VictorJuiz/thesis huggingface dataset:
The Production and Use of Administrative Documents in Somerset from Glanvill to Magna Carta
Keywords: Administrative history
Charters and diplomatics
Medieval England

The Production and Use of Administrative Documents in Somerset from Glanvill to Magna Carta Robin Sutherland-Harris Doctor of Philosophy Centre for Medieval Studies University of Toronto 2016 Abstract This thesis studies how various kinds of administrative documents were produced and used through the late twelfth and early thirteenth centuries within the geographical and administrative territory bounded by the shire of Somerset and the diocese of Bath and Wells. Documents were increasingly part of administration in medieval England at all levels, from royal government to the local land market, from archbishops to cathedral canons. Parallel to the growing importance of administrative texts, an increasingly regularized body of administrative personnel also emerged during the twelfth and thirteenth centuries. This thesis is therefore situated in the intersection of a flourishing documentary culture and a burgeoning administrative class. Theoretical frameworks provided by scholarship on the partial shift from memory to the written word, on textual communities, and on pragmatic literacy inform the analysis throughout. Focussing on the production and use of administrative documents over a short time period and in a specific region makes it possible to approach them in detail and at multiple levels. At the level of the institution, both the diocese of Bath and Wells and the monastery of Glastonbury made use of administrative documents while in conflict with one another. At the level of the individual, the archdeacons of the diocese found a range of administrative roles in royal government, in which they relied on pragmatic literacies tailored to their individual circumstances. At the level of the documents themselves, connections between surviving charter originals reveal the articulation of large-scale changes in documentary and administrative culture in the uneven small-scale nuances of scribal and chancery production. Each chapter examines documentary culture and pragmatic literacy in the local context, exposing bureaucratic rather than literary or religious reading communities. Rather than the high-culture focus adopted by most studies of medieval literacy, the emphasis here is on the more wide-spread and practically engaged world of administrative bodies, personnel, and documents; this allows a â core sampleâ of evidence from a local temporal and geographical microcosm to be tested against our understanding of macrocosmic changes in the uses of texts and the roles of literacy in the medieval west.
Genetic Analysis of Tumor Progression in the Mouse Mammary Gland
Keywords: Breast Cancer
Mouse Models
p53
PI3K
Sleeping Beauty Mutagenesis
Stat3

Genetic alterations that cooperate with TP53 mutation in breast cancer (BC) are largely unknown. Using a dominant-negative Trp53LSL-R270H/+ mouse strain, I found Trp53 alteration cooperates with Her2/Neu over-expression, but not with hemizygous deletion of Gata3, Runx1, or Nf1. To identify other genes cooperating with mutant Trp53, I completed a Sleeping Beauty (SB) mutagenesis screen in mice. This identified known cooperators such as Met, and other candidates such as Notch1. Cooperation between activated Notch1 and Trp53LSL-R270H/+ was validated in vivo. In addition to coding mutations, chromosomal copy number changes are also important in BC. To identify genes that contribute to mammary tumorigenesis upon copy number alteration, I compared genes targeted by transposons in SB mice carrying Trp53LSL-R270H/+, R26LSL-Pik3ca(Mut)/+, R26LSL-Stat3C/+, or no mutant allele. This enabled me to identify genes altered in all cohorts (e.g. Rasa1), in several but not all backgrounds (e.g. Met), and those that only occurred in the presence of a single driver (e.g. Mll3, Exoc4, and Cul1 loss in Pik3ca-mutant tumors). Importantly, many genes targeted by SB transposons map to loci syntenic with regions commonly gained/lost in human BC. Thus, they likely represent haploinsufficient tumor suppressors or oncogenes. Guided by SB results, the oncogenic interaction between R26LSL-Pik3ca(Mut)/+ and loss/activation of Notch1 was validated in vivo. Additionally, I distinguished genes altered in metastatic lesions from SB mice. This revealed genes previously implicated in BC dissemination (e.g. Hipk2) and novel abnormalities (e.g. loss of Fbxl17). Lastly, to assess the oncogenic potential of ELF3 (which maps to human chromosome 1q and is frequently gained/amplified in human BC), I generated a Cre-conditional Rosa26-targeted Elf3 transgenic strain (R26LSL-Elf3). Using SB mutagenesis, I showed genes such as Cul5 and FoxP1 were disrupted in Elf3 over-expressing SB mammary tumors, while metastases from these mice selected for a distinct set of insertions (e.g. Pard3 disruption).
Surface Adsorption Studies of CO2 and H2 on Defected Indium Oxide: Insights into Gas-Phase Heterogeneous Photocatalysis
Keywords: Adsorption
Carbon dioxide
Catalysis
Nanochemistry
Photocatalysis
Surface science

The conversion of CO2 into fuels or chemical feedstocks is valuable for not only mitigating the rising atmospheric concentration of CO2, but also for utilizing CO2 as a globally available, abundant, and renewable resource. Indium oxide defected with oxygen vacancies and hydroxides, In2O3-x(OH)y, is a catalyst material that facilitates the light-assisted, gas-phase heterogeneous reduction of CO2 via the reverse water gas shift (RWGS) reaction, CO2 + H2 -> CO + H2O. The extent of defects in In2O3-x(OH)y correlates strongly with the rate of CO2 conversion as well as the CO2 adsorption capacity. Prior to this work, the specific interactions between the RWGS reactants, CO2 and H2, and the In2O3-x(OH)y surface were largely unknown. The work herein explores the In2O3-x(OH)y surface chemistry through carefully designed in situ thermogravimetric analysis and infrared spectroscopy techniques to identify and investigate surface-adsorbed CO2 and H2 species. CO2 adsorbs as a complex mixture of carbonates, bicarbonates, carboxylates, and linear CO2 species, which adsorb at readily available and specific surface sites, forming a partial monolayer with varying adsorption strengths. H2 easily reduces the In2O3-x(OH)y surface, resulting in a broad and intense infrared absorbance peak due to the delocalization of conduction band electrons, the intensity of which decreases with an increase in defects, agreeing with our understanding that defects promote charge trapping at the surface to be used in chemical reactions. The coadsorption of CO2 and H2 results in a strongly adsorbed formate species, providing indirect evidence for H2 heterolytic dissociation, in addition to possibly identifying formate as an intermediate for the RWGS reaction or a bystander that instead leads to methanol synthesis. Through detailed CO2 and H2 adsorption studies, this thesis has provided us with valuable insight into the In2O3-x(OH)y surface and its complex chemistry â a critical contribution to the development of a viable CO2 utilization technology.
The Relations of the Crimean Khanate with the Ukrainian Cossacks, the Polish-Lithuanian Commonwealth and Muscovy during the Reign of Khan Islam Giray III (1644-1654)
Keywords: Bohdan Xmel'nyc'kyj
Islam Giray III
Muscovy
Poland-Lithuania
The Crimean Khanate
Ukraine

This dissertation analyzes the relations of the Crimean Khanate with the Ukrainian Cossacks, the Polish-Lithuanian Commonwealth and Muscovy during the reign of Khan Islam Giray III (1644 - 1654). Islam Giray’s reign coincided with some of the most turbulent years of the Crimean Khanate’s history. Shortly after his accession to the throne in summer 1644, a quarrel between his nobles and palace guards during the return from a Circassian campaign turned into an exhausting civil war between him and his nobility. The Khanate’s relations with its northern neighbours were also deteriorating as Warsaw and Moscow decided to take action against the attacks of the Tatars and stopped tribute/gifts payments to Crimea. Under these circumstances, the Cossack rebellion of 1648 against the Commonwealth under the leadership of Bohdan Xmel’nyc’kyj was a golden opportunity for Islam Giray to reassert his position as ruler in Crimea and strengthen the Khanate’s position in eastern European affairs. While the khan gave military support to the Ukrainian Cossacks throughout their war with the Commonwealth, he was never willing to allow the collapse of Warsaw’s authority over Ukraine. Instead he aimed to be a mediator between the Cossacks and the Commonwealth forcing them to agree to peace treaties that would reconcile their contending demands. Islam Giray also intended to ally with Warsaw and Xmel’nyc’kyj for the conquest and partition of Muscovy, acquiring the Volga patrimony of the Golden Horde, Kazan and Astrakhan, for the Khanate. However, as the Cossacks and the Commonwealth were overwhelmed by their mutual problems, they were uninterested in participating in an anti-Muscovite alliance. Eventually, a decisive blow to Islam Giray’s mediatory position and his anti-Muscovite schemes came as the Ukrainian Cossacks could not reach a settlement with Warsaw and decided to submit to Muscovy in 1654. Now, towards the end of his reign, the khan found himself at a crossroads between maintaining his alliance with the Ukrainian Cossacks and taking sides with the Commonwealth against the Ukrainian-Muscovite rapprochement.
Dynamics of Speciation in Neotropical Birds: Diversification Rates, Introgression and Reproductive Isolation
Keywords: Birds
Extinction
Hybridization
Neotropics
Reproductive Isolation
Speciation

Tropical rainforests â covering 7% of the earth's surface â are areas of exceptionally high biodiversity compared to other ecosystems. However, no consensus has been reached as to the primal cause of high tropical diversity. In this thesis, I used a combination of phylogenetic and population genetic methods to address whether speciation is an important driver of diversification patterns and to determine the genetic architecture of reproductive isolation and the frequency of introgression during the diversification process in the species-rich Neotropics. I developed and fit a character-state dependent diversification model to a global avian phylogeny and found consistent support across replicate clades for extinction as a key driver of species richness gradients. In contrast, an association between speciation or dispersal rates with species richness was not consistently found. To better understand the process of speciation in the tropics, I studied reproductive isolation in two genera of suboscine birds. My results showed that pre-zygotic reproductive barriers play a less important role in the tropical speciation process than at high latitudes, with reproductive isolation driven largely by post-zygotic genetic incompatibilities. I also found evidence of frequent introgression events during the diversification process in the Neotropical genus Dendrocincla. My analyses showed different instances of historical introgression events among closely and distantly related lineages of Dendrocincla, demonstrating that introgression may often be a common phenomenon during the diversification process in the Neotropics. These results contribute to our understanding of the evolutionary processes that drive diversification and how speciation evolves in areas of high species richness.
The "Whys" of Charity Regulation
Keywords: Charity Law
Regulation

Why do we regulate charities? What is it about charities that requires them to be regulated because they are charities? What should charity regulation aim to achieve and why? These are the questions this thesis sets out to address. I begin by emphasizing the need for critical analysis of the underlying purposes, or “whys”, of charity regulation. I then go on to identify two such purposes: encouraging the pursuit of charitable purposes; and holding those who pursue charitable purposes to account. The thesis outlines how these regulatory “whys” result from and can, thus, be justified by the particular problems charities face thanks to their legal definition, which I argue is the only possible basis for illuminating the purposes of charity sector specific regulation. I conclude by commenting on the further research needed to develop a more complete theory of charity regulation capable of informing institutional design.
On the Topology of Collective Integrable Systems
Keywords: collective
convexity
gromov width
hamiltonian
integrable
thimm

This thesis studies the topological properties of momentum maps of a large family of completely integrable systems called collective completely integrable systems. The first result concerns the topological monodromy of a collective completely integrable system on a product of three two-spheres. This system is called a "Heisenberg spin-chain" for its connection with a quantum integrable system of the same name. The remainder of the thesis is concerned with collective systems that are "constructed by Thimm's trick'' with the "action coordinates of Guillemin and Sternberg.'' We observe that the open dense subset of a symplectic manifold where such systems define a Hamiltonian torus action is connected. This observation was absent from the literature until this point. We also prove that if a system is constructed in this manner from a chain of Lie subalgebras then the image is given by an explicit set of inequalities called branching inequalities. When the symplectic manifold in question is a multiplicity free Hamiltonian U(n)-manifold, the construction of Thimm's trick with the action coordinates of Guillemin and Sternberg yields a completely integrable Hamiltonian torus action on a connected open dense subset. If the momentum map is proper, then we are able to prove lower bounds for the Gromov width of the symplectic manifold from the classification of the connected open dense subset as a non-compact symplectic toric manifold. Convex multiplicity free manifolds of compact Lie groups have been classified by Knop [51] and, accordingly, our lower bounds are given in terms of the combinatorics of the classifying data: the momentum set and a lattice. This result is the first estimate for the Gromov width of general multiplicity free manifolds of a nonabelian group. This result relies crucially on connectedness of the open dense subset and the explicit description of the momentum map image. The proof is a generalization of methods used by Pabiniak [71] to prove lower bounds for the Gromov width of U(n+1) coadjoint orbits, which are an example of multiplicity free U(n)-manifolds.
Thermosensitive Liposome Formulation of Cisplatin for Cancer Treatment
Keywords: Cervical Cancer
Cisplatin
Hyperthermia
Liposome
Lung Cancer

Cisplatin (CDDP) is a platinum-based antineoplastic drug that is approved by the U.S. Food and Drug Administration (FDA) and Health Canada for treatment of many cancers. However, CDDP is associated with severe toxicities, including nephrotoxicity, gastrointestinal toxicity, and neurological toxicity. A number of advanced drug delivery platforms, including liposomes, have been investigated in order to reduce the systemic toxicity associated with this drug. SPI-77 and LipoplatinTM are liposome formulations of CDDP that have been successfully developed and moved forward into clinical evaluation. These liposome formulations demonstrated significantly increased tumor drug accumulation relative to free drug, yet, there was lack of improvement in therapeutic efficacy over free drug as a result of limited release of drug from carriers at the tumor site. This thesis aims (1) to develop a heat-activated thermosensitive liposome formulation of CDDP (HTLC) to overcome the limited drug release of conventional liposome formulations of CDDP, (2) to assess the therapeutic efficacy of the HTLC formulation in combination with local hyperthermia (HT) in comparison to free drug and LipoplatinTM, (3) to evaluate the impact of tumor microenvironment (TME) of cervical cancer on treatment response to the HTLC formulation to identify potential prognostic markers, and (4) to investigate the short-term (i.e. 24 hr) effect of local HT on tumor morphology, microvessel density (MVD), and innate inflammatory response in non-small-cell lung cancer (NSCLC). Overall, this work demonstrated successful development of the HTLC formulation, which revealed superior therapeutic benefit in combination with local HT relative to free drug and LipoplatinTM in mouse xenograft models of cervical carcinoma and NSCLC, including four distinct patient-derived xenograft (PDX) models. TME parameters, in particular elevated levels of both tumor-associated stroma and hypoxia were shown to be overriding factors that limit drug efficacy in cervical cancer. Furthermore, local HT resulted in a significant change in the TME of NSCLC at 24 hr post-treatment, including widespread necrosis, reduction of MVD, and activation of the innate immune system.
Transgenerational Effects of Synthetic Glucocorticoids on Offspring Behaviour and HPA Development in Guinea Pigs
Keywords: Brain
Epigenetics
Gene regulation
Glucocorticoids
Guinea pig
Transgenerational

Glucocorticoids are essential for fetal maturation. However, exposure to high levels of glucocorticoids (i.e. maternal stress/anxiety or synthetic glucocorticoid treatment [sGC]) alters the trajectory of development and increases the risk for chronic diseases later in life. Approximately 10% of pregnant women are at risk for delivering prematurely and receive treatment with sGC to reduce neonatal morbidity and mortality. Studies in children and animals demonstrated that single- and multiple-course sGC program alterations in hypothalamic-pituitary-adrenal (HPA) function and stress-associated behaviours in first generation (F1) offspring. Emerging studies in animals determined that sGC results in transmission of HPA and behavioural effects to the next generation (F2) of offspring, but no study has investigated transmission to the third generation (F3). We hypothesized that prenatal treatment with sGC results in maternal and paternal transmission of altered HPA activity and stress-related behaviours to three generations of guinea pig offspring. Prenatal treatment with either single- or multiple-course sGC resulted in transmission of effects to F2, but there were fewer effects with single-course treatment. Prenatal treatment with multiple-course sGC resulted in maternal transmission to F3. The strongest effects of sGC occurred in juvenile females from the paternal line; increased HPA response to stress, hyperactivity, impaired attention. Molecular analyses in the brains of these animals revealed that sGC programs large changes in gene expression that dissipate across generations. DAVID pathway analysis identified significant changes in the expression of genes associated with the HPA and behavioural phenotypes. This is the first study to demonstrate transgenerational programming to F3 of HPA activity and behaviours resulting from prenatal sGC transmitted. Paternal transmission to F3 strongly implicates epigenetic mechanisms. Transgenerational programming by sGC is a hallmark of in utero sGC exposure irrespective of current or past dosing regimens. These studies highlight the importance of developing new treatment approaches that maximize therapeutic efficacy while minimizing long-term adverse outcomes.
An Unexpected Journey: A Medicinal Chemistry Exploration through the Realm of Protein Tyrosine Phosphatases, Signal Transducers, and Receptor Tyrosine Kinases
Keywords: biological chemistry
drug discovery
medicinal chemistry
molecular recognition
small-molecular inhibition

This thesis details the medicinal chemistry research undertaken from the perspective of three drug targets; protein tyrosine phosphatase 1B (PTP-1B), signal transducer and activator of transcription 3 (STAT3), and the proto-oncogene receptor tyrosine kinase (ROS1). Concerning PTP-1B, initial library screening and follow-up biological evaluation of a library of compounds led to a series of salicylic acid-based inhibitors. Additionally, absorption spectroscopy enzymatic assays intended for the evaluation of novel compounds, revealed aggregation based inhibition of PTP-1B by an inhibitor with an ene-rhodanine core, linked to pan assay interference compounds (PAINS). In the work concerning STAT3, the potential electrophilic character of the pentafluorobenzene sulfonamide functional group in SH-4-054 was hypothesized, and subsequently proven, a metabolic liability. Discussed is the chemical evaluation of the kinetic reactivity profile for the nucleophilic aromatic substation (SNAr) substrate and initial evaluations of its potential protein modification of Cys-based nucleophiles. Continuing the STAT3 focused research concerning protein alkylators, is the exploration of the reactivity of the small molecule inhibitor S3I-201, shown to be a non-specific chemical modifier of STAT3 through tosyl mediated substitution. Finally, progress towards inhibition of ROS1 is described. Where initial attempts were aimed at expanding the research of cabozantinib, an FDA-approved drug known to overcome a clinically significant ROS1 mutation. We describe the computational chemistry, cellular, and biophysical analysis of this compound and several structural derivatives. Furthermore, the screening of a focused library of low molecular weight compounds used to identify potential hit molecules as starting points for chemically novel ROS1 inhibitors as future research is described.
Expression and Function of Kir2.1 and Kv1.3 Channels in Cytokine-induced Activation of Rat and Mouse Microglia: A Tale of Two Rodents
Keywords: Central Nervous System
Inflammation
Ion Channels
Microglia
Migration
Proliferation

After acute CNS damage, microglia undergo complex molecular and functional changes. Pro-inflammatory (M1) activation can exacerbate tissue damage, while multiple anti-inflammatory (M2) states can help resolve inflammation and promote tissue repair. Potassium (K+) channels are potential targets for modulating inflammation, but their expression and roles in activated microglia are poorly understood. Also, whether rat and mouse microglia respond the same is unclear. This thesis presents two studies: 1) expression and roles of Kir2.1 in rat microglial migration and proliferation in unstimulated (CTL) and two M2 states, M2a and M2c; and 2) a comparative analysis of the molecular (gene expression) and functional (K+ channel activity, migration) responses between rat and mouse microglia in M1, M2a and M2c states. Study 1: Kir2.1 channels are necessary for microglial Ca2+ signaling and migration but weakly inhibit proliferation under CTL, M2a and M2c states. Microglial Kir2.1 expression (transcript, currents) were comparable in CTL, M2a and M2c states. Kir2.1 blockers (Ba2+ or ML133) increased proliferation slightly in CTL or M2a (but not M2c) microglia. While M2 states increased migration and chemotaxis, blocking Kir2.1 reduced both. In all three states, ML133 reduced Ca2+ influx through Ca2+-release-activated Ca2+ channels. Study 2: This collaborative project showed that pro-inflammatory genes increased only in the M1 state, but genes associated with the M2a state were not consistent between species and/or were induced in multiple activation states. Gene expression for several Kir2 and Kv1 family members was detected in both species, but the currents were mainly Kir2.1 and Kv1.3, and depended on the activation state and species. Migration was affected similarly in both species by the activation state (reduced in M1, increased in M2a or M2c), and by channel blockers (reduced by Kir2.1 block, increased by Kv1.3 block). Thus, caution is recommended in generalizing microglial responses to activating stimuli between species.