VictorJuiz/thesis huggingface dataset:
Using The Protein Corona to Train Deep Neural Networks and Build Patient-specific Nanomaterials
Keywords: Mass Spectrometry
Nanoparticles
Neural Networks
Personalized Nanomaterials
Predictive Biology
Protein Corona

When nanoparticles are exposed to biological environments, proteins rapidly adsorb to the surface and form a structure known as the protein corona. The protein corona always forms irrespective of the material composition, surface chemistry, size and shape. This interfacial network of protein is one of the biggest banes to nanomedicine as it mediates how nanoparticles behave in the body despite our synthetic control. Investigations outside the body have shown that it is possible to predict protein corona adsorption based on nanoparticle size, shape and surface chemistry. At present, no insight and forecast exists of protein assembly patterns in vivo, nor has this interfacial chemistry been used toward building new applications in medicine. This thesis presents an original contribution to biomedical nanotechnology as it exploits the protein corona across two themes with a collective effort to improve translation of nanomaterials into the clinic. First I demonstrate that the protein corona can be deciphered and used as input data to train a neural network that is able to predict nanoparticle biodistribution in an animal model. Second, a new class of nanomaterial is created by isolation, separation and materials ligation of the protein corona from a nanoparticle template. The latter provides a solution to a major problem facing nanomaterial design; the engineering of size and shape tunable organic nanomaterials under 100 nm. They are biodegradable and do not activate innate or adaptive immunity following single and repeated administrations in vivo. Together, these findings provide insight and foundational materials design to create a patient-specific nanomaterial that can have predictable biodistribution inside of the body.
Model-Guided Transdermal Formulation of 1α,25-Dihydroxyvitamin D3 for Improved Safety and Efficacy
Keywords: chronic kidney disease
Controlled drug delivery
Model-guided drug formulation
Pharmacokinetics/Pharmacodynamics
Physiologically-based Pharmacokinetic Modeling
vitamin D

1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active ligand of vitamin D receptor (VDR), is useful for the prevention and treatment of various diseases, including chronic kidney disease (CKD), cardiovascular disease, hypercholesterolemia and neurodegenerative diseases. However, the therapeutic utility of 1,25(OH)2D3 is limited due to its propensity to cause hypercalcemia. Our aim is to develop a transdermal formulation of 1,25(OH)2D3 that allows for controlled drug delivery with minimal stimulation of the intestinal calcium ion channel (TRPV6), thereby avoiding the toxic outcome of hypercalcemia. By incorporation an ethylene vinyl acetate (EVA) rate-controlling membrane to slow down and regulate the rate of drug release, we were able to control the slow release from the patch not skin as the rate-limiting step for permeation. A physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model was further established to interpret the complex PK and PD interplay of 1,25(OH)2D3 and guide dosing selection. Based on the modeling and studies in vivo, we were able to determine that patches containing loadings of 70-560 pmol‧cm-2 1,25(OH)2D3 (or ~0.0004-0.0048% w/w) to be noncalcemic. The apparent half-life of 1,25(OH)2D3 in mice following the patch formulation was prolonged when compared to the repeated intravenous (IV) and intraperitoneal (IP) doses, due to the more gradual release of 1,25(OH)2D3 from the patch, rendering lesser stimulation of the degradation enzyme, Cyp24a1, for 1,25(OH)2D3 elimination and Trpv6 for calcium absorption. Additionally, the 1,25(OH)2D3 transdermal patch (~0.0004-0.0048% w/w) provided sustained, desirable pharmacodynamic effects in the suppression of the parathyroid hormone (PTH) in CKD mice in vivo for the correction of secondary hyperthyroidism (SHPT) without notable toxicity. In conclusion, our transdermal 1,25(OH)2D3 delivery system provides a safe and effective way for the delivery of 1,25(OH)2D3.
Targeting Metabolic Dysregulation for the Treatment of Radiation Fibrosis
Keywords: Cell therapy
Fatty acid oxidation
Fibrosis
Glycolysis
Metabolism
Pharmacogenomics

Extracellular matrix (ECM) homeostasis is essential for normal tissue function. Disruption of homeostasis by iatrogenic injury, trauma, or disease can lead to fibrosis. Skin ECM homeostasis is maintained by a complex process involving an integration of cytokine and environmental mediators. It is currently unclear, in both normal and disease states, as to how these multifactorial processes converge to shift ECM homeostasis towards accumulation or degradation. In this study, an interplay between fatty acid oxidation (FAO) and glycolysis was observed to be a key convergence point governing ECM homeostasis in skin. A consistent shift from FAO to glycolysis was observed in human and murine skin with ECM accumulation, and in dermal fibroblasts induced to upregulate ECM production by multiple mediators (TGF-Β1, PDGF-BB, hypoxia). Pharmacologic inhibition and genetic knockdown of key FAO and glycolysis pathway enzymes in dermal fibroblasts confirmed that FAO and glycolysis have opposing roles in ECM regulation. Specifically, glycolysis induced an anabolic fibroblast that upregulated ECM production. This was counteracted by shifting fibroblasts to FAO, which induced a catabolic phenotype inhibiting both transcription of components of the ECM, as well as enhancing ECM internalization and lysosomal degradation. CD36, a multifunctional fatty acid transporter, was discovered to be a critical mediator connecting the metabolic state of fibroblasts with their capacity for ECM regulation. CD36 promoted the catabolic effect of a FAO fibroblast, as its knockdown abrogated the internalization and degradation of collagen-1. Restoring FAO and upregulating CD36, either through pharmacotherapy or by autologous transplantation of CD36high fibroblasts, reduced ECM accumulation in murine radiation fibrosis. Our data demonstrate that metabolic regulation may be an integration point downstream of molecular signaling pathways that govern ECM homeostasis by shifting fibroblasts between anabolism and catabolism. These results have broad implications for therapies aimed at ECM reduction, such as fibrosis, or ECM buildup, such as regenerative medicine and aging.
Molecular Mechanisms of Bone Destruction and Central Nervous System Invasion in B Cell Acute Lymphoblastic Leukemia
Keywords: Acute Lymphoblastic Leukemia
B-ALL
CNS leukemia
CXCR4
RANKL

The use of intensified multiagent and prophylactic central nervous system (CNS)-directed chemotherapy has achieved improved survival for pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL). However, skeletal morbidities and CNS leukemia continue to pose significant clinical challenges in B-ALL patients underscoring the need to identify the underlying mechanisms and to develop effective targeted therapies. My thesis project aimed to elucidate molecular mechanisms of bone destruction and CNS invasion in B-ALL and to provide evidence for potential targeted therapies to ameliorate these complications. Using a genetically sensitized mouse model of spontaneous B-ALL and primary patient-derived xenograft (PDX) mouse models, we demonstrated that B-ALL cells cause bone destruction and identified the receptor activator of nuclear factor kappa-B (RANK-RANKL) ligand axis as critical in these effects. Treatment of PDX mice with a RANKL antagonist recombinant Osteoprotegerin-Fc (rOPG-Fc) conferred robust protection from bone destruction. We examined routes of leukemic cell entry into the CNS and demonstrated that both mouse and primary human B-ALL cells migrated to the skull and vertebral bone marrow (BM) and further transited into the subarachnoid (SA) space of the CNS. Strikingly, rOPG-Fc protected both skull and vertebral BM from human B-ALL cell invasion and prevented transit into the SA space. Moreover, pharmacological inhibition of the C-X-C chemokine receptor type 4 (CXCR4) in human BCR-ABL+ PDX mice prevented leukemic cell migration from skull/vertebral BM into the SA space. Overall, these findings demonstrate two mechanisms of CNS invasion by B-ALL that can be opposed by targeted treatments. Finally, we identified unique transcriptional and functional signatures in pediatric mixed lineage leukemia (MLL) which reveal distinct cell intrinsic behavior of lymphoid- and myeloid-like MLL populations and striking adaptations to the CNS microenvironment. Collectively, this thesis reports novel molecular mechanisms of B-ALL mediated bone destruction and CNS invasion and identifies actionable therapeutic targets to reduce these morbidities.
The Dearest Butterfly: A Nonlinear, yet Stratified, Human-butterfly Ethnography
Keywords: Animal Studies
Multi-sited Ethnography
Multi-species Ethnography
NAFTA
North American Nature Conservation
Posthumanities

This dissertation is a multi-sited and multi-species ethnography which follows the migration of the monarch butterfly across the East Coast of Canada and the United States to the Oyamel Forest of central Mexico. The project builds upon ethnographic research at four nodal locations for monarch conservation: Point Pelee National Park in Ontario, Canada; Monarch Lab in Minnesota, U.S.; The Monarch Butterfly Biosphere Reserve in Mexico; and an online community named DPlex-L. The thesis develops the concept of the “Dearest Butterfly” to index the emergence of a new way of valorizing this migratory insect after it entered international networks of species conservation and to navigate what I call a non-linear and stratified assemblage that exists around the aspirations of conserving this charismatic insect. Along with this proposition, I chronicle and utilize the monarch’s sharp population decline as a means to unearthing North America’s devastated socioecology. The thesis argues that the insect’s falling numbers are related to the outcomes of nature-extensive exploitation and displacement of indigenous forms of knowing nature at the sites of study. In a non-linear fashion, I connect these outcomes with NAFTA’s circulation of goods and new forms of human displacement from Mexico to its northern neighbors to argue that protecting this tri-national butterfly was part of a plan to consolidate the North American region as an economic block that prizes mobilities of goods even while it seeks to prevent the movement of people, and, ironically, of monarchs. The thesis engages with the field of Science and Technology Studies by describing the everyday tensions of rendering the iconic monarch as a working and captive insect in the laboratory in order to conserve it. From the introduction Pendant Egg to the conclusion chapter Egg Under Review, I maintain that thinking with monarchs and their exceptional life cycle achieves a twofold outcome for anthropological research: it approaches the devastated monarch migratory corridor as an ecological, social, and technological assemblage; and it investigates existent cooperative and often uncooperative relations to critique this crisis, and hopefully re-vitalize it through a proposition of an ecosophy for migrating humans and nonhumans of North America.
Roads to Resources: Uneven Development, Mobile Work, and the Extractive Imaginary in Canada
Keywords: Labour markets
Mobility
Resource extraction
Uneven Development
Welfare state
Work

In recent years it has become common for workers to commute from high unemployment areas of eastern Canada to work in the Alberta oil sands and related industries. Through a genealogical investigation that moves from the post-war decades to the present, this dissertation asks how, and to what end, mobile extractive work has become normal for east coast communities. Drawing on participant observation and action research, in-depth interviews, and archival research in provincial and federal state archives, I illustrate that welfare state policy, rural restructuring, and targeted recruitment have driven workers into long-distance work, but that a narrow set of stories about work and the economy have normalized these extreme labour relations. In the decades after World War Two, as the Canadian state set its sights on modernization and national economic expansion, it formulated the Maritime region as a national problem. Framing the region’s seasonal economies, low productivity, and “underdevelopment” as barriers to national growth, planners and policy-makers worked to remake Maritime economies and people to fit with a vision of the national economy rooted in industrialization, urbanization, and expanded industrial resource extraction. Welfare state programs focused on rural development, modernization, and labour re-organized local material life in powerful ways, but they also broadcast narrow ideas about what types of work, livelihoods, and economies could be part of the future. These enduring stories about economic viability, I argue, have naturalized decline, mobility, and market volatility, rendering the region’s remarkable reliance on long-distance resource employment ordinary. By obscuring workers’ experiences of volatility and the underdevelopment that shapes extractive labour markets, this normalization has been a linchpin in Canadian extraction. This research highlights the central role of welfare state policy in producing relations and geographies of extraction in Canada. But the state’s intensive investment in managing peripheral workers and regions also underscores the persistence of economies, lives, and forms of valuation that break from the logic of unending accumulation.
The Limits of Legality: The Rule of Law Principles Governing the Common Law Public Policy Exception in Private International Law
Keywords: Common Law Constitutionalism
Conflict of Laws
Private International Law
Public Policy Exception

The public policy exception is a well-established part of common law choice of law doctrine. But to use the exception, judges must identify the forum’s fundamental values that cannot be violated by foreign law. Scholars have argued that it is impossible to provide a general account these values and have criticized the exception for introducing indeterminacy into choice of law doctrine. As result, scholars argue, the exception represents a threat to the rule of law. This standard scholarly critique is rooted in a formal account of the rule of law. But in the common law tradition, there is a well-established alternative theory: under the common law constitutionalist account of the rule of law, judges must do much more than simply ensure that the law is consistent, predictable, and determinate. Judges must also ensure that the law’s content does not violate the fundamental rule of law values of the unwritten ‘common law constitution.’ This project offers a novel common law constitutionalist account of the relationship between the rule of law and the public policy exception. Instead of undermining the rule of law, this account sees the public policy exception as a means through which courts uphold the rule of law. The exception allows courts to ensure that the content of foreign private law selected by the forum’s choice of law rules does not violate the forum’s substantive rule of law values. This account also offers guidance as to which values cannot be violated by foreign law: the rule of law norms of the ‘common law constitution.’ In addition, this account helps make sense of English and Canadian public policy jurisprudence, offering a compelling account of the leading cases and the reasons that judges have used to invoke public policy. Ultimately, common law constitutionalism would not see the public policy exception as a ‘unruly horse,’ but as a necessary aspect of the rule of law; and as a unique doctrine offering important insight into the fundamental values of the common law tradition and the success of common law constitutionalism qua theory of the rule of law.
Vital Movements: Feminist Aesthetics and Popular Culture 1920–1945
Keywords: feminism
movement
popular culture
vitality
women

Vital Movements argues for the crucial importance of women’s physical movement to the aesthetics of American popular culture between 1920 and 1945. Tracking female bodies as they run up and down stairs, enter and exit rooms, and strut across spaces and places, my dissertation reveals an array of self-determining women, defiant in their mobility and their right to choose and take pleasure in a life outside the accepted roles of wife and mother. Aesthetic modernism’s institutionalization as the critical high-water mark of the period has largely rendered works that circulated in the commercial realms of Broadway, Hollywood, and Book-of-the-Month Clubs devoid of substance. Further, critical emphasis on language and discourse, according to dance critics, has caused us to ignore the expressive capacities of the body in motion. I argue that sustained attention to embodied movement forces a reconsideration of popular realist texts by revealing other ways they tell their stories, ways that are complex and layered in their own right. This method of engagement restores agency to the texts, lost, as Rita Felski has argued, in the emphasis on historical context, by rendering their capacity to solicit our “affective attachments.” Combining insights from middlebrow studies, “physical cultures” of the period, philosophies of movement, dance studies, and spatial theory, each chapter applies them to a different genre. Chapter one uses Edna Ferber and George S. Kaufman’s play Stage Door to establish women’s movement as the dissertation’s overall subject and to introduce the essential role played by work in the freedom and autonomy expressed by it. Chapter two focuses on resistance to norms of feminine embodiment and their relation to social and economic mobility in Dorothy Arzner’s film Dance, Girl, Dance. Stage directions and the inherent visuality of film attune readers to moving bodies before encountering the narrative forms of chapters three and four, which, respectively, connect moving bodies to unarticulated thoughts and desires in Zona Gale’s novel Miss Lulu Bett, and to personal growth and fulfillment in Mabel Dodge Luhan’s autobiography, Intimate Memories. Throughout bodies “speak” through movement, generating a realism richly attuned to the textures of women’s everyday lives.
A Dominican Master of Theology in Context: John of Naples and Intellectual Life Beyond Paris, ca. 1300-1350
Keywords: Dominicans
History of Education
Intellectual History
Naples
Pastoral Care
Theology

This dissertation provides the first comprehensive biography of the Dominican scholar John of Naples (Giovanni Regina di Napoli), who flourished during the first half of the fourteenth century. John studied and taught at the Dominican schools in Naples and Bologna, and at the University of Paris, where he was made a master of theology in 1315. He spent most of the rest of his life in Naples, where he was closely associated with the Angevin court. Chapter 1 surveys John’s life and works, setting his career in its Neapolitan context. Chapters 2-4 deal with different aspects of his teaching. Chapter 2 contrasts his contributions to debates about the nature of theology at Paris with the way he introduced this subject to his Dominican students in Naples. Chapter 3 examines the role of medicine in his theological teaching, where it served as a tool for interpreting core texts as well as a source of material for preaching. Chapter 4 analyzes the symbiotic relationship between his quodlibets and the literature of pastoral care. Chapter 5 looks at John as a Dominican friar and preacher, turning to his sermon collection as a source of information about Dominican life in southern Italy, and Chapter 6 investigates his relationship with the Angevin rulers of Naples and the role of politics and political theory in his works. Appendices to chapters 2-6 provide transcriptions of unpublished quodlibetal questions, sermons, and other texts used as the basis for this study. Two additional appendices provide descriptions of the main manuscripts and discuss the dating and placing of John’s works. This study considers John from a variety of angles – teacher, preacher, friar, courtier, Neapolitan – and suggests that these overlapping identities cannot be productively separated from one another. It highlights the vibrancy of intellectual life in early-fourteenth-century Naples, and the strong cultural ties between Naples, Paris, and Avignon, as well as other regions such as the Kingdom of Hungary. Furthermore, it illustrates how mendicant convents could help to disseminate theological teachings from the University of Paris to the provinces, while also serving as sites of innovation in their own right.
Freedom Dues: Negotiating Race, Servitude, and Freedom in Early American Law and Literature
Keywords: American literature
freedom dues
law and literature
Nineteenth Century
Race
Servitude

Freedom dues were typically payments of money, land, or clothing that masters gave to servants upon completion of servitude. Using case studies, this thesis captures the arc of a historic transformation in how freedom dues were perceived between the mid-seventeenth and mid-nineteenth centuries; it illuminates how these dues became a humanitarian symbol and the narrative of self-actualization that arose about them. The narrative focus on freedom dues was generated through tracts advocating immigration to colonial America and was integral to early understandings of the promise of New World prosperity. The texts I address use this narrative to critique a society failing to live up to its implied ideal: enfranchisement through hard work. My thesis reveals that often relations of servitude morph into something that looks dangerously akin to chattel slavery. In Chapter One, I contrast the Lawes and Libertyes (1648), where servants were to be prevented from “be[ing] sent away emptie,” to the revisioning of this framework in the Fugitive Slave Law (1850), which enshrined slaves’ perpetual indebtedness. In Chapter Two, I use the Records of the Salem Witch-Hunt (1692-93) to examine how Tituba’s claim that the devil offered her an indenture followed by many “fine things” came to influence other testimonies. I argue that the narrative Tituba and others craft regarding the Devil's promise of servitude properly rewarded but not supplied by Massachusetts’s governors would have been shocking in New England at the time. Chapter Three analyses The Scarlet Letter (1850) and reveals that, by presenting Hester Prynne as a branded, lifelong indentured servant, Hawthorne effectively portrays a variety of servitude that appears similar to black slavery. Hester and Pearl have their customary white privileges undermined, I argue, and Hawthorne’s novel reveals abolitionist leanings. In Chapter Four, I consider Harriet Wilson’s autobiographical text, Our Nig (1859). The Bellmonts’ refusal to provide proper freedom dues to the novel’s protagonist highlights the degree to which her servitude has been slavish, and Wilson’s plea for support to remedy this wrong provides a final critique of "free" New England.