VictorJuiz/thesis huggingface dataset:
Structural and Functional Studies of ATP7B, the Copper(I)-transporting P-type ATPase Implicated in Wilson Disease

Copper is an integral component of key metabolic enzymes. Numerous physiological processes depend on a fine balance between the biosynthetic incorporation of copper into proteins and the export of excess copper from the cell. The homeostatic control of copper requires the activity of the copper transporting ATPases (Cu-ATPases). In Wilson disease the disruption in the function of the Cu-ATPase ATP7B results in the accumulation of excess copper and a marked deficiency of copper-dependent enzymes. In this work, the structure of ATP7B has been modeled by homology using the Ca-ATPase X-ray structure, enabling a mechanism of copper transport by ATP7B to be proposed. The fourth transmembrane helix (TM4) of Ca-ATPase contains conserved residues critical to cation binding and is predicted to correspond to TM6 of the ATP7B homology model, containing the highly conserved CXXCPC motif. The interaction with Cu(I) and the importance of the 3 cysteines in TM6 of ATP7B has been shown using model peptides. ATP7B has a large cytoplasmic N-terminus comprised of six copper-binding domains (WCBD1-6), each capable of binding one Cu(I). Protein-protein interactions between WCBDs and the copper chaperone Atox1 has been shown, contrary to previous reports, to occur even in the absence of copper. 15N relaxation measurements on the apo and Cu(I)-bound WCBD4-6 show that there is minimal change in the dynamic properties and the relative orientation of the domains in the two states. The domain 4-5 linker remains flexible, and domain 5-6 is not a rigid dimer, with flexibility between the domains. Copper transfer to and between WCBD1-6 likely occurs via protein interactions facilitated by the flexibility of the domains with respect to each other. The flexible linkers connecting the domains are important in giving the domains motional freedom to interact with Atox1, to transfer copper to other domains, and finally to transfer copper to the transmembrane site for transport across the membrane.

Keywords: Wilson disease
ATP7B
Cu-ATPase
Atox1
Cu(I)
Copper
NMR relaxation
dynamics
rotational diffusion
homology modelling
Advisor: Forman-Kay, Julie Deborah
Sarkar, Bibudhendra
Pressure Induced Quantum Phase Transitions in Metallics Oxides and Pnictides

Quantum phase transitions occur as a result of competing ground states. The focus of the present work is to understand quantum criticality and its consequences when the competition is between insulating and metallic ground states. Metal-insulator transitions are studied by means of electronic transport measurements and quantum critical points are approached by applying hydrostatic pressure in two different compounds namely Eu2Ir22O 7 and FeCrAs. The former is a ternary metal oxide and the latter is a ternary metal pnictide. A major component of this work was the development of the ultra-high pressure measurements by means of Anvil cells. A novel design is introduced which minimizes the alignment accessory components hence, making the cell more robust and easier to use. Eu2Ir22O7 is a ternary metal oxide and a member of the pyrochlore iridate family. Resistivity measurements under pressure in moissanite anvil cells show the evolution of the ground state of the system from insulating to metallic. The quantum phase transition at Pc ∼ 6 GPa appears to be continuous. A remarkable correspondence is revealed between the effect of the hydrostatic pressure on Eu2Ir22O7 and the effect of chemical pressure by changing the R size in the R2Ir2O7 series. This suggests that in both cases the tuning parameter controls the t2g bandwidth of the iridium 5d electrons. Moreover, hydrostatic pressure unveils a curious cross-over from incoherent to conventional metallic behaviour at a T* > 150 K in the neighbourhood of Pc, suggesting a connection between the high and low temperature phases. The possibility of a topological semi-metallic ground state, predicted in recent theoretical studies, is explained. FeCrAs is a ternary metal pnictide with Fermi liquid specific heat and susceptibility behaviour but non-metallic non-Fermi liquid resistivity behaviour. Characteristic properties of the compound are explained and compared to those of superconducting pnictides. Antiferromagnetic (AFM) order sets in at ∼125 K with the magnetic moments residing on the Cr site. Pressure measurements are carried out in moissanite and diamond anvil cells in order to suppress the AFM order and resolve the underlying electronic transport properties. While AFM order is destroyed by pressure, the non-metallic non-Fermi liquid behaviour is shown to be robust against pressure.

Keywords: pressure
quantum
Advisor: Julian, Stephen R.
The Making of International Trade Law: Sugar, Development, and International Institutions

This historical study focuses on the multilateral regulation of sugar to provide a broader institutional history of trade law. I argue that theories of development and tensions between the global North and South have always been central to the formation, function, and transformation of international trade institutions. Sugar consistently appears as a commodity throughout the history of modern trade law. The sugar trade provides an immediate way for us to work through larger questions of development, free trade, and economic world order. I examine the 1902 Brussels Sugar Convention, the 1937 International Sugar Agreement (ISA), and the 1977 ISA. These international agreements provide a narrative of the development ideas and concerns that were a central feature of the trade institutions that preceded the World Trade Organization. In the context of the sugar trade over the last century, very few challenged the idea of free trade. Instead, they debated over what free trade meant. The justification for free trade and the function of those international institutions charged to implement trade agreements has changed throughout history. Yet, despite multiple historical and doctrinal definitions of free trade, two dynamics remain consistent: trade law has always been configured by the relationship between policies of tariff reduction and market stabilization and has been defined by the tension between industrial and agricultural interests.

Keywords: International trade
Law and development
Advisor: Rittich, Kerry
Host Inflammatory Pathways in Malaria Infection: Potential Therapeutic Targets and Biomarkers of Disease Severity

Severe malaria infections cause almost 1 million deaths annually, mostly among non-immune African children. The pathogenesis of severe malaria is poorly understood. It is increasingly appreciated that while host innate immune responses such as inflammation and phagocytosis are critical for control of parasite replication, they can become dysregulated and contribute to severe disease. The goals of this work were: (1) to characterize inflammatory responses to malaria by defining their relationship to phagocytosis and identifying novel molecular mediators, and (2) to evaluate the utility of biomarkers of inflammation and other host responses for predicting outcome in severe malaria infection. Using an in vitro model of the malaria-macrophage interaction, inflammatory and phagocytic responses to Plasmodium falciparum were found to be partially coupled. Activation of Toll-like receptors (TLRs) by purified parasite components increased internalization of parasitized erythrocytes, but uptake of parasitized erythrocytes did not require TLRs, nor did it trigger cytokine production via TLRs or other receptors. Two candidate molecules – Triggering receptor expressed on myeloid cells-1 (TREM-1) and Chitinase-3 like-1 (CHI3L1) – did not appear to critically modulate inflammation to malaria in vitro or in murine models. However, exogenous TREM-1 activation enhanced the pro- inflammatory nature of the response to P. falciparum, with potential implications for malarial-bacterial co-infection. CHI3L1-deficient mice showed a trend towards earlier death in experimental cerebral malaria, suggesting that CHI3L1 may protect against severe malaria; however, further investigation in more informative models is required. Admission levels of plasma TREM-1, CHI3L1, and other biomarkers of inflammation and endothelial activation were increased in Ugandan children with severe malaria. Simple combinations of these biomarkers predicted mortality among severe malaria patients with high accuracy, warranting larger validation studies. Taken together, these findings identify host responses as putative targets for adjunctive therapies, and suggest the utility of host biomarker combinations as prognostic tests for severe malaria.

Keywords: Malaria
Innate immunity
Inflammation
Phagocytosis
Infectious disease
Biomarkers
Advisor: Kain, Kevin C.
Using High Resolution Measurements and Models to Investigate the Behaviour of Atmospheric Ammonia

Atmospheric ammonia contributes to a number of environmental problems, but many questions regarding the behaviour of ammonia in the atmosphere remain. Field studies were performed to investigate the gas-particle partitioning of ammonia, the surface-atmosphere exchange, and to compare measurements with an online chemical transport model and offline thermodynamic models. A state-of-the-art instrument, Quantum Cascade Tunable Infrared Laser Differential Absorption Spectrometer (QC-TILDAS), with a novel sampling technique was used to measure ammonia. The detection limit of the instrument was found to be 690 ppt at 1 Hz and 42 ppt when averaged to 5 minutes. The uncertainty in the measurement is 10 % based on calibration from a permeation tube source. Laboratory and field tests show the ammonia time response to be slower at lower mixing ratios, and when the ambient relative humidity is high. Observations from the first field campaign discussed, the Border Air Quality and Meteorology Study (BAQS-Met), were compared to a chemical transport model AURAMS (A Unified Regional Air quality Modeling System). The model was often biased low in ammonia and ammonium and predicted an incorrect diurnal profile. Observations suggest a coupling between gas-particle and surface-atmosphere equilibria whereby a large atmospheric condensation sink induces emission of ammonia from the surface. A simple approach at representing the ammonia bi-direction flux more closely matched the observations, indicating that a fully coupled bi-directional flux parameterization in chemical transport models is necessary to accurately predict atmospheric ammonia. A suite of instrumentation during the CalNex 2010 field campaign allowed for in-depth analysis of gas-particle partitioning and estimation of aerosol pH. Observations were compared to predictions from the thermodynamic equilibrium models ISORROPIA and E-AIM. Deviations form equilibrium were found during periods of high levels of aerosol nitrate and positive net charge. The gas-particle partitioning was found to be very sensitive to aerosol pH.

Keywords: ammonia
field measurements
model comparison
gas-particle partitioning
surface-atmosphere exchange
Advisor: Murphy, Jennifer
Acute Post-ischemic Seizures are Associated with Increased Mortality and Brain Damage Following Hypoxia-ischemia in Adult Mice

Post-stroke seizures are associated with worsened outcome following stroke, but the underlying pathophysiology is poorly understood. Here I combined behavioral, electrophysiological and histological assessments to examine acute seizures in adult mice following hypoxia-ischemia (HI). C57BL/6 mice aged 4-9 months received a permanent occlusion of the right common carotid artery and were then exposed to systemic hypoxia (8% O2, ~30 minutes). The HI episode resulted in decreases in cerebral blood flow, suppression of EEG activities and extensive brain injury in the hemisphere ipsilateral to the carotid artery occlusion. Generalized motor seizures were observed within 72 hours following HI. These seizures occurred nearly exclusively in animals with the extensive ipsilateral brain injury, but their generation was not associated with EEG discharges in bilateral hippocampal and cortical areas. Animals exhibiting these seizures had a high rate of mortality. Post-HI treatments with diazepam and phenytoin suppressed these motor seizures and improved post-HI animal survival. Based on these data, I conclude that these seizures are a consequence of HI brain injury, contribute to mortality following HI, and that they may originate from deep subcortical structures.

Keywords: Seizure
Ischemia
Advisor: Carlen, Peter Louis
Genetic and Environmental Risk Factors for Psoriatic Arthritis among Patients with Psoriasis

Aim: Most of the patients with Psoriatic Arthritis (PsA) develop arthritis following the onset of psoriasis. The aim of the project is to identify genetic and environmental risk factors for PsA among psoriasis patients. Methods: PsA and psoriasis patients from two prospective cohorts were analyzed. The incidence of PsA among a prospective cohort of psoriasis patients was assessed. The distribution of Human Leukocyte Antigen (HLA) alleles and Killer Cell Immunoglobulin like Receptors (KIRs) and their combinations was compared between PsA, psoriasis and healthy controls. In addition, the association between a wide range of environmental exposures and PsA was evaluated by comparing the frequencies of exposed individuals among patients with recent onset PsA and psoriasis. The association between smoking and PsA was further investigated. The prevalence of smoking was in PsA, psoriasis and the general population. The interaction between HLA-C*06 and smoking was also tested. Results: The genetic analysis revealed several HLA-B alleles and HLA haplotypes that are associated with PsA compared to psoriasis and can potentially serve as independent markers for PsA. Furthermore, several combinations of KIR genes and their respective HLA ligands were also found to be associated with PsA compared to psoriasis. The incidence of PsA among psoriasis patients was found to be higher than previously reported and its rate was constant over time. HLA-C*06 was associated with increased interval between psoriasis onset and PsA. Several environmental factors including occupational exposures, infections, injuries and smoking were associated with development of PsA. The prevalence of smoking was decreased among PsA patients compared to psoriasis. The interaction between HLA-C*06 and smoking was found to be significant. Conclusions: Genetic and environmental factors are associated with the development of PsA in patients with psoriasis. These factors may serve as specific markers to identify psoriasis patients at increased risk for PsA.

Keywords: Psoriatic Arthritis
Genetic epidemiology
Risk factor
Psoriasis
Advisor: Gladman, Dafna D.
China's State Capitalist Turn: Political Economy of the Advancing State

The thesis explores puzzling change in Chinese state sector over the past two decades. China’s debt-ridden state-owned enterprises (SOEs) were long seen as the most thorny reform dilemma; however, in the past decade, the surging profitability of large SOEs in the so-called “monopoly sectors” (longduan hangye 垄断行业) have made them lynchpins of an emerging state capitalist system. The main argument is that the state sector’s apparent reversal of fortunes is, in large measure, a legacy of the brief period of neoconservative rule (1989-1992) following the Tiananmen uprising in spring 1989. The fleeting ascendance of Chen Yun’s neoconservative faction provided them the opportunity to redirect the reform course set by Deng Xiaoping and embed a market vision which saw SOEs as pillars of the economy. The neoconservative leadership laid the normative and institutional foundations of a robust SOE-directed industrial policy regime which has gained momentum through the 1990s and into the last decade. The study also sheds lights on the political and economic drivers of China’s unfolding market order through analysis of the industry foundations of China’s emerging state capitalist system. In recent years, state ownership has concentrated in some industries and largely retreated from others. What is driving this process of what Pei (2006) terms the “selective withdrawal” of the state from the economy? To address this question, the nature of ownership change across Chinese industry in recent years is first analyzed. Focus then shifts to comparative analysis of the reform pathway of two industries in which state ownership remains dominant: telecommunications and airlines. Combining insights from the partial reform equilibrium model and historical institutionalism, the study argues that both the particularist interests of “short-term winners” in industry and the neoconservative policy legacy have left an imprint on the process of selective withdrawal.

Keywords: Chinese Capitalism
State Sector Reform
State Owned Enterprises
Industrial Policy
Advisor: Pauly, Louis
Emotion in Speech: Recognition by Younger and Older Adults and Effects on Intelligibility

Spoken language conveys two forms of information: transactional (content, what is said) and interactional (how it is said). The transactional message shared during spoken communication has been studied extensively in different listening conditions and in people of all ages using standardized tests of speech intelligibility. However, research into interactional aspects of speech has been more limited. One specific aspect of interactional communication that warrants further investigation is the communication of emotion in speech, also called affective prosody. A series of experiments examined how younger and older adults produce affective prosody, recognize emotion in speech, and understand emotional speech in noise. The emotional valence and arousal properties of target words from an existing speech intelligibility test were rated by younger and older adults. New stimuli based on those words were recorded by a younger female and an older female using affective prosody to portray seven emotions (anger, disgust, fear, happiness, pleasant surprise, sadness, neutral). Similar to previous studies, the acoustical parameter that best differentiated the emotions was fundamental frequency (F0). Specifically, discriminant analysis indicated that emotional category membership was best predicted by the mean and range of F0. Overall, recognition of emotion and intelligibility were high. While older listeners made more recognition errors and had poorer intelligibility overall, their patterns of responding did not differ significantly from those of the younger listeners on either measure. Of note, angry and sad emotions were recognized with the highest degree of accuracy, but intelligibility was highest for items spoken to portray fear or pleasant surprise. These results may suggest that there is a complementarity between the acoustic cues used to recognize emotions (how words are said) and those used to understand words (what is said). Alternatively, the effect of emotion on intelligibility may be modulated primarily by attentional rather than acoustical factors, with higher performance associated with alerting emotions.

Keywords: emotion
aging
speech intelligibility
Advisor: Pichora-Fuller, Margaret Kathleen
A Trace of Genocide: Racialization, Internal Colonialism and the Politics of Enuncation

This analysis examines the implicatedness of the self as an embodied space of marginality, knowledge, and resistance to the discursive and material effects of systemic oppression. It explores the implications and possibilities as they relate to social collectives [in nation-state contexts] in resisting and contesting the constraining forces of dominant/dominating institutionalized power and authority in the context of speaking and/or enunciating from the space of abjectification, racialization, and outcastness that has been constructed historically by the nation-state of Britain as a body codified as included-as-excluded-as-removed from the dominant sociopolitical collective’s sense of self and identity? This study argues that enunciation in this form carries with it a politics of ontological transformation that has profound implications for the social collective that is Britain as a whole specifically in the context of social justice affirmation and the reclamation [and assertion] of a collective sense of self that is grounded in a refusal and contestation of the multi-layered hegemonic conceptual frameworks that continue to naturalize, {re}produce and sustain systemic oppression as a state of permanency [Bell, 1992]. This study will explore the permanency of oppression further in relation to the discursive and material negation and amputation of social difference [i.e. class, gender, disability, and sexuality] while centering race [and its prostheticization] as a salient organizing tool in the (re)production of a hegemonic social order. To this end this study utilizes two key interconnecting concepts, internal/internalized colonialism, and racialization. ii It suggests that racialization mediated and channeled by and through a process of internal/internalized colonialism underpins the hegemonic social order of Britain and as such both terms are re-conceptualized and subjected to a complex analysis. Finally, this study examines the theoretical possibilities for developing an anti-racialization framework as a politics of enunciation that makes usage of the concept of racialization as a tool for [1] demystifying systems of oppression, [2] understanding the processes of collective implicatedness in oppression, [3] refusing pathologization and [4] mobilizing transformation through and within a refusal of the amputative and negative capacities of the racialization process.

Keywords: racialization
internal colonialism
moral welfare work
eugenics
pathologization
Barnardo's
nation state and Britain
Advisor: Dei, George Jerry Sefa
Proliferation and Potential of Neural and Retinal Stem Cells

The term “stem cell” is often broadly applied to a range of cell types that are relatively undifferentiated and have some capacity for proliferation. In this thesis, I employ a strict definition of stem cells as cells that are capable of both self-renewal and multilineage differentiation. These properties are tested in single precursor cells from the forebrain and its derivative, the retina, using clonal assays. Poor survival is a common problem in single cell cultures, and I show that low oxygen dramatically improves viability in neural stem cells clonally derived from mouse embryonic stem cells, as well as in cultured forebrain neural stem cells. Caspase-dependent and apoptosis-inducing factor-dependent cell death pathways were found to be differentially influenced in low oxygen culture of early, primitive and later, definitive neural stem cells. I isolate precursors from 2 separate regions of the adult mouse forebrain, the lateral ventricle and the hippocampus and argue that only cells resident in the lateral ventricle can be classified as stem cells while the hippocampus contains restricted progenitor cells. Unlike neural stem cells, the very existence of retinal precursors in the adult mammal is controversial. I investigate methods to prospectively identify a rare stem cell population in the pigmented ciliary epithelium of the adult mouse eye and show that, although this population intrinsically gives rise to all retinal cell types, cells can be directed specifically towards a photoreceptor fate by the addition of exogenous factors to the culture media. Pigmentation of retinal stem cells is used as a convenient marker to isolate a retinal stem cell from human embryonic stem cells differentiating under conditions known to promote neural differentiation. Retinal stem cells derived from human embryonic stem cells have highly similar properties to those directly isolated from the eye, and their progeny can similarly be driven to differentiate into photoreceptors. The findings presented in this thesis help to define intrinsic properties of adult neural and retinal precursors and provide a basis for manipulating these cells, potentially for future use in clinical applications.

Keywords: Stem cell
forebrain
retina
Advisor: Kooy, Derek van der