VictorJuiz/thesis huggingface dataset:
Novel Machine Learning Models for Identification, Characterization and Prioritization of Phenotype-Genotype Associations
Keywords: Genome variation
Genome Wise Association Studies
Genomics
GWAS
Machine Learning
Phenotype variation

This thesis is centered on the broad problem of inferring, characterizing and prioritizing molecular and functional phenotype effects of genetic variants. I first investigate the problems caused by phenotype heterogeneity in association studies of complex traits. Many complex diseases, such as autism, diabetes and cancer, are very heterogeneous in terms of the realized phenotypes, i.e. individuals diagnosed with the same disease might experience substantially different symptoms. I introduce the JBASE: Joint Bayesian Analysis of Subphenotyping and Epistasis model, which simultaneously accounts for non-additive interactions and phenotype heterogeneity while searching for associations. Next, inspired by the hypothesis that some phenotypes can be better explained by additive (small) effects of a large number of variants, I investigate the applicability of sparse supervised learning models for association studies of complex traits. In particular, I investigate integrative machine learning models that can leverage additional biological knowledge about phenotypes and genetic variants while searching for genetically informed associations. Towards this goal I present AAALasso: Accounting for Antagonistic Associations in Lasso, a novel sparse additive multi-task learning model that takes network structured information between markers and phenotypes into account. While identifying variants associated with a phenotype is important, being able to validate them by establishing causal biomolecular links is equally important. As such, in the last part of this thesis, I focus on the problem of predicting stability effects of non-synonymous coding mutations as a tool for the prioritization of variants discovered in association mapping studies. I introduce ELASPIC: Ensemble Learning Approach for Stability Prediction of Interface and Core mutations, a supervised ensemble learning approach to accurately predict effects of non-synonymous single nucleotide polymorphisms (SNPs) on protein stability and, for the first time, on protein-protein binding affinity. Overall, this thesis proposes three new complementary machine learning models for inferring, characterizing and prioritizing the phenotype effects of genetic variants. The first two approaches propose novel tools for finding underlying variants of a given phenotype, whereas the third approach focuses on predicting the molecular effects of the discovered variants.
Essays on Organizational Strategy and Social Networks
Keywords: computational models
informal networks
organizational identity
organizational strategy
social networks
strategic change

This dissertation proposes that the success of organizational strategic change is influenced by the reconfiguration of the interpersonal interactions among individual members, and that the reconfiguration is influenced by individual preferences for the strategic change. It is the contention of the three chapters that self-interested actors may possess different understandings of, and preferences for, the strategic choices of leaders. The main argument of this dissertation asserts that individual preference for the implementation of organizational strategy differentially motivates the search behavior of individuals as they self-organize and interact with others in the organization. The outcome of this search is a network of interactions that affects the success of the strategic change through performance adjustments by both leaders and individuals. A dynamic agent-based network simulation and a supporting empirical study are used in support of this argument to investigate the relationship between an organization’s strategy choice, the emergent internal interpersonal network, and the success of organizational strategic change.
A Concord of Alchemy with Theology: Isaac Newton's Hermeneutics of the Symbolic Texts of "Chymistry" and Biblical Prophecy
Keywords: Alchemy
Bible
Book History
Chemistry
Hermeneutics
Isaac Newton

That early modern natural philosophers such as Isaac Newton were deeply preoccupied by religious concerns, which were entwined with their study of nature, has become—at last—a fairly uncontroversial commonplace. In the area of the relationship between Newton’s natural philosophy, alchemy, and theology, Dobbs’ Janus Faces of Genius has had an enduring impact. However, the new historiography of alchemy and insights gained from the application of book history to the history of science—particularly the bookishness of alchemy—require Newton’s alchemy and theology to be revisited. Accordingly, this dissertation makes two main arguments: 1) Specific connections between Newton’s alchemy, or, to use the more inclusive term, “chymistry”, and his theology can be found by considering Newton’s methods of interpreting symbolic texts—as opposed to searching for specific unity of subject matter. Analysis of Newton’s textual research methods reveals his cross-comparative organization of textual sources and his particular descriptive-translational approach to symbolic texts: figurative alchemical texts and the prophetic texts of the Bible. 2) General connections between Newton’s chymistry and theology can be seen as his overall trend to incorporate statements of God into his natural philosophy was specifically manifested in physico-theological and divine metaphysical arguments that he built from chymical phenomena in his optical writing, particularly the Queries to the Opticks. The dissertation develops these arguments through analysis of Newton’s reading practices, evidenced by his particular method of dog-earing the books he owned and his organizational lists of hermeneutical rules and figurative vocabulary. Additionally, it analyses Newton’s integration of chymical sources and experimentation into his published optical work and its accompanying natural-philosophical discourse of God. While the necessary connectedness of Newton’s thought, the “unified mind” thesis articulated by Dobbs, may no longer be a viable way of conceiving Newton’s various intellectual (and practical) pursuits, this does not mean that they were unrelated. On the contrary, a uniquely textual connection can be seen within Newton’s work with the symbolic texts of alchemy and prophecy: his descriptive-translational approach. Moreover, Newton’s well-documented integration of matter theory and concepts of God are revealed to have an essential foundation in alchemical experimentation and theory.
UV-advanced Oxidation Treatment of Micropollutants in Secondary Wastewaters
Keywords: advanced oxidation processes (AOP)
coagulation
effluent organic matter (EfOM)
micropollutant removal
scavenging capacity
UV/hydrogen peroxide (H2O2)

Ultraviolet light+hydrogen peroxide (UV/H2O2) advanced oxidation is known to effectively oxidise micropollutants in wastewater. Its relatively high cost and energy requirements in comparison to other treatment options, however, have limited its implementation. This research evaluated the use of coagulation as a modification to the pre-tertiary component of the wastewater treatment process. The objective was to reduce the background scavenging capacity of the wastewater as a means of improving the oxidation efficiency of UV/H2O2 while reducing the cost and energy requirements. Effluent organic matter (EfOM) was identified as the primary wastewater component responsible for scavenging of the hydroxyl radicals required for oxidation in UV/H2O2 treatment. The organic constituents of EfOM that are the driving force for its reactivity with the hydroxyl radical were identified as the high molecular weight components (biopolymers) and tryptophan-protein like components. Since EfOM concentration and composition can vary from one water matrix to another, a comparison of secondary wastewaters from membrane bioreactor (MBR) and activated sludge (AS) treatment systems showed that the average scavenging capacity of the AS systems exceeded the average of the MBRs such that MBRs may be more amenable to UV/H2O2 treatment. Coagulation of the wastewater using ferric chloride, aluminium sulphate, and polyaluminium chloride primarily removed the high molecular weight components and significantly reduced the EfOM scavenging capacity. This improvement in wastewater quality also resulted in an improvement in the degradation rates of micropollutant compounds, reduced the energy requirements required to achieve 1-log removal of the compounds, and significantly reduced the costs associated with the UV/H2O2 system. No one coagulant outperformed any of the others; however the study demonstrated that coagulation is a feasible modification for a wastewater treatment plant upstream of an UV-AOP system. It was also found that the cost benefit to UV/H2O2 exceeded the chemical costs of coagulation. Nevertheless, facilities considering UV-AOP systems should weigh the benefits of increasing the H2O2 concentration or using coagulation as the cost savings are relatively similar at high H2O2 concentrations.
"The Passions of A Discontented Minde": The Earl of Essex and Elizabethan Literature and Culture
Keywords: Devereux
Robert
Early Modern Literature
Essex
Earl of
Renaissance England
Subjectivity
History of

Where recent criticism has focused disproportionately on drama as social influence, this dissertation investigates early modern thinking about theatre and the powers of spectacle by exploring the motivations and strategies of Robert Devereux, the third Earl of Essex. Although chiefly the subject of political and historical studies of the late Elizabethan period, I argue that he is an exemplary figure in his capacity to illuminate through his writing and that of his contemporaries the emotional and political implications of the major cultural and literary transitions of the late sixteenth century. My argument, articulated through analyses of medicine, psychology, and religion as well as of literature, begins with the proposition that Essex, like those drawn to him, understood the self, politics, and the theatre as transcendent and collective, where the divisions between and among component individuals were, at most, porous. I suggest that he and his contemporaries were well aware of the odds at which he stood with the prevailing modality of individuation; not only do Essex’s own writings express this malaise, but so, too, do those of his immediate and wider circles, most notably Donne, Greville, Bacon, and Shakespeare. Finally, I turn to the theatre itself, placing the theatrical experience of the Essex circle in the context of the same evolving phenomenology, arguing that in this light the political motives of the bespoke performance of Richard II on the eve of Essex’s rebellion are less revealing than the conspirators’ apparent belief in its potential to rouse its audience to action. In so doing, I both contextualize and limit the utility of “self-fashioning” as a hermeneutic.
The T Cell Co-stimulatory Molecule GITR in the Control and Treatment of a Persistent Viral Infection
Keywords: B cells
Co-stimulation
GITR
LCMV
T cells
TNFR

During persistent viral infections such as human immunodeficiency virus (HIV) in human or lymphocytic choriomeningitis virus (LCMV) in mice, the immune response must achieve a balance between immune control and pathology. CD4 T cell help and co-stimulatory factors remain under-investigated in this context. This thesis explores the role of the Glucocorticoid-Induced Tumour Necrosis Factor Receptor-Related Protein (GITR) and its efficacy as a target for therapy in chronic infection. Mice that lack the T cell co-stimulatory molecule GITR have impaired LCMV-specific CD8 T cell responses and control of chronic LCMV infection. The effects of GITR were lost when mice were depleted of CD4 T cells. GITR directly supports the accumulation of IL-2+ T helper type 1 (Th1) cells, thereby indirectly facilitating early LCMV-specific CD8 T cell responses, late B cell responses, and viral control. In vivo GITR-induced signals were detected at day 3 post-infection, and defects in CD4 T cell accumulation in GITR-deficient T cells were apparent starting at day 5 post-infection. GITR-Ligand (GITRL) is maximally induced on antigen presenting cells at day 2 post-infection, but is downregulated to below baseline levels by day 8 post-infection, and remains so at the chronic stage of infection (day 21 post-infection). GITR expression was highest on regulatory T cells (Tregs) but was also detected on Th1 and LCMV-specific CD8 T cells at day 8 post-infection and was maintained at low levels at day 21 post-infection. As GITRL was limiting at this late time point, we investigated the potential of therapeutic stimulation of GITR using an anti-GITR agonist monoclonal antibody. Anti-GITR treatment at day 21 post-infection increased the frequency and number of LCMV-specific CD8 T cells and improved viral control. These effects of anti-GITR were CD8 T cell-intrinsic. Taken together, this thesis demonstrates that GITR plays an important early role on CD4 T cells to support CD8 T and B cell responses to persistent LCMV infection, but at later time points, anti-GITR therapy acts directly on the CD8 T cells to improve viral control. These studies may inform the development of novel immune therapies for human persistent viral infections as well as malignancies.
Exploring FGL2 Immunomodulatory Activity in Models of Transplantation and Colitis using the FGL2 Overexpressing Mouse
Keywords: Colitis
Regulatory T cells
T cell Immunology
Transplantation

CD4+Foxp3+ regulatory T cells (Treg) are critical in the maintenance of immune homeostasis and in controlling immune responses to pathogens. Fibrinogen-like protein 2 (FGL2) is an immunosuppressive effector of Treg and negatively regulates T cell, B cell and DC responses. To gain further insight into FGL2’s immunoregulatory function, we generated an fgl2Tg mouse that overexpresses FGL2 ubiquitously. FGL2 expression was increased >6-fold in the plasma of fgl2Tg. Fgl2Tg did not have altered growth and development but they were protected against the development of glomerulonephritis seen in fgl2-/- mice. We showed that FGL2 overexpression regulates the function of Treg and T cells. Fgl2Tg Treg had increased suppressive activity in a standard suppression assay. Fgl2Tg T cells were hypo-responsive to stimulation with alloantigen, anti-CD3 and anti-CD28 antibodies, and ConA. In a mouse model of fully mismatched cardiac transplantation, 50% of fgl2Tg recipients showed indefinite graft survival in the absence of immunosuppression. Fully accepted BALB/c cardiac grafts from fgl2Tg recipients lacked evidence of rejection such as vasculitis and cardiomyocyte necrosis. Accepted BALB/c grafts showed increased numbers of Foxp3+ T cells compared to BALB/c grafts from C57BL/6 recipients. Furthermore, the proportion of Foxp3+ to CD3+ T cells was significantly increased in accepted grafts. In a murine model of T cell dependent colitis, the co-transfer of fgl2Tg Treg with C57BL/6 Teff into rag1-/- mice showed enhanced protection from colitis compared to C57BL/6 Treg co-transfer as seen by improved colonic tissue architecture and decreased cellular infiltrate. The cellular infiltrates of fgl2Tg Treg-treated mice had increased proportions of Treg in the mesenteric lymph nodes and the colon. In two in vivo models, FGL2 overexpression skewed the balance of Treg to Teff to a protective, Treg-regulated immune response. In the studies presented in this thesis, FGL2 overexpression was shown to alter the function of Treg and Teff establishing an important role for FGL2 in immune regulation. These studies provide the basis for studies to use FGL2 as a therapeutic to induce transplant tolerance and/or in the treatment of inflammatory bowel disease in the clinic.
Antiretroviral Therapy in Walvis Bay, Namibia
Keywords: Antiretroviral Therapy
Gender
HIV/AIDS
Masculinity
Namibia
Political Ecology

Highly Active Antiretroviral therapy (HAART) is a successful means of treating infection with the Human Immunodeficiency Virus (HIV). Namibia was among the first countries in sub-Saharan Africa to achieve universal access to HAART for HIV-positive citizens through the public sector. In this thesis, I explore treatment outcomes in Walvis Bay, a busy port city at Namibia’s coast. I find that gender is the most important factor shaping HAART, with women reporting for testing and treatment in greater numbers than men, sooner in the course of their illness, and enjoying lower mortality after treatment initiation. There are no compelling biological explanations for this distribution; I postulate a series of socio-cultural and political-ecological factors driving outcomes in Walvis Bay. In particular, changing gender roles and different points of entry into care are important at the individual level. I describe a ‘toxic masculinity’ that, however fragile, actively interferes with testing, treatment, and health-seeking behavior. Female identity, conversely, emerges as altogether more stable and more suited to the clinical and social demands of HAART. More broadly, actions are shaped by large-scale processes of urbanization and globalization, and especially the effects these have on labour, subsistence, and culture change. I conclude by suggesting modifications to the rollout program that may help to distribute the benefits of HAART more equitably through the treatment population. This research has important implications for other countries in sub-Saharan Africa as they gradually move toward universal access to HAART. More generally, it may presage future challenges of globalization and infectious disease.
The Role of the Atypical Cadherin Fat4 during Early Mouse Kidney Induction and Mesenchymal to Epithelial Transition
Keywords: cadherins
duplex kidneys
Fat4
kidney development
Mouse
nephron progenitors

Mammalian kidney development is a tightly regulated process that requires proper signaling among three different cellular compartments: the ureteric bud (UB; epithelial), the condensing mesenchyme (CM) and the stroma. Improper signaling between these three cell lineages can result in renal hypoplasia and/or dysplasia. Fat4 is an atypical cadherin involved in planar cell polarity (PCP), growth and cell adhesion. It has been proposed that Fat4 might work with another atypical cadherin Dachsous1 (Dchs1) and the Golgi-localized kinase Four-jointed1 (Fjx1). My thesis examined Fat4 and novel genetic interactions with Fat4 during two stages of mouse kidney development: nephron progenitor renewal and early kidney induction. I determined that Fat4-/- single mutants have an expanded renal progenitor pool (i.e. larger CM aggregates) and found that this phenotype is independent of core PCP and Hippo signaling. Loss of Dchs1 also resulted in expansion of the CM. Tissue-specific deletions show that Fat4 acts non-autonomously in the renal stroma to regulate the nephron progenitor pool. Gene expression analyses demonstrated that BMP, Notch and FGF signaling are altered in Fat4 mutants. I also found that Fat4-/-;Fjx1-/- double mutants exhibit duplex kidneys. Since increased GDNF-RET signaling also leads to duplex kidneys, I reduced GDNF signaling by examining GDNF+/-;Fat4-/-;Fjx1-/- triple mutants. Importantly, these mice did not exhibit duplex kidneys, suggesting that Fat4 and Fjx1 suppress excessive levels of GDNF-RET signaling. Overall, my thesis supports a model whereby 1) FAT4 in the stroma binds to DCHS1 in the CM to restrict renal progenitor self-renewal and, 2) Fat4 and Fjx1 restrict GDNF-RET signaling during kidney induction and subsequent branching.
Novel Boron Subphthalocyanines for Organic Electronic Devices
Keywords: charge carrier
mobility
photovoltaic
singlet fission
triplet

Boron subphthalocyanines (BsubPcs) are a class of organic semiconductor materials that have been identified as having desirable properties for use in photovoltaic devices due to their strong light absorbance and the flexibility to develop tunable chemical derivatives. In particular, a lack of variety in available electron acceptors is an area where BsubPc derivatives can be readily substituted into existing photovoltaic device architectures. There are, however, no metrics to facilitate the rapid screening of different BsubPc derivatives. In this thesis, admittance spectroscopy is used to measure charge carrier mobility of these BsubPc derivatives, and photovoltaic cells are fabricated to evaluate these derivatives’ performance in devices. We find that the measured electron carrier mobilities in thin films of BsubPc correlate with the single crystal structural parameters determined by X-ray diffraction. We also find that for BsubPcs, electron mobility measured by admittance spectroscopy is insufficient to predict photovoltaic performance when BsubPcs are used as an electron accepting layer in a device. BsubPc derivatives, however, are discovered as a new class of versatile molecules that can be designed and synthesized for use in photovoltaic devices to harvest singlet fission derived triplet excitons and consequently boost photovoltaic device photocurrent. This thesis also reports vacuum system design and construction to address experimental challenges arising from dealing with low solubility, high molar mass materials and limited amounts of high purity material.
A Struggle for Hearts and Minds: Statebuilding and Origins of Political Legitimacy in Post-2001 Afghanistan
Keywords: Afghanistan
Political legitimacy
Political trust
Statebuilding

This thesis tackles a central puzzle of externally-assisted statebuilding: why international efforts to rebuild states with more capacity do not necessarily result in more internal legitimacy. It examines the dynamics of state legitimacy in Afghanistan since the fall of the Taliban by tracing dominant understandings of political legitimacy that came to characterize the international statebuilding project; (de)legitimizing practices of the Afghan state and external actors; and in turn, citizen evaluations of state institutions. Unlike scholars who interpret legitimacy as automatically following from particular kinds of institutions (namely those associated with liberal democracy), this thesis suggests that legitimacy is best understood as resulting from complex interactions between state, society and – in the context of externally-assisted statebuilding – international actors. The study finds that despite initial optimism and the existence of a state that provides more to its citizens than has historically been the norm, many Afghans have grown critical of state institutions. This shift in perceptions owes in large part to the conflicted approach to governance taken by the international statebuilding project. I argue that international actors first positioned good governance as a core criterion against which to judge the legitimacy of the Afghan state, which represented a departure from traditional understandings of political legitimacy in the country. Despite this emphasis, external actors then contributed to a dysfunctional governance environment characterized by a polarization of power, an uneven distribution of resources, and high levels of external intrusiveness in local politics, especially in Afghanistan’s insecure southern provinces. Aligning with these arguments, this dissertation finds that local attitudes towards international actors are instrumental in determining Afghans’ perceptions of state legitimacy, especially in the South where external actors were more invasive in shaping the statebuilding project. Secondly, it finds that key governance indicators – namely the state’s perceived inclusiveness, responsiveness and fairness – are critical drivers of legitimacy, particularly in the South where the gap was especially great between the rhetoric of good governance and governance failings on the ground. These findings help to position political legitimacy at the center of conversations about statebuilding efforts, and contribute to a richer understanding of state legitimation during international intervention.