VictorJuiz/thesis huggingface dataset:
Agobard of Lyon: An Exploration of Carolingian Jewish-Christian Relations

Agobard of Lyon has usually been studied because of his writings about Jews. This dissertation likewise began from a desire to understand Agobard’s anti-Jewish writings, their content, motives, and impact. Approaching that topic from the basis of Agobard’s whole corpus of writings, however, forces an acknowledgment that Agobard cannot be reduced to simply “Agobard and the Jews,” although the subject clearly created a great amount of anxiety for him. Also, by beginning with Agobard’s own works, this dissertation discusses him on his own terms first, without relying on the historiographical tradition which defines him as a Visigoth, a tradition ultimately found wanting. This dissertation effectively dismantles the model of Agobard as a Visigoth working in the Carolingian world, and replaces it with a model of Agobard as a Carolingian. As such, this study explores his anti-Judaism in terms of his immediate historical context and links it with his other anxieties and the Carolingian desire for a perfect, Christian, society. Doing so also opens the door for a re-evaluation of the traditional interpretation of the Carolingian period as the last “golden age” of European Jews outside of Muslim Spain. At its conclusion, this study argues that the Carolingians, by deliberately attempting to create a Christian society, however “well” they treated Jews in their own time, laid some of the ideological groundwork for the later isolation and persecution of Jews in Europe. The introduction begins the exploration of Agobard’s historical context by discussing the history of both Louis’s empire and Agobard’s Lyon. The first chapter provides a quick summary of his life and works. From there, the dissertation turns to its in-depth study of Agobard in the second through fourth chapters. An analysis of his main anti-Jewish work, De iudaicis superstitionibus et erroribus in Chapter 3 is prefaced by a study of the character and possible roots of his anti-Judaism in Chapter 2. The last chapter looks at Agobard’s other concerns, how they relate to his writings on Judaism, and finally how his great amount of worry around Judaism can help shape our understanding of medieval Jewish-Christian relations.

Keywords: Agobard of Lyon
Jewish-Christian relations
anti-Judaism
Carolingians
Advisor: Meyerson, Mark
Everett, Nicholas
The Role of the Glutamatergic System in Psychiatric Behavioral Endophenotypes in Mice: Implications for Schizophrenia

Reduced activity of the N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a glycine site on the NR1 subunit that may be a promising therapeutic target for psychiatric illness. Recently, D-serine has been discovered to be a high-affinity endogenous activator of the NMDAR glycine site. Levels of D-serine in the brain are controlled by its synthesis enzyme serine racemase (Srr) and its catabolic enzyme D-amino acid oxidase (DAO). This work investigates the NMDAR glycine site, D-serine, and D-serine-regulatory enzymes Srr and DAO in the pathophysiology and treatment of symptomatology relevant to schizophrenia and other psychiatric disorders. Pharmacological and genetic mouse models were used to alter glycine site function and D-serine availability. Behavioral responses in these models were assessed. Administration of exogenous D-serine and the glycine transporter 1 (GlyT-1) inhibitor ALX-5407 improved performance of C57BL/6J mice in behavioral tests examining prepulse inhibition (PPI) or latent inhibition (LI). These compounds also reversed impairments induced by the NMDAR antagonist MK-801, and produced similar beneficial effects to the classical atypical antipsychotic clozapine. Mice carrying a point mutation that leads to diminished NMDAR glycine site function demonstrated abnormally persistent LI and deficits in social approach and spatial recognition that were reversible by D-serine or clozapine administration. Similarly, mutant mice that lacked Srr function and had a severe reduction in D-serine displayed impairments in sociability, PPI, spatial recognition and memory. Behavioral deficits in mice without Srr were exacerbated by MK-801 and rescued by treatment with D-serine or clozapine. A genetically-induced loss of DAO function in mice resulted in the elevation of brain D-serine levels, and produced improvements in spatial reversal memory and extinction of a learned response in the Morris water maze, consistent with the effects of exogenous D-serine application in wild-type mice. Thus, deficiencies in NMDAR glycine site function and D-serine availability produce behavioral disturbances that are relevant to the negative and cognitive symptoms of schizophrenia. Activation of the NMDAR glycine site by D-serine, GlyT-1 inhibition, or diminished DAO activity may be beneficial for the treatment of schizophrenia and other psychopathologies involving cognitive dysfunction and persistent repetitive behaviors.

Keywords: NMDA receptor
D-serine
genetic animal models
behavioral neuroscience
schizophrenia
Advisor: Roder, John C.
The Role of Munc18 Proteins in Physiologic and Pathologic Exocytoses in the Pancreatic Acinar Cell

Distinct membrane fusion events in the polarized pancreatic acinar cell involve highly specific interactions between distinct sets of SNARE proteins forming exocytotic complexes, whose assembly is modulated by distinct Munc18 proteins. The Munc18 isoform responsible for these exocytotic events in the acinar cell is unknown. Here, I postulate Munc18b to regulate apical exocytosis in the acinar cell. Current dogma for the pathogenesis of acute pancreatitis, including alcoholic pancreatitis, is mis-targeting and deregulated fusion of zymogen granules with lysosomal bodies in the acinar cells. This derangement results in premature activation of proteolytic zymogens and autophagic digestion of cellular contents. I have hypothesized an alternate mechanism, which is pathologic exocytosis occurring at the basolateral plasma membrane, and further propose Munc18c to mediate this process in alcoholic pancreatitis. The aims of this thesis are to demonstrate the roles of Munc18b and Munc18c in regulated apical exocytosis and pathologic basolateral exocytosis underling alcoholic pancreatitis, respectively. In Chapter Three, using both real-time and static imaging techniques and biochemical tools, I demonstrated that Munc18c is dissociated from the acinar basal plasma membrane (BPM) when stimulated with postprandial CCK8 preceding preincubation of acini with postprandial 20-50mM ethanol concentrations. This activated Syntaxin (Syn)-4 and SNAP-23 on the BPM to complex with VAMP proteins on the granule to form the exocytotic SNARE complex that triggered basolateral exocytosis. This molecular mechanism of pathologic basolateral exocytosis was recapitulated in an Ethanol-diet rat model of pancreatitis. In Chapter Four, I determined Munc18b to be in the apical pole of the acinar cell to appropriately bind cognate Syn-2 and Syn-3 in the apical PM and ZGs. Here, I examined the structure-function of Munc18b on amylase secretion by employing Munc18b mutants with distinct affinities to Syn-2 and Syn-3. In Chapter Five, I discovered a novel EF-hand Ca2+-binding protein called Cab45b, which binds Munc18b to regulate its membrane targeting and interactions with Syntaxins in the acinar cell in a manner that influenced Ca2+-induced amylase release. Taken together, these studies clarify our understanding of the role of Munc18 proteins involved in regulated and pathologic membrane fusion events underlying physiologic digestive enzyme secretion and clinical alcoholic pancreatitis.

Keywords: Pancreatitis
Exocytosis
Acinar Cell
Molecular Biology
SNARE proteins
Munc18
Advisor: Gaisano, Herbert Young
Activity-based Functional Annotation of Unknown Proteins: HAD-like hydrolases from E. coli and S. cerevisiae

In all sequenced genomes, a large fraction of predicted genes encodes proteins of unknown biochemical function and up to 15% of the genes with ‘‘known’’ function are mis-annotated. Several global approaches are being employed to predict function, including sequence similarity searches, analysis of gene expression, protein interaction, and protein structure. Enzymes comprise a group of target proteins that require experimental characterization for accurate functional annotations. Here I applied enzyme genomics to identify new enzymes by screening individually purified proteins for enzymatic activity under relaxed reaction conditions, which allowed me to identify the subclass or sub-subclasses of enzymes to which the unknown protein belongs. Further biochemical characterization of proteins was facilitated by the application of secondary screens with natural substrates (substrate profiling). Application of general enzymatic screens and substrate profiling greatly sped up the identification of biochemical function of unknown proteins and the experimental verification of functional predictions produced by other functional genomics approaches. As a test case, I used this approach to characterize the members of the haloacid dehalogenase (HAD)-like hydrolase superfamily, which consists mainly of uncharacterized enzymes, with a few members shown to possess phosphatase, beta-phosphoglucomutase, phosphonatase, and dehalogenase activities. Low sequence similarity between the members of the HAD superfamily precludes the computational prediction of their substrates and functions. Using a representative set of 80 phosphorylated substrates I characterized the phosphatase activities of 21 soluble HADs from Escherichia coli and seven soluble HADs from Saccharomyces cerevisiae. E. coli HADs show broad and overlapping substrate specificity against a wide range of phosphorylated metabolites. The yeast enzymes were more specific, and one protein also showed protein phosphatase activity. Comparison of HAD substrate profiles from two model organisms showed several “functional niches” that are occupied by HADs, which include hydrolysis of nucleotides, phosphoglycolate, phosphoserine, and pyridoxal phosphate. I proposed the cellular function for a number of HADs from both organisms based on substrate specificities. The physiological relevance of the phosphatase activity with the preferred substrate was validated in vivo for one of the HADs, E. coli YniC.

Keywords: Biochemical proteomics
enzymatic activity
haloacid dehalogenase-like hydrolases
substrate specificity
phosphatases
uncharacterized proteins
Advisor: Edwards, Aled M.
Pre-quantization of the Moduli Space of Flat G-bundles

This thesis studies the pre-quantization of quasi-Hamiltonian group actions from a cohomological viewpoint. The compatibility of pre-quantization with symplectic reduction and the fusion product are established, and are used to understand the necessary and sufficient conditions for the pre-quantization of M(G,S), the moduli space of at flat G-bundles over a closed surface S. For a simply connected, compact, simple Lie group G, M(G,S) is known to be pre-quantizable at integer levels. For non-simply connected G, however, integrality of the level is not sufficient for pre-quantization, and this thesis determines the obstruction, namely a certain 3-dimensional cohomology class, that places further restrictions on the underlying level. The levels that admit a pre-quantization of the moduli space are determined explicitly for all non-simply connected, compact, simple Lie groups G. Partial results are obtained for the case of a surface S with marked points. Also, it is shown that via the bijective correspondence between quasi-Hamiltonian group actions and Hamiltonian loop group actions, the corresponding notions of prequantization coincide.

Keywords: Symplectic Geometry
Homotopy Theory
Advisor: Meinrenken, Eckhard
Selick, Paul
A Two-colour Reporter Screen and Application to Cell Cycle Transcription

Development of genome-wide reagents has allowed systematic analysis of gene function. The experimental accessibility of budding yeast makes it a test-bed for technology development and application of new functional genomic tools and resources that pave the way for comparable efforts in higher eukaryotes. In this Thesis, I describe a two-color GFP-RFP reporter system I developed to assess the consequences of genetic perturbations on a promoter of interest. The dual-reporter system is compatible with the synthetic genetic array methodology, an approach that enables marked genetic elements to be introduced into arrays of yeast mutants via an automated procedure. I use this approach to probe cell cycle-regulation of histone gene transcription by introducing an HTA1 promoter-GFP reporter gene construct into an ordered array of ~4500 yeast deletion mutants. I scored defects in reporter gene expression for each mutant, generating a quantitative analysis of histone promoter activity. The results of my screen motivated a number of follow-up experiments, including chromatin immunoprecipitation, transcript profiling and genome-wide analysis of nucleosome positions, which revealed a previously unappreciated pathway that specifies regions of repressed chromatin in a cell cycle-sensitive manner. A novel aspect of this pathway is that it involves histone chaperones and a chromatin boundary element. Specifically, we discovered that the histone chaperone Rtt106 works with two other chaperones, Asf1 and the HIR complex, to create a repressive chromatin structure at histone promoters which is bound by the protein Yta7. It was clear from previous work that Asf1 and HIR repress transcription at HTA1 and that HIR localizes to and functions through a specific element in histone promoters. However, there was no previous data demonstrating a role for Rtt106 in cell cycle-dependent gene transcription. In sum, I describe a new genomic screen that I used to discover a novel pathway regulating cell cycle-dependent transcription. While I examined histone gene expression as proof-of-principle, my screening system could be applied to virtually any pathway for which a suitable reporter can be devised. I anticipate this methodology will enable yeast researchers to collect quantitative data on hundreds of gene expression pathways.

Keywords: Saccharomyces cerevisiae
functional genomics
Advisor: Andrews, Brenda
Investigation of the Mechanisms of Drug-induced Agranulocytosis

Idiosyncratic drug reactions (IDRs) are unpredictable adverse drug reactions. Their exact mechanisms are unknown but most appear to be immune-mediated. Mechanistic studies require valid animal models, but there are very few available and none for the study of drug-induced agranulocytosis. Thus, the first part of my thesis has focused on the development of an animal model of agranulocytosis. We pursued many attempts to develop one in rabbits, guinea pigs, and rats by treatment with aminopyrine, amodiaquine, and clozapine and manipulating the factors hypothesized to be involved in the mechanism of IDRs such as reactive metabolite formation/detoxication and immune stimulation. Clozapine-induced agranulocytosis is not associated with immune memory, which suggests that it may not be immune-mediated. Therefore, other factors, specifically selenium and vitamin C deficiencies, were assessed as possible risk factors for clozapine-induced agranulocytosis. Despite many attempts, we were not able to develop an animal model of idiosyncratic drug-induced agranulocytosis. The second part of this thesis was focused on investigating the effects of clozapine on neutrophils. It is known that the reactive metabolite of clozapine increases neutrophil apoptosis in vitro; however, it was not clear that the conditions of these experiments reflect in vivo conditions. Therefore, the effect of clozapine on neutrophil kinetics in vivo was examined. We found that clozapine treatment decreased the half-life of circulating neutrophils and increased the rate of release of neutrophils in rabbits. Thus, even though these animals did not develop agranulocytosis clozapine did appear to cause neutrophil damage that was compensated for by an increased production of neutrophils. Failure of the bone marrow to keep up with the increased rate of neutrophil destruction in certain individuals could result in agranulocytosis. Alternatively, damage to neutrophils could lead to an immune response in some patients that results in agranulocytosis. The failure to develop an animal model of drug-induced agranulocytosis despite many attempts using interventions based on the current mechanistic hypotheses suggests that these hypotheses are wrong. However, it is also possible that we are just unable to overcome the default response of immune tolerance; future studies will examine this possibility and the mechanism of clozapine-induced neutrophil damage.

Keywords: idiosyncratic drug reactions
drug-induced agranulocytosis
Advisor: Uetrecht, Jack
Structure and Dynamics of AcrA, a Periplasmic Component of a Multidrug Efflux Pump

AcrA is the periplasmic component of an efflux system AcrA-AcrB-TolC, which can expel different classes of antibiotics. AcrB is the inner membrane (IM) pump that utilizes proton-motive force for the active transport, TolC is the outer membrane (OM) channel, and AcrA coordinates the actions of AcrB and TolC, so that substrates are expelled across the two membranes, bypassing the periplasm. It has been proposed that AcrA either provides a static seamless link between AcrB and TolC, or acts like its analogous viral membrane fusion protein (MFP) and actively brings the IM and OM closer for substrate transfer. To better understand the role of AcrA in the efflux mechanism, site-directed spin labeling (SDSL)/EPR (electron paramagnetic resonance) spectroscopy is used to investigate the structure and dynamics of AcrA in solution. My results demonstrated that AcrA is a dynamic protein that undergoes pH-dependent and reversible conformational changes. AcrA contains an interrupted alpha-helical, coiled-coil domain flanked by a pair of beta-stranded lipoyl motifs, and my SDSL/EPR analysis revealed that the pH-induced conformation change mainly involves the coiled-coil and the lipoyl domains. In addition, I found that each AcrA monomer folds into an intra-molecular hairpin and AcrA monomers oligomerize with their coiled-coil hairpins aligned in parallel. Unlike the pH-induced conformational rearrangement of a viral MFP, change in pH alters both intra- and inter-molecular interaction along the coiled-coil of AcrA without rearranging the hairpin fold. The organization of AcrA protomers and its pH-induced conformational switching are, however, congruent with the TolC coiled-coil hairpins in the iris-like opening of the TolC channel. Together, my studies suggest that rather than being a passive structural linkage between AcrB and TolC, AcrA plays an active role mediating the drug efflux. The reported AcrA dynamics provides new insights into the AcrA-TolC interactions for the channel opening during the efflux process.

Keywords: Site-directed spin labeling
Electron paramagnetic resonance
Membrane fusion protein
TolC
Conformational change
Proton-motive force
Advisor: Liu, Jun
Seismic Imaging of Gas Hydrate Reservoir Heterogeneities

Natural gas hydrate, a type of inclusion compound or clathrate, are composed of gas molecules trapped within a cage of water molecules. The presence of gas hydrate has been confirmed by core samples recovered from boreholes. Interests in the distribution of natural gas hydrate stem from its potential as a future energy source, geohazard to drilling activities and their possible impact on climate change. However the current geophysical investigations of gas hydrate reservoirs are still too limited to fully resolve the location and the total amount of gas hydrate due to its complex nature of distribution. The goal of this thesis is twofold, i.e., to model (1) the heterogeneous gas hydrate reservoirs and (2) seismic wave propagation in the presence of heterogeneities in order to address the fundamental questions: where are the location and occurrence of gas hydrate and how much is stored in the sediments. Seismic scattering studies predict that certain heterogeneity scales and velocity contrasts will generate strong scattering and wave mode conversion. Vertical Seismic Profile (VSP) techniques can be used to calibrate seismic characterization of gas hydrate expressions on surface seismograms. To further explore the potential of VSP in detecting the heterogeneities, a wave equation based approach for P- and S-wave separation is developed. Tests on synthetic data as well as applications to field data suggest alternative acquisition geometries for VSP to enable wave mode separation. A new reservoir modeling technique based on random medium theory is developed to construct heterogeneous multi-variable models that mimic heterogeneities of hydrate-bearing sediments at the level of detail provided by borehole logging data. Using this new technique, I modeled the density, and P- and S-wave velocities in combination with a modified Biot-Gassmann theory and provided a first order estimate of the in situ volume of gas hydrate near the Mallik 5L-38 borehole. Our results suggest a range of 528 to 768×10^6 m^3/km^2 of natural gas trapped within hydrate, nearly an order of magnitude lower than earlier estimates which excluded effects of small-scale heterogeneities. Further, the petrophysical models are combined with a 3-D Finite Difference method to study seismic attenuation. Thus a framework is built to further tune the models of gas hydrate reservoirs with constraints from well logs other disciplinary data.

Keywords: Gas Hydrate
Seismic Imaging
Advisor: Milkereit, Bernd
Massage Therapy Visits By The Aged: Testing a Modified Andersen Model

Growing evidence suggests that chronic health conditions and disability act as reliable predictors of complementary/ alternative medicine (CAM) use. Such use may have the potential for some to increase independence and quality of life. Moreover, research indicates that older people are significant consumers of CAM services. Yet, understanding profiles of older individuals of these services continues to remain under researched. Here, a widely used type of CAM was considered – massage therapy (MT). Towards better understanding MT user profiles, this study tested a modified version of the Andersen Health Behavior Model to help ascertain if it is useful towards understanding factors associated with massage therapy (MT) utilization. Respondents represented an elderly sample (aged 60+) that resided within a large urban city in Ontario Canada (Toronto). Eligible respondents at the time of the study were non-institutionalized and self-reported having one of more current chronic illness conditions which they have had for six months or more, and had been diagnosed by a medical doctor. Using a quantitative method, retrospective data were gathered using a pre-tested English-only mail questionnaire, developed specifically for this study. Data were gathered over a period of 6 months, between late 2000 to mid 2001. Bivariate analysis suggests that inequity exists whereby the ability to access massage therapy varies according to one’s socioeconomic status. This is further supported using backwards step-wise regression analysis, whereby one’s total annual household income was a strong predictor of MT use status. One’s CAM-related health and social network as well as having back problems also emerged as strong predictors of MT use. Overall findings suggest that a modified Andersen model as used in this study does have utility in relation to helping to identify potential factors associated with the utilization of massage therapy. Based on regression analysis, findings here suggest, for example, that those with higher incomes are 1.5 times more likely to use MT. This provides support that there are existing inequities regarding access to rehabilitation-oriented health care services. With population aging and rising numbers of people needing restorative and rehabilitation services, study findings will increasingly have important public health as well as health care policy related implications.

Keywords: Andersen Model
Massage Therapy
Advisor: Myers, Ted