings
Advisor: Holes, C
Conceptualising political candidacy as a human right

This thesis examines the justificatory basis of the right to candidacy, otherwise referred to as the right to stand for election, and assesses the implications of characterising political candidacy as a human right. It examines the extent of the right's legal recognition in international, regional and domestic human rights law with specific focus on the jurisprudence of the United States, Canada and the ECtHR.
This dissertation then offers a theoretical justification for the existence of a moral right to candidacy in all liberal democracies. This justificatory account highlights how the following values and interests underlie the right to candidacy: dignity (as social recognition of one’s equal moral status), autonomy, self-expression and self-development. It further examines the derivative justifications for the right to candidacy by outlining the extent to which it is necessary for the effective exercise of the right to vote, freedom of association and the maintenance of a common liberal culture.
The correlative duties to which the right gives rise are also examined. It is argued that the right entails duties to respect, protect and fulfil. The duty to respect imposes a negative obligation on the State to refrain from imposing unjustifiable disqualifications or eligibility requirements for elective office. The duty to protect entails an obligation to safeguard against infringements of the right by political parties in their candidate selection processes. Thirdly, the duty to fulfil involves a positive obligation to organise and administer free and fair elections with a reasonably level playing field in which candidates may compete.
This thesis subsequently explores the institutional implementation of these duties and how the values and interests underlying the right should help inform the scope and content of such duties in the jurisdictions specified above.

Keywords: citizenship
right to vote
political rights
electoral rights
right to stand for election
candidacy
Advisor: Craig, P
Redox-dependent signalling via protein Kinase A type I within distinct subcellular compartments

Background and Aims : Numerous proteins, important for cell signalling, are modified by the balance of oxidative or reducing stimuli within the cell – the redox state. The regulatory subunit Iα (RIα) of Protein Kinase A (PKA) contains conserved cysteine residues that are readily oxidised to form a disulphide bond via the thiol group of other cysteines. It has been suggested that the formation of the disulphide bond between RIα subunits of the PKA holoenzyme increases the activity of the enzyme. The aims of the project were to examine whether the intrinsic activity of the enzyme or its functional localisation were increased by redox modification.
Methods : Live-cell fluorescent imaging of Fluoresence Resonance Energy Transfer (FRET) has been used to investigate real-time changes in PKA activity and Fluorescence Resonance After Photo-Bleaching (FRAP) has been used to investigate changes in sub-ceullar localisation of PKA regulatory subunits.
Results : The addition of the oxidant, hydrogen peroxide, to cells expressing FRET-based reporters of PKA activity was not associated with an increase in PKA activity compared to cells that expressed PKA-RIα that were incapable of undergoing disulphide bond formation. Mutation of the cysteine residue in PKA-RIα was, however, associated with subtle differences in sub-cellular diffusibility of the protein, which supports the hypthesiss that such redox modification appears to influence the mobility and hence anchoring of the protein within the cell.
Conclusions : In summary, the data presented in this thesis do not support the notion that PKA can be activated directly through oxidation the RIα subunit. However, modulation of classical cAMP-PKA signalling by the redox state of the cell may be brought about by subtle changes in the anchoring and hence localisation of PKA-RIα as implied by changes in diffusibility within the cytoplasm.

Advisor: Casadei, B
Zaccolo, M
Inferring the translation speed and determining its relationship to the protein structure produced

The central dogma outlines the flow of information within a cell, whereby a DNA sequence is transcribed into RNA, which, in turn, is translated into a protein. This flow is unidirectional, meaning that once constructed, a protein should retain no knowledge of either the RNA or DNA sequence which led to its creation. Due to the degeneracy of the genetic code, multiple synonymous mRNA sequences can result in the same protein being produced. However, an increasing volume of experimental work shows that while these synonymous sequences produce the same amino acid sequence, the encoded proteins may differ in their physical properties. These results suggest that there is information contained in the mRNA sequence pertaining to the structure of the encoded protein above and beyond mere specification of the amino acid sequence. This thesis investigates whether the speed with which a codon is translated biases the protein structure produced. The initial chapters focus on determining a suitable metric for the translation speed, comparing various theoretical estimates to a new experimental measure. Finding that the estimators perform poorly, we construct a transcriptome-wide database relating the experimentally derived translation speeds directly to a large number of experimentally derived protein structures. Using this database to test our hypothesis, we observe various associations between the translation speed and the protein structure produced. Our analysis is the first time that the relationship between translation speed and protein structure has been investigated on a transcriptome-wide scale using purely experimental data. Our findings provide strong support for the cotranslational folding hypothesis which suggests a protein folds while it is being produced.

Advisor: Deane, C
The rise and fall of FidoNet: the geographic growth and decline of an ICT community

This thesis studies the time evolution of a computer mediated community called FidoNet. The introduction explains what FidoNet is, briefly details its history and sociological significance and sets out research goals for the thesis as a whole. The second chapter—covering background and relevant literature—relates FidoNet to other social phenomena and reviews relevant sections of work on dynamic approaches to social systems. It also describes how FidoNet Nodelists were combined with geographic data on US telephone lines and 1990 Census data so that the geographic growth and decline of FidoNet could be mapped and analysed.
The third through fifth chapters are substantive starting with an empirical analysis on the spatial growth of FidoNet in the United States, covering a variety of different ways in which distance could have mediated the contagiousness of FidoNet as a system. The fourth considers decline as a similarly contagious process, demonstrating that FidoNet’s most obvious competitor—the internet—may in fact have discouraged its decline while the short-term influence of leaving events on current sysops fits the data far better as an explanation. The other explanatory variable of this section—long-term social influence—exhibits an unexpected sign, suggesting that perhaps there were incentives to maintain FidoNet that were most prevalent in the long-term.
The fifth chapter attempts to tease out which different mechanisms may have been at work during decline, using an Agent-Based Modelling (ABM) approach and specifically considering individual rather than aggregated behaviour. The 6th and final chapter summarises the findings.

Keywords: Growth
Decline
Community
Contagion
Geospatial
Advisor: Reed-Tsochas, F
Democracy, press independence, and constitutional structure: the crisis of journalism and the checking function of the press

This thesis undertakes a comparative doctrinal analysis of the checking function of the press in public libel cases in Canada, the United Kingdom, and the United States. This examination reveals serious deficiencies associated with a common under-theorizing of the checking function. The primary consequence of this under-theorizing is inadvertent over and under protection of speech. The thesis concludes by recommending that precise evaluation of its doctrinal and methodological outcomes must await further interdisciplinary efforts to evaluate them within the context of differing conceptions of 'democracy', and each comparator's unique constitutional and media structures.

Keywords: Checking Function
Democratic Accountability
Defamation
Institutional Press
Advisor: Young, A
Changes in inequality of educational opportunity: a cross-national comparison and the long-term development in Germany

This thesis provides a long-term cross-national comparison of changes in educational at-tainment and a detailed longitudinal analysis of the changes in inequality of educational opportunity in East and West Germany. Using data from the 2011 PIAAC study, the the-sis examines how a different focus on equality (equality of condition and equality of op-portunity) in different welfare regimes reveals cross-national variations in educational expansion, the association between educational background and educational attainment and the change in this association over time. Based on longitudinal data from the NEPS, the thesis then focuses on how far educational reforms have changed the character of the old clear-cut divisions between academic and vocational tracks in lower and upper sec-ondary school as well as in the landscape of higher education in East and West Germany. The empirical findings indicate that educational expansion and educational inequality vary significantly across welfare regimes and over time. In Germany, I find strong and persistent associations between family resources and the probability of making the transi-tion from primary school to the academic track. Educational reforms in lower secondary school did not provide more openness between the non-academic and academic tracks in Germany. However, reforms in the vocational education and training system have in-creased the permeability between tracks tremendously, so that the vocational and academ-ic tracks are much more integrated today. More permeability is, however, not connected with more educational equalities. Overall, educational inequality in the attainment of a tertiary degree has remained surprisingly stable across birth cohorts.

Advisor: Mills, C