VictorJuiz/thesis huggingface dataset:
Genomic approaches to pre-clinical drug target prioritisation in immune-related traits

Drug discovery is time-consuming and expensive; bringing a novel compound to regulatory approval can take several years and billions of dollars. A significant portion of costs stem from compounds that have failed in clinical development, for reasons including a lack of clinical efficacy. Simultaneously, the emergence of genomic approaches like genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) has enabled better functional understanding of human genetics and robust mapping of effects of gene perturbations on phenotype. This thesis focuses on the aggregation of genomic approaches for the purposes of drug target prioritisation in pre-clinical stages of development, in immune-related traits.
The Priority Index (Pi) approach combines GWAS knowledge with cell-specific eQTLs, promoter-capture Hi-C, ontologies, and network information to prioritise genes in a disease-specific manner, using solely genetics (’discovery mode’) or combining genetic data, clinical trial information, and machine learning (’supervised mode’). The outputs of Pi are computationally validated and benchmarked using multiple sclerosis as a case example, and the performance of Pi as a drug discovery prioritisation pipeline is quantified.
Pi is further implemented in the context of myasthenia gravis, and analysis is conducted at the gene, pathway, and network-level to develop an understanding of drivers of pathogenesis, functionally-relevant cell types, and genetic differences between early and late onset forms of disease. Moreover, the outputs are refined through statistical fine-mapping, eQTL, and colocalisation analysis, in addition to comparison with externally-generated datasets. Lastly, experimental validation is conducted to test hypotheses generated by Pi analysis. Specifically, prioritised targets for Dupuytren’s disease and systemic lupus erythematosus are examined via epigenetic probe inhibition and siRNA knockdown, within the context of patient-derived tissue. Effects are interrogated from the perspective of both gene expression and cellular phenotype/function.
This thesis demonstrates the utility of integrative genomics for target prioritisation, highlighting the potential for informing and enabling pre-clinical drug discovery.

Advisor: Knight, J
Green, C
Handunnetthi, L
Determinants of migration: the role of social and trade policies

The main aim of this thesis is to investigate the role of social and trade policies as determinants of migration. The thesis has four core independent chapters that aim to address five major challenges in migration and development research: the effect of non-migration policies, the interplay and dichotomy of internal and international migration, the challenge in conducting impact evaluation of policies on migration, the bridging of structure and agency in migration research, and the way to approach explanatory complexity in migration determinants research. The contribution of this thesis falls mainly in explaining the determinants of South-North and internal migration.
On social policy, this thesis finds overwhelming evidence on the robust role of welfare services and programs in origin countries through risk-diversification and relative-redistribution channels. I propose a term called reverse magnet hypothesis and provide the identification strategy to test its robustness. One finding is that the scope and type of welfare programs influence migration decision through the behavioural influence it provides through the relaxation of financial constraints.
On trade policy, this thesis finds no migration theory can individually explain global migration. Instead, I find evidence of multiple pathways and combination of different migration theories that serve as causal conditions for total migration and high-skilled migration. This thesis finds that capital linkages play a focal role in migration. It also finds a counterfactual evidence of migration hump, which indicates that the relationships between capital, trade, and migration flows are indeed dynamic.
This thesis shows that methodological and theoretical pluralism enrich explanations on migration determinants. Also, the role of origin country determinants should no longer be neglected nor underutilised in migration determinants literature.

Keywords: Migration Determinants
Social Policy
Trade Policy
Advisor: de Haas, H
Czaika, M
Stochastic transport models in confined networked environments

Diffusion of macromolecules within the intracellular environment, tissue generation in scaffolds, and the transport of blood cells through aortic media, are examples of processes which hinge upon the optimal transport of biological agents within complex crowded environments. For example, the organelles within a typical mam- malian cell create an environment with a range of heterogeneous microscopic spatial structure known to impede macromolecular motion. A significant challenge for bio- mathematicians is to develop mathematical transport models on macroscopic length scales that incorporate the key effects of the microscopic spatial structure and the spatial exclusion between biological agents. A useful abstractification is to approx- imate complex environments as networked topologies that are capable of describing a huge range of heterogeneous spatial structures. This thesis focusses broadly on the extension of stochastic transport models confined to networked environments and their analysis. We introduce a framework for macromolecular transport in a domain that is deconstructed into two region types; one where molecules move freely, and another where there are strong macromolecular crowding effects. Through analysis of the equilibration time, algorithms for optimal network construction are designed and tested. Additionally, we explore search processes for multiple interacting searchers within a networked environment. Quantifying the efficiency of the search process via the parallel cover time, we provide optimal strategies that minimise the cover time of a fixed population of particles. Finally, we propose a new measure of particle displace- ment that accounts for the total winding of the path of a particle as it moves through a network, finding that statistics of the particle displacement are a function of network topology. Together, this work represents a key step in developing generic algorithms for topological optimisation of stochastic networked systems. Such concepts are of growing importance within modern information theory, biophysics, biotechnology, network science, statistical physics, traffic flow and robotics.

Keywords: Stochastic Modelling
Transport on networks
Stochastic transport
Networks
Advisor: Maini, PK
Baker, RE
Woodhouse, FG
Algebraic methods for chemical reaction networks with extrinsic noise

Many biological mechanisms can be understood as a complex interaction of chemical reactions. In order to explain the wealth of biochemical phenomena in systems biology, a sophisticated analytic framework for these chemical reaction networks is needed. This thesis investigates the role of extrinsic fluctuations in biochemical reaction mechanisms and develops mathematical tools for the systematic study of extrinsic noise.
The first part of this thesis studies variability in biological processes which manifests itself as randomised rate constants. This variability can stem from many sources, such as different cellular environments, or upstream stochastic effects, which directly influence the reaction network under study. As variability is often modelled as constant, but unknown parameters, parameter-free algebraic methods are developed in this thesis to study large classes of chemical reaction networks named families. In particular, these methods allow for parameter-free model rejection, or model testing and give upper bounds on the algebraic complexity of these tasks. Further, a parameter-free result on the capability of multistationarity in infinite classes of networks is proved.
The second part of this thesis studies time-varying extrinsic noise, such as fluctuating experimental conditions, which directly influences the reaction rates. A particular focus is on upstream stochastic networks, propagating their stochasticity into the main network under study. Crucially, as the stochasticity in the system is imposed externally, the analysis of such models is not subject to the constraints of stochastic methods. While intrinsic noise imposes rigid restrictions on the modelling process, it is shown how in extrinsic noise models the deterministic model structure stays intact. Consequently, in this thesis, algebraic methods for deterministic networks are extended to be applied to networks subject to extrinsic noise in order to find oscillations and preclude stochastic switching. The effects of intrinsic stochasticity are also compared to the effects of extrinsic noise and the framework is extended to correlated (coloured) noise.

Keywords: Toric Varieties
Extrinsic Noise
Reaction-Diffusion
Chemical Reaction Networks
Advisor: Gaffney, E
Harrington, H
Woolley, T
Ghaziabad’s daughters: educated subjectivity and social haunting in India

Critical sociological studies of education have investigated whether education enables young women to lead independent lives and have argued that it reproduces gender inequalities (Holland & Eisenhart, 1990). In the past decade, since the shooting of the Pakistani teenager Malala Yousafzai, the debates about women’s education the world over have been brought back into focus. Contemporary discourses surrounding women’s education have often been implicitly premised on an assumption that the education of young women would enable them to gain autonomy over their bodies, and reproductive and sexual freedoms. Based on ten months of fieldwork among lower middle-class young women (18-30) who are completing or have completed their college education in Ghaziabad district, twenty miles east of Delhi, I examine the role of education in bringing about a change in gender relations in this region. In analysing education ethnographically, I focus on the meanings and practices of education as a lived experience and investigate the subjectivities and affective practices of educated young women as they negotiate their presence in the city.
My examination of the subjectivities of educated young women in UP makes three contributions. First, it highlights that for lower middle-class young women, education is a daily practice that allows certain spatial and sexual freedoms. The practices of education entail an expression of emotional dispositions of rage and pleasure by young women in public spaces, which is an emerging middle-class practice in India. Second, it illustrates that while education enables pre-marital heterosexual intimacy in India, in line with global and Bollywood-inspired romances, it does not transform the institution of marriage. Marriage continues to be decided by parents, and young women are unable to realise their ideals of a companionate marriage, with egalitarian relations between husbands and wives. Third, I argue that young women are haunted by the promises of freedom and autonomy that education had inspired in them. Despite education’s inability to bring promised benefits, young people continue to invest in education because it is the only social institution that makes it possible for them to inhabit, even if for a short period, their imaginations for a better life. Thus, in this post-education landscape, young people maintain a ‘cruel optimism’ (Berlant, 2011) about the institution of education.

Advisor: Gellner, D
Hashing, pooling and coding: towards optimal embedding in linguistic steganography

The goal of steganography, the art of hiding information, is to send hidden messages without revealing their existence to outside observers. So-called cover objects are modified to convey the payload, the hidden message. In the majority of literature, covers are images; this work is concerned with the sub-field of linguistic steganography, where covers are pieces of natural language.
This area has received little attention, and as a result has lagged behind the state-of-the-art approaches present in image steganography. This work identifies the following weaknesses of the current linguistic steganography literature: methods to assign values to cover sentences are inefficient; the amount of data hidden in covers (capacity) is low; security is rarely tested. The first two weaknesses are linked, low capacity caused, in part, by inefficient value assignment techniques. The last weakness is an inexcusable flaw; the evolution of linguistic steganography is impossible without thorough security analysis.
This work applies concepts from image steganography and steganalysis in order to address these flaws, and to provide a robust framework for future linguistic steganography research. A novel linguistic stegosystem is developed, utilising hashing to assign values to cover objects, and manual input to ensure fluency of generated steganography. Security of the system is evaluated twice: first against a human attacker, an approach uniquely appropriate to the linguistic setting; then against a novel automated attack, utilising the paradigm of pooled steganalysis.
The automated attack is powerful against the generated steganography, until adaptive embedding, a technique well known in image steganography, is applied to the linguistic setting for the first time. This utilises coding to minimise distortion (a measure of the detectability of generated steganography). Four linguistic distortion measures are described, the first of their kind. The resulting steganographic objects are shown to be secure both against humans, and the developed attack.

Advisor: Ker, A
Beyond stomach infrastructure: party membership and political ideology in Nigeria’s Fourth Republic

This thesis explores political ideology in contemporary Nigeria through tracing the origins of two mass membership parties: The All Progressives Congress (APC) and the People’s Democratic Party (PDP). Mainstream scholars of African democracy explain mass political mobilisation through “ethno- clientelism,” that is, through a combination of primal ties and gift-giving. However, ethno-clientelistic explanations are susceptible to two significant explanatory weaknesses. These explanations prevent scholars from considering the domain of political “affect”, that is to say the role of utopian desires and fantasies in propelling wide-scale political mobilisation, including mass party membership. Secondly these perspectives offer us an elitist gaze of non-Western democracies. This is because these explanations are used to promote a “common good” defined not by the citizenry, but by elevated, often non-local, analysts — those thought best equipped to assess the quality of a government’s management of a capitalist economy under conditions of fiscal austerity. In place of these explanations, I offer a de-exoticized, left- populist conception of mass mobilization grounded in Chantal Mouffe’s agonistic definition of ideology. I argue that in Nigeria’s current democratic republic, the two parties of government, the APC and the PDP are both centre-right populist parties and, thus, that Nigeria’s main parties are ideological, even if they are ideologically convergent rather than opposed.
To empirically assess these claims, I examine the testimonies and practices of APC and PDP party loyalists throughout an election and post-election period. Nine months of fieldwork — including attending scores of party meetings and interviewing numerous party members — was conducted in Ekiti state (a Yoruba majority, south-west state) and in Kaduna state (a Hausa-Fulani majority, north-western state). These states were selected for their accessibility as well as to allow me to inductively examine what differences and similarities would emerge by contrasting two historically and ethno-culturally distinct states. Across both locations, both the APC and the PDP are centre-right populist parties in social composition, practice, and economic policy. I find that a mixture of cultural norms, populist and liberal institutional rules, and centrist economic policies govern political practice and thought in these parties. I also find that the character of political parties is best seen not in the words of political speech-writers, but in the practices of democratic citizens on the public calendar of party activities known as the electoral cycle. Through the study of ideology in Nigeria’s Fourth Republic, my thesis makes an empirical contribution to left-populist theory and a conceptual contribution by reintroducing the left/right ideological spectrum into the comparative study of African democracy.

Advisor: Alexander, J
Adebanwi, W
Cross-hierarchical corticothalamic plasticity in the mouse visual system

Almost all sensory information reached our brain via the thalamus. The thalamus is considered the relay center for sensory information to the cortex and has an essential role in the regulation of fundamental brain processes, including sleep, alertness, consciousness and cognition, via various distinct nuclei. Specifically in the visual system, inputs from the retina project to the “first-order” dorsal lateral geniculate nucleus (dLGN) of the thalamus, which projects to the primary visual cortex (V1). Layer V neurons selectively project to the “higher-order” lateral posterior nucleus (LP) and do not normally innervate dLGN. It has been recently proposed by Grant et al., (2016), that layer V projections rewire to innervate dLGN fter monocular enucleation (MoE); however, the cortical origin of these projections has not been determined. In my study, I examined neuronal rewiring of cortical layer V projections and their plasticity to structurally rearrange following neonatal MoE. After performing MoE in layer V-labelled transgenic mice (Rbp4-Cre::tdTomato) at birth, I studied the effects on the ingrowth of tdTomato-labelled corticofugal projections into visual thalamic nuclei, the dLGN and the LP. In order to investigate the corical origin of aberrant layer V projections in the sensory deprived dLGN, I performed AAV viral injections in the primary visual (V1) and somatosensory (S1) cortices of adult Rbp4-Cre::tdTomato mice (n=3 for V1, n=3 for S1) that had been monocularly enucleated at birth. My findings indicate innervation of layer V corticothalamic (GFP+) axons in the lower part of dLGN and LP only from V1 with formation of aberrant side branches and VGluT1+ boutons in the deprived dLGN. No alterations in the S1 projections to thalamus were observed following MoE with S1 axons completely bypassing dLGN. However, projections from A1 or other sources, such as secondary cortical areas, should also be further investigated. What is more, an increase in the bouton density was identified in the dLGN after input deprivation. Additionally, I examined the molecular changes induced by MoE in the thalamus at P8 by in situ hybridization and confirmed differential pattern of expression in control and deprived dLGN (n=3). Otx2 and Cbln2 showed increased expression in deprived dLGN accompanied by upregulation of gene expression in vLGN. Kcnk9 and Calb2 were downregulated in dLGN upon enucleation, also showing increased expression in vLGN. EphA5 was differentially expressed in dLGN and LP in control hemisphere with dLGN showing stronger labelling, whereas this difference was no longer evident after enucleation in dLGN of reduced volume. All the aforementioned results demonstrate the necessity of peripheral input for proper layer V axonal ingrowth, synaptic formation and transcriptional profile of the dlGN and might indicate its importance in the establishment of the specific characteristics of each order of thalamic nuclei.

Advisor: Molnar, Z
Hoerder-Suabedissen, A
Philo on male homosexuality

This thesis discusses Philo of Alexandria's views on male homosexuality. In addition to clarifying the use of the term 'homosexuality' in this research, the Introduction investigates Philo's place in the history of scholarship on sexuality in the ancient Mediterranean world. A preliminary chapter on Philo's life and oeuvre (Chapter One) is followed by a review of the main attitudes towards homosexuality as emerging primarily from literary sources of both gentile and Judaeo-Christian provenance contemporary to Philo (Chapter Two). Building on Philo's interpretation of the biblical myth of Adam and Eve, Chapter Three probes the limits of love, sex, and gender according to Philo, arguing that his system of thought is grounded in a strict gender binarism which leaves no space for any sexually ambiguous entity—not even on a figurative level. The next three chapters focus on three relevant passages in Philo's work: Philo decries male homosexuality in relation to Plato's Symposium (Chapter Four; Contempl. 57-64), within a retelling of the events of Sodom and Gomorrah (Chapter Five; Abr. 133-146), and with respect to the prohibitions of same-sex intercourse in Leviticus (Chapter Six; Spec. 3.37-42). Philo's arguments and rhetorical strategies are informed by varied traditions, ranging from philosophical hermeneutics to biblical exegesis as well as legal thinking, and the relevant writings and passages tie in with many Graeco-Roman literary genres and imageries. The effect produced is an unprecedented, multi-faceted attack on behaviour which Philo presents as highly problematic not only for those directly involved in it, but for the entire community where it appears. This study aims to emphasise the originality of Philo's contribution to ancient discourses on sexuality, and suggests that his peculiar approach to τὸ παιδεραστεῖν modifies the conceptual universe of this idea. The Conclusions point to possibilities for developing further research on these themes in the Christian reception of Philo.

Advisor: Goodman, M
Hutchinson, G
Recognizing victims' perspectives: toward a human rights-based approach to human trafficking

A human rights-based approach to human trafficking promotes victim-centred responses that facilitate victims’ empowerment, exercise of agency, and realization of their rights. The thesis engages with this approach through the qualitative exploration of sex trafficking victims’ experiences with and perspectives on the criminal justice process and the post-trafficking assistance they receive in the Netherlands. This includes their experiences with law enforcement, lawyers, and a specialized shelter, the factors they considered when deciding whether to cooperate with authorities in the case against their traffickers, and their views on testifying, special measures, and sentencing. The empirical data is analysed through a human rights lens to discern the extent to which the Netherlands utilizes a human rights-based approach and meets its obligations to trafficking victims under international, regional, and domestic law in practice. Through both the successes and failures identified in this regard, victims’ desire to be treated with respect and compassion, have their needs and cases taken seriously, and be updated frequently about the status of their cases became clear. Yet, there emerged a degree of diversity in participants’ views about the types of assistance, support, and protection they need, such as with respect to the use of special measures in criminal proceedings, which underscores the importance of eliciting and accounting for individual victims’ perspectives throughout the process. However, recent cuts to the level of resources devoted to combating trafficking and assisting its victims in the Netherlands raise serious concerns about whether victims’ needs can be met and whether a human rights-based approach can be realized going forward.

Advisor: Hoyle, C