VictorJuiz/thesis huggingface dataset:
Cardioprotective Effects of Combined Treatment with Sodium-glucose Co-Transporter-2 Inhibitor and Glucagon-like Peptide-1 Receptor Agonist in a Mouse Model of Ischemia-reperfusion Injury
Keywords: Cardioprotection
Cardiovascular sciences
Diabetes
Ischemia-reperfusion injury
Metabolism
Myocardial infarction

Following myocardial infarction (MI), reperfusion of coronary flow is necessary to rescue the ischemic myocardium, limit infarct size and improve prognosis. Paradoxically, reperfusion results in additional ‘ischemia-reperfusion injury’ (IRI), accounting for ~50% of infarct size. Despite several Phase II/III trials of candidate treatments, there remains no approved therapy against IRI. Recently two anti-diabetic drug classes, the sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have independently demonstrated cardiovascular benefits in subjects with and without type 2 diabetes (T2D). However, it is not known whether the cardiovascular effects of SGLT2i and GLP-1RA are through shared or distinct mechanisms, and whether combining these agents would result in additive effects. Thus, this Dissertation examines whether combined treatment with SGLT2i dapagliflozin (Dapa) and GLP-1RA exenatide (Ex-4) would be more cardioprotective than treatment with either agent alone, in non-diabetic and diabetic mouse models of IRI. Chapter 3 demonstrates combined pre-treatment with Dapa+Ex-4 better protects against infarct remodeling in a non-diabetic mouse model of IRI, than treatment with Dapa alone. Mice pre-treated with Dapa+Ex-4 exhibited the greatest reductions infarct size and improvements in ejection fraction (EF) on d-28 post-IRI. Cardiac proteome/ phosphoproteome and systemic metabolome analyses demonstrated distinct enrichment of mitochondrial electron transport chain metabolism with Dapa+Ex-4 treatment. The effects of in vivo treatment extended to isolated cardiomyocytes which demonstrated enhanced aerobic respiration uniquely following Dapa+Ex-4 treatment—plausibly contributing to the greater cardioprotective effects of combination therapy. Chapter 4 demonstrates pre-treatment with Dapa+Ex-4 preserves EF to a similar extent as single agent, in an obesity-induced diabetic mouse model of IRI. However, pressure-volume loop analysis revealed improved cardiac loading conditions exclusively with Dapa+Ex-4 treatment. Systemic effects of in vivo treatment and T2D-induced metabolic disturbances characterized by metabolomics, once again extended to the myocardium, as isolated cardiomyocytes exhibited increased aerobic metabolism accompanied (and plausibly blunted in benefit) by elevated glycolytic metabolism uniquely following Dapa+Ex-4 treatment. Taken together, this Dissertation begins to elucidate the complex cardioprotective actions of combined SGLT2i+GLP-1RA in IRI with or without T2D, and provides rationale for their combined use in a condition (IRI) for which there remains no approved therapy.
Variation In Immunization Post-implementation Policy-making in Canada: A Comparative Case Study of Four Provinces
Keywords: Canada
Comparative policy analysis
Immunization Policy
Policy-making
Vaccines

Post-implementation immunization policy-making are complex evidence-informed deliberative processes aiming to optimize existing programs. In Canada, however, lack of explicitness, limited transparency, and substantial variation in vaccine decisions taken across jurisdictions have raised questions regarding the way these processes unfold and the rationale used to inform decisions. In this dissertation, I examined how and why immunization post-implementation policy-making varies across Canadian provinces with the aim of increasing knowledge on competing factors influencing these processes and their outputs, so that support could be targeted to enhance their transparency, timeliness, consistency, and rigor in the future. A comparative case study design was employed to examine these processes using the experience of four Canadian provinces (Alberta, British Columbia, Manitoba and Quebec) during two post-implementation decisions, selected as instrumental cases. Guided by a realist approach and a multi-level post-implementation immunization policy-making conceptual framework, I examined the role of structural, procedural, and contextual factors on the variation observed. For each province and decision, information from documents and interviews were analyzed using descriptive and interpretative approaches. Results from these cases were subsequently compared during a cross-case synthesis, allowing the identification of key insights and actionable lessons. Findings from this study underscore the complexity of immunization post-implementation policy-making in Canada, where variation across provinces appears to be multifactorial, but largely influenced by non-technical contextual factors (i.e., values, interests, and risk-tolerance of individuals and organizations involved in these processes). While it is important to continue ensuring that high-quality relevant scientific evidence is readily available for vaccine policy-making in a timely way, increasing attention should be paid to how decisions are made and to the role of individuals and organizations in influencing the way evidence is ultimately used to inform policy. Moving forward, immunization post-implementation deliberation processes should be transparent and include explicit discussion of the values, logic, assumptions, and trade-offs considered when examining the relative importance to be assigned to evidence, ethics, economics, and political considerations. This could enable more systematic/rigorous assessments and more nuanced discussions, potentially enhancing the overall policy-making process, and its outputs.
Signaling Mechanism and Pharmacological Manipulation of Bcl-2 Family Proteins in Apoptosis
Keywords: Apoptosis
Bcl-2
cell death

Programmed cell death (apoptosis) dysregulation can drive disease pathologies in humans. Too much cell death is an unmet issue in neurodegenerative disease, is associated with decreases in tissue engraftment success, and is a hurdle in biotechnology applications. Conversely, too little cell death is partly associated with the formation of cancer and resistance to chemotherapy treatments. In a single cell, Bcl-2 family proteins orchestrate the life-or-death decision by complex interactions at the mitochondrial outer membrane. Anti-apoptotic proteins like BCL-XL can sequester activator proteins (BID), and pore-forming proteins (BAX and BAK) to keep the cell from undergoing apoptosis. Sensitizer proteins such as BAD, can bind to anti-apoptotic proteins leading to the activation of pore-forming proteins by free activator proteins. When a BAX/BAK pore is formed on the outer membrane of the mitochondria, the cell is committed to apoptosis with no return. Pro-apoptotic factors released from the mitochondrial intermembrane space trigger an apoptotic cascade. Here, I aid in the discovery of a novel inhibition mechanism at the mitochondria where homodimerized BCL-X¬L¬ can also act as the scaffold for a “trigger like” activation of a pro-apoptotic signal. Although Bcl-2 family proteins have been studied for about 40 years, we are still observing novel mechanisms, understanding the function of structural domains, and developing small molecules as future therapies. The first success in clinic to target Bcl-2 family proteins is the anti-apoptotic protein inhibitor, Venetoclax, used to treat chronic lymphocytic leukemia. The purpose of Venetoclax is to repress inhibitory proteins to cause activation of apoptosis in cancer. However, little is known about inhibiting cell death to treat disease. BAX and BAK form pores that commit the cell to death, and by blocking pore formation we can keep cells alive for longer, allowing stressed cells time to recover. Here, I aid in the development of small-molecule BAX/BAK inhibitors to save cells from an apoptotic stimulus. I found that pyrimidine or quinazoline based, FDA-approved kinase inhibitors have low-micromolar affinities for BAX and BAK. With aid from synthetic chemists, I was able to predict chemical changes that removed kinase binding while maintaining the propensity to inhibit BAX and BAK.
The Productivity of Mistrust: Negotiating Partnerships in Ghana’s Development Sector
Keywords: Development
Mistrust
Non-Governmental Organisations
Partnerships
Sustainable Development Goals
Trust

Under the global Sustainable Development Goals (SDGs), partnerships have become central to the work of national non-governmental organisations (NGOs). Partnerships are underpinned by moral justifications of building trust and combating mistrust. A better understanding of how partnership policies are implemented in the everyday work of NGOs is critical for understanding the effects of moral imperatives in development ideologies as well as the current position and contributions of NGOs in the implementation of the SDGs. This dissertation examines how national NGOs in Ghana navigate the growing expectation that they build trust and how they affirm, negotiate, and contest partnerships. This ethnographic research draws on data from fifteen months of participant observation and in-depth interviews with a prominent network of NGOs working on the SDGs as well as the network’s government, private sector, and donor partners. As Ghana is considered a “development darling,” it offers an exemplary context for analysing the uptake of current aid policies. While trusting partnerships are framed in development ideologies as morally good, these policies occlude the uneven structures in which partnerships take place. I demonstrate that NGO leaders use practices and sentiments akin to mistrust to navigate the politics and hierarchies of partnerships in a development sector in which they have little decision-making power and are financially dependent on foreign donors. These operations of the development sector are revealed by paying attention to everyday practices of mistrust and emotional registers in partnerships, through which NGO leaders affirm their authority and recognition, even if they are unable to change the sector’s hierarchies. The ethnographic chapters on NGO relationships with government and private companies show how practices of mistrust constitute a moral positioning of integrity for NGOs as independent and working towards a social good. The chapters exploring partnerships within NGO networks and with donors demonstrate how the circulation of affective registers of suspicion and frustration develop common narratives of how partnerships should work, particularly in the top-down development context. Thus, this dissertation opens up to theoretical and empirical consideration the productive potentiality of mistrust and the surprising ways that practices and affects of mistrust constitute and sustain partnerships.
Investigation of the Biological Function of Plant Cyclic Nucleotide Gated Ion Channel 2 in Auxin Signaling
Keywords: biology
genetics
plant

Calcium (Ca2+) is a ubiquitously important signaling molecule in eukaryotic cells. For plants, developmental cues, and signals from the environment lead to changes in cellular Ca2+ concentrations that are required to activate appropriate responses. CYCLIC NUCLEOTIDE GATED CHANNELS (CNGCs) are ion channels that are thought to conduct cations like Ca2+ in plant cells. Of the 20 members of the Arabidopsis CNGC family, the isomer CNGC2 is of special interest as the loss-of-function of CNGC2 leads to defects in multiple physiological processes. In this thesis, I investigated the biological function of CNGC2 and propose that CNGC2 is important in auxin homeostasis in addition to its prescribed role in immunity. The first suppressor of the autoimmune CNGC2 null mutant was found to carry a mutation in the auxin biosynthesis gene YUCCA6 (YUC6). An investigation into alterations in auxin signals revealed that the CNGC2 knockout mutant cngc2 exhibits abnormalities in auxin signaling and hyper-accumulates endogenous auxin, indole-3-acetic acid (IAA). This is the first report of CNGC2 being potentially involved in auxin signals through auxin biosynthesis. I next showed that a loss-of-function of another IAA biosynthesis gene, TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS 1 (TAA1) also suppresses phenotypes associated with cngc2. This indicated that hyper-accumulation of IAA is a source of cngc2 phenotypes. IAA-induced Ca2+ influx is impaired in cngc2, and this phenotype is alleviated in the absence of YUC6. This indicates that CNGC2 functions in auxin-induced Ca2+ signals that can influence auxin homeostasis. The hyper accumulation of auxin in cngc2 positions CNGC2 in a negative feedback loop of auxin biosynthesis. Since all 11 members of the YUC gene family are thought to be involved in auxin biosynthesis, we asked whether a loss-of-function in any YUC gene could suppress cngc2 phenotype. Of all the yuc mutants tested, only yuc6 could suppress cngc2 phenotypes. YUC6 and TAA1 have been shown to exhibit similar tissue-specific expression patterns at the vasculature, a pattern not observed with other YUCs. This indicates a specific role of YUC6 in the CNGC2-mediated auxin feedback loop, which may be governed by its unique expression pattern. Collectively, these findings cast a new light of CNGC2’s complex regulation by auxin signaling and immune responses.
Ni-catalyzed Amination of a-Aryl Methyl Ethers and Synthesis of Nitriles via Transnitrilation
Keywords: Amines
Catalysis
Nickel
Nitriles
Synthesis

This thesis describes new methods for amination of -aryl methyl ethers and synthesis of nitriles via transnitrilation. The strategies discussed represent novel approaches to synthesis of -aryl amines, aliphatic nitriles, benzonitriles and alkenyl nitriles. Along with these novel approaches, previously reported synthetic strategies and their advantages is discussed. Chapter I provides an overview of nickel catalysis and use of alcohol derivatives in Ni-catalyzed cross-coupling reactions. Chapter II describes strategies for synthesis of amines and new method for Ni-catalyzed amination of -aryl methyl ethers. Naphthalene and heterocycle derived -aryl methyl ethers can be used for Ni-catalyzed amination using aryl and aliphatic amines. Preliminary mechanistic investigation suggest oxidative addition is facilitated by anionic ligand and that reductive elimination is reversible. Chapter III describes strategies for synthesis of nitriles and new methods developed for synthesis of aliphatic nitriles and benzonitriles via transnitrilation. Aliphatic lithium reagents and broad range of electrophiles can be used for synthesis of aliphatic nitriles via transnitrilation and anion-relay. Aryl halides and pseudohalides can be used for synthesis of benzonitriles using Ni-catalyzed transnitrilation from C–bound electrophilic nitrile reagent under reductive conditions. Chapter IV describes strategies for synthesis of alkenyl nitriles and new method developed for synthesis of alkenyl nitriles via arylcyanation of alkynes. Alkenyl nitriles can be synthesized in moderate yields using aryl bromide, alkynes and C–bound electrophilic nitrile reagent. While exclusive cis-addition product was observed, optimization and preliminary mechanistic studies suggests isomerization of alkene likely occurs on catalytic cycle. Chapter V describes further extension to carbocyanation strategy leading to discovery of methods for synthesis of alkenyl nitriles via alkylcyanation and hydrocyanation of alkynes. Hydrocyanation and alkylcyanation of alkynes can be achieved using conditions similar to arylcyanation of alkynes. Preliminary investigations suggest alkyl pseudohalides can be used for alkylcyanation via in situ formation of alkyl halide. Preliminary investigations for hydrocyanation suggests that stereoselective transformation can be achieved with alterations in the ligand.
Solar Methanol: From Process Engineering and Photoreactor Development to Materials Discovery and Photocatalysis
Keywords: carbon dioxide utilization
photo reactor development
photocatalysis
process engineering
renewable energy
solar methanol

Renewable methanol (MeOH) is a vital feedstock for an environmentally sustainable society. The ability to transform renewable electricity into the chemical bonds of hydrogen and further with solar energy into MeOH is invaluable from a delocalized renewable-energy generation standpoint. It allows for ease of storage, transportation and use of clean hydrogen. In this work, Ch. 1 outlines the current context for research into solar heterogeneous catalysis, and lays the groundwork for answering the question of ‘why to pursue liquid fuels?’ as a future hydrogen carrier. Ch. 2 outlines the thermodynamics of MeOH synthesis and the kinetics and performance of the commercial copper-zinc oxide-alumina (CZA) MeOH catalyst. It also envisions and evaluates solar-assisted MeOH processes and compares them to each other and the commercial process in a technoeconomic analysis. Ch. 3 outlines a few optimizations to lower the minimum MeOH selling price (MSPMeOH) of the best strategy from Ch. 2, introduces photocatalysis, and highlights the current research on CZA-inspired photocatalysts. Finally, the scientific objectives and hypotheses of the experimental portion of this work are postulated. Ch. 4 outlines the development of a pressurized solar-CSTR reactor built for the purpose of assessing light enhanced catalysts with CZA-baselining data. Ch. 5 focuses on a nature- and CZA-inspired solar analogue catalyst that exhibits MeOH synthesis and reforming activity in thermal and thermal + light operating conditions, respectively. This material could be operated in a day- and night-cycle operation, and with further development could allow cyclic energy storage and distribution that would be advantageous to distributed energy-storage systems. Ch. 6 concludes with a summary of the completed objectives as outlined in Ch. 1 and the future direction.
Profiles and Predictors of Reading Comprehension for English Language Learners: A Longitudinal Investigation of Language Comprehension Skills and the Lexical Quality Hypothesis
Keywords: English language learners
Language comprehension
Reading comprehension

The overall goals of this two-study dissertation were to (1) examine longitudinally the contribution of different language skills to the reading comprehension (RC) of English Language learners (ELLs) and English-speaking monolingual students (EL1s) (Study 1), and (2) determine the reading and language profiles associated with ELLs and EL1s at different developmental timepoints (Study 2). 379 ELLs and 159 EL1s were tested annually for six years beginning in Grade 1. In Study 1, multi-level modelling was used to determine which language skills (i.e., vocabulary, syntactic awareness/knowledge, and listening comprehension) contribute to RC for ELLs and EL1s in Grades 1-3 and 4-6. In each analysis there was significant variability in initial (i.e., Grade 1 and Grade 4) RC scores, but not in rate of growth in RC. In Grade 1, various language skills contributed to RC for both ELLs and EL1s. By Grade 4, syntactic knowledge and listening comprehension were predictors of RC for ELLs, but only vocabulary was a predictor for EL1s. Overall, this study demonstrated that each language skill captures unique aspects of language that contribute to RC, and that from a developmental lens, the relative importance of specific language skills changes over time for both language groups. In Study 2, latent profile analysis was used to assess whether the lexical quality hypothesis(LQH) is supported at different developmental time points, along with additional components of language. For EL1s in Grades 1, 3, and 6, and for ELLs in Grade 1, analyses revealed a 2-subgroup solution consisting of a good readers group, who displayed strong RC and performance across both word-level and language skills, and a poor readers group, who performed below average on RC and each skill. For ELLs in Grade 3, three groups emerged, consisting of poor readers, and good readers with either average or strong word-level skills. For ELLs in Grade 6, groups of poor, average, and good readers emerged. Overall, results provide nuanced support for the LQH in both language groups, but suggest that it takes longer for the components of the LQH to align for ELLs than for their EL1 peers.
Orientalismus und unvollständige Vergangenheitsbewältigung: Arabische Identitätsfigurationen in deutschsprachiger Literatur und Film nach 1945
Keywords: Arabs
gender
German film
German literature
migration
Orientalism

In meiner Arbeit analysiere ich die Darstellungen von AraberInnen in literarischen und filmischen Werken und Diskursen der Nachkriegsgeneration und dem Jahrzehnt nach dem 11. September. Anhand der Repräsentation von AraberInnen veranschauliche ich die Mangel und Lücken im Prozess der Vergangenheitsbewältigung in Deutschland und Österreich. Dabei demonstriere ich, inwieweit rassistische Grundgedanken, die zu den Verbrechen und Massakern des Dritten Reiches führten, weiterhin in veränderter Form fortbestehen. Durch den Vergleich mit den Repräsentationen nach dem 11. September, zeige ich wie diese Bilder und die Diskurse um AraberInnen sich verändert haben. Von besonderem Interesse sind die kritischen Dekonstruktionen hegemonialer Orientdiskurse in den untersuchten Werken. Meine Arbeit demonstriert die Komplexität und Heterogenität des deutschsprachigen Orientalismus und veranschaulicht dies an exemplarisch ausgewählten Romanen und Filmen, die in den einzelnen Kapiteln in Form von Fallstudien untersucht werden. Im ersten Kapitel: Tourismus in Ägypten und Reiseliteratur: Barbara Frischmuths Vergiss Ägypten (2008) und Ingeborg Bachmanns Das Buch Franza (1965/1978) werden die Werke der österreichischen Autorinnen untersucht. Anhand der Repräsentationen von AraberInnen demonstriere ich, wie Bachmann, beeinflusst durch Fanon, antikoloniale Diskurse thematisiert und ein frühzeitiges Verständnis von Intersektionalität entwirft. Frischmuths Roman wird unter dem Gesichtspunkt ihrer Auffassung von Multikulturalismus analysiert. Ihre Verwendung von orientalischen Tropen werden nachgezeichnet und ihrer Intervention in eurozentrische Hegemonialdiskurse durch die Verwendung von Mystik gegenübergestellt. Im zweiten Kapitel: Arabische Migranten in Deutschland: Benjamin Heisenbergs Schläfer (2005) und Rainer Werner Fassbinders Ali: Angst essen Seele auf (1974) wird das Thema Migration und die Präsenz arabischer Migranten in Deutschland diskutiert. Die Weiterführung kolonialer Arbeitsmigrationspolitik wird anhand der Filme nachgezeichnet, um zu zeigen welche Funktion arabische Migranten innerhalb des Migrationsdiskurses einnehmen. Das dritte und abschließende Kapitel: Arabische Länder in deutschen Nachrichten: Volker Schlöndorffs Film Die Fälschung (1981) und Lancelot von Nasos Film Waffenstillstand (2009) befasst sich mit dem Thema der Medienrepräsentation von AraberInnen und im Besonderen der Nachrichtenberichterstattung von Kriegen im Nahen Osten. Durch den Vergleich von Diskursen in der Auslandsberichterstattung in arabischen Ländern in deutschen Medien und der filmischen Darstellung von Auslandsreportern zeige ich welche orientalischen Narrative weitergeführt und welche kritisch dekonstruiert werden.