VictorJuiz/thesis huggingface dataset:
Understanding the Role of an Adaptor Protein, XB130, in Tumorigenesis
Keywords: Adaptor protein
Hypothyroidism
Multinodular goiter
Thyroid function
Tumorigenesis
XB130

Adaptor proteins are essential proteins involved in the regulation of signal transduction pathways. XB130 is one type of adaptor proteins, which functions as an intracellular mediator for regulating cellular activities, such as cell proliferation, cell survival, cell migration, invasion, and cytoskeleton regulation, in various normal and cancer cells. Currently, the exact physiological roles of XB130 in in vivo tumorigenesis remain unknown. To investigate its functions, two studies were performed using XB130-deleted mice: (1) a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumorigenesis study, and (2) a study on spontaneous tumorigenesis of aged mice. First, through the carcinogen-induced tumorigenesis approach, XB130 is identified as a putative tumor suppressor and regulator of inflammatory response. The multiplicity and size of DMBA (mutagen)/TPA (tumor promoter)-induced epidermal tumors in XB130 knockout (XB130-/-) males were significantly increased compared with those of wild-type (XB130+/+) littermate males. In the absence of XB130, keratinocyte proliferation, edema formation, neutrophil infiltration, expression of pro-inflammatory cytokines, as well as inflammation- and cell proliferation-related signaling pathways were altered dramatically in response to repeated TPA stimuli in males. These changes may have orchestrated tumor microenvironment favoring the skin tumorigenesis in XB130-/- mice. In the second study, aged XB130-/- mice had increased spontaneous occurrence of benign enlarged thyroid glands with various nodules, which were diagnosed as multinodular goiters. XB130-/- thyroid glands exhibited architectural distortion with higher proliferation of follicular cells in nodules, as well as disrupted expression and distribution of cytoskeleton elements and junction proteins. XB130-/- mice were hypothyroid, displaying defective organification of iodide during perchlorate discharge test and reduced expression of iodinated thyroglobulin. XB130 was confirmed to be localized at the apical side of thyroid follicles at which thyroglobulin iodination normally occurs. As compensatory mechanism to the loss of XB130, thyroperoxidase (TPO) activity was enhanced in aged XB130-/- thyroid glands, with increased affinity of TPO for iodide and higher expression of TPO protein. Thus, XB130 deficiency led to the pathogenesis of benign multinodular goiters as the manifestation of dyshormonogenic hypothyroidism. In summary, this work highlighted the tumor-suppressive role of XB130 in carcinogen-induced tumorigenesis study and introduced its novel involvement in thyroid function through spontaneous tumorigenesis study.
Severe RSV-related IIlness among Ontario Children: Using Population-based, Administrative Data to Comprehensively Identify High-risk Children and Evaluate Population Interventions
Keywords: Pediatrics
Public health policy
Respiratory syncytial virus

Respiratory syncytial virus (RSV) is the most common cause of respiratory tract infection and hospitalization among children globally. Early-life infection with RSV has long-term impacts, including increased risk of developing asthma, and there is increasing recognition of the burden RSV imposes upon the health of older adults. In this dissertation, I present three studies pertaining to the epidemiology and prevention of severe RSV-related illness, particularly among young children, using unique multi-linked health and socio-demographic administrative data for the population of Ontario, Canada. Using a quasi-experimental design, I evaluated the effectiveness of RSV prophylaxis programs for high-risk infants. Severe RSV-related illness substantially declined over the 24-year study period, particularly among high-risk children. While we cannot firmly attribute causality, the magnitude and timing of changes, along with diminished social inequities, among prophylaxis-eligible infants are noteworthy and suggest these programs have noticeable real-world effectiveness, albeit to a lesser degree than observed in efficacy studies. In a birth cohort study, I investigated the contribution of multiple socio-demographic factors to early-life RSV admissions. To date, these factors have received little attention relative to medical factors, despite the known role they have in influencing the transmission, severity and uptake of interventions for other common respiratory viruses. Multiple novel socio-economic factors were independently associated with significantly greater RSV-related admission rates, including young maternal age, maternal involvement with the criminal system, and maternal mental health and/or addiction concerns. I developed the first RSV transmission model for any Canadian population, which also uniquely captures the entire population age spectrum. Relative to other common communicable diseases, few RSV transmission models exist. Our model accurately captured the seasonal RSV epidemic curves observed among infants and suggests RSV burden is greatest at the extremes of the age spectrum. This calibrated base model can be adapted to investigate the potential impacts of emerging RSV vaccination strategies in Ontario and could be further calibrated for use in other populations. Overall, these results contribute to our understanding of the real-world impact of RSV prophylaxis programs and highlight impactful targets for revisions to prophylaxis guidelines and emerging vaccination strategies. These results may inform the selection of optimal policies and interventions which not only reduce RSV burden but also minimize social inequities.
Cognitive Sensitivity - Investigation of Construct Across Cultures and Settings
Keywords: Child Development
Cross-cultural Research
Early Childhood Education
Measurement
Parent-child Relationships
Parenting

The current dissertation includes 3 research papers investigating the construct of cognitive sensitivity across different cultures, populations, and settings. Cognitive sensitivity refers to an individual’s ability to create a cognitively stimulating environment for their interaction partner, while being attuned to this partner’s emotional state. Study 1 investigated the role mother’s ethnicity (Caucasian, Asian, Black; N=354) plays in maternal cognitive sensitivity and in children’s later cognitive outcomes (n=245). Results indicated that maternal cognitive sensitivity skills differ as a function of the mother’s ethnicity. Additionally, ethnicity moderated the relationship between maternal cognitive sensitivity and children’s later cognitive outcomes, but only for children from Asian backgrounds. Study 2 investigated cognitive sensitivity within a sample of Israeli parent-child dyads (N=44), its relation to children’s emerging literacy skills, and whether cognitive sensitivity differed as a function of the parent’s gender. The psychometric properties of the cognitive sensitivity measure were solid, providing preliminary evidence of the applicability of this construct to this Israeli population. Parent cognitive sensitivity was found as a significant predictor of children’s phonological awareness, but only in families with small sibship size (≤2 children). No significant differences were found between mothers’ and fathers’ cognitive sensitivity ability. Interestingly, parents were found to be more cognitively sensitive towards their daughters compared to their sons. Study 3 adapted and validated the Cognitive Sensitivity scale from the family to the Early Childhood Education and Care (ECEC) settings to capture educator-child interactions. The measure was designed to be short and efficient to train and administer. Results indicated strong psychometric and concurrent validity properties for the new scale, Educator Cognitive Sensitivity (ECS). Using multilevel data, with educators (N=350) nested within classrooms (n=135) and within centres (n=69), a variance component analysis indicated that the majority of variance in cognitive sensitivity scores was accounted for by individual differences between educators. This brings into question methods currently used with gold-standard measures capturing the quality of educator-child interactions. Taken together, research findings highlight the complexity of factors playing in measuring parent-child and educator-child interactions. As a result, researchers need to develop measures that are empirically strong, efficient, and culturally sensitive.
A Theory of Tort Liability for Autonomous-machine-caused Harm
Keywords: Autonomous Machines
Corrective Justice
Legal Agency
Legal Personhood
Robot Law and Ethics
Tort Law and Tort Theory

Developments in artificial intelligence and robotics promise increased interaction between humans and autonomous machines, presenting novel risks of accidental harm to individuals and property. This thesis situates the problem of autonomous-machine-caused harm within tort law’s doctrinal and theoretical framework, conceived as a practice of corrective justice. Crucially, due to machine-learning capabilities, harmful effects of autonomous machines may be principally un-foreseeable, and therefore, not legally attributable to the human agency of designers, manufacturers or users. This thesis assesses which tort doctrines—negligence, strict liability or vicarious liability—are most amenable to developing a theory of liability for autonomous-machine-caused harm. To this end, it argues that the doctrine of vicarious liability may be reconceived to hold human or corporate deployers vicariously liable for tortious harm caused by autonomous machines in the course of deployment. Under this approach, autonomous machines constitute a novel category of legal subject: pure legal agents without legal personhood.
Noisy Soundscapes: Women's Institutions, Sound, and the Body in Early Modern Florence
Keywords: Early Modern
Florence
Gender
Institutions
Italy
Sound

This dissertation examines soundscapes in and around women’s residential institutions in sixteenth and seventeenth century Florence (1537-1670). Over these two centuries, an unprecedented number of girls and women entered or were entered into a variety of convents, charity homes, and reform houses. Religious and civic institutions expanded rapidly in both number and size, and adopted increasingly strict rules of enclosure. Racket, clatter, silence, and the quotidian sounds of sociability took on profound significance in these spaces. Using institutional manuals, criminal records, letters, and legislative records, this project uncovers the sounds that continually flowed in and out of Florence’s many enclosures from women, linking these communities to the larger city. While other studies have examined material practices of enclosure in the early modern period, immaterial practices of enclosure have been largely unstudied. Yet, the ephemeral senses fundamentally patterned how thousands of girls and women experienced institutionalization. This project offers new insight into the institutional shifts that marked the early modern period, showing how a sonic boundary increasingly characterized institutionalization. An early modern emphasis on the power and potency of sound found expression on multiple fronts. Medical, health, and spiritual literature discussed the impact of sound on the environment, body, and soul in detail. Tridentine period religious reforms increasingly advocated the importance of careful listening and sonic decorum. In Florence, the centralizing Medici Duchy and Grand Duchy crafted a corpus of sonic legislation that aimed to discipline space, sound, and sociability. Women’s institutions were pivot points around which these combined sonic cultures turned. Rather than focusing on one particular type of institution, this project examines a range of lay and monastic enclosures that housed diverse girls and women from across the socio-economic spectrum. Moreover, my analysis focuses on the sonic interactions that connected institutionalized girls and women to the various Florentines who lived, lingered, and laboured near their enclosures, challenging early modern discourses of "public" and "private". These groups include women sex workers, rowdy male youths, aggressive men, gamblers and game-players. This project positions institutionalized girls and women at the centre of the early modern Florentine soundscape, showing how the rapid expansion of women’s institutions fundamentally shaped urban socio-sonic experience.
Palaeoenvironmental Reconstruction and Geochronology of the Archaeological Localities at Kathu Pan, South Africa
Keywords: Archaeology
Geochronology
Palaeoenvironment
Sedimentology
South Africa

Investigation of palaeoenvironments along the semi-arid Kalahari desert margin is necessary for understanding the processes driving modern desertification as well as providing context for the evolution of early hominin populations. By investigating Kathu Pan (KP), an archaeological site with several exposed sediment profiles (KP1, KP6 and KP9), this dissertation constructs a well-dated record of palaeoenvironmental change through the use of luminescence dating and sedimentological methods. To provide a secure age for the stratigraphy, the sequence was dated using multiple minerals and luminescence signals. Discrepancies exist among the results of these techniques, with quartz optically stimulated luminescence providing the most consistent set of ages. These results have important implications for our understanding of the Howiesons Poort technology. The KP exposures were investigated using a multi-proxy approach, including a suite of sedimentological and mineralogical techniques to reconstruct palaeoenvironmental shifts across the site. The resulting record reflects a consistently semi-arid environment fluctuating among a number of thresholds for accumulation of different kinds of transported and authigenic sediments. The sands at the base of the sequence, deposited during the late Pleistocene, are coated in the clay mineral palygorskite, indicative of moderate evaporative control within a semi-arid environment throughout Marine Isotope Stages 6-3. Increased moisture availability during Marine Isotope Stages 5a and 5c is reflected in these sands by the formation of palygorskite in concert with the deposition of organic material. KP crossed a threshold during the Last Glacial Maximum, when deposition of CaCO3 dominated over that of palygorskite, revealing an increasingly arid climate possibly responding to global cooling. In the Holocene beds, repeated alternation of CaCO3- and organic-dominated deposits reflects variable water availability. Through integration with nearby palaeoenvironmental archives, the KP record is discussed in the context of complex southern African climate systems and the variable responses of different proxies to changing moisture regimes, especially seasonality of precipitation. Given the presence of dense artefact assemblages at KP, the availability of water here evidently influenced hominin populations in the region; this dissertation brings southern African moisture records into the pan-African conversation around hominin evolution.
Spreading and Sealing: Epithelial Morphogenesis Regulated by the Cytohesin Arf-GEF Steppke
Keywords: Actin
Arf
Cytohesin
epithelia
Morphogenesis

Epithelial tissue must maintain structural integrity to carry out secretion, absorption and barrier functions. Maintaining integrity becomes especially important as tissues undergo dynamic shape changes for morphogenesis during animal development, homeostasis, and tissue repair. For epithelial morphogenesis, regulating the actin cytoskeleton is critical for modulating cell shape and adhesion that facilitates changes to tissue topology. Actin networks are regulated by a wide variety of proteins that allows them to adopt diverse configurations and activities. ADP ribosylation factors (ARFs) are molecular switches that control various cellular responses, and their activation at the cell cortex by Cytohesin Arf-guanine nucleotide exchange factors (GEFs) modulates actin networks in cultured cells. However, it is not clear how Cytohesins regulate actin networks and how this contributes to epithelial morphogenesis in vivo. For my thesis, I studied the role of the sole Drosophila Cytohesin, Steppke (Step), during embryonic epithelial morphogenesis. I found that Step is critical for promoting orderly tissue spreading and it does this by antagonizing actomyosin networks. Step depletion resulted in an ectopic accumulation of actomyosin networks that was correlated with increased tissue tension. Interestingly, actomyosin networks are required for subcellular recruitment of Step indicating that the antagonism occurs through negative feedback. A collaboration revealed a similar role for Cytohesins in Zebrafish. In a second study, I found that Step is required for efficient tissue sealing. For this role, Step promotes F-actin and actin-based protrusions at the leading edge of epithelial sheets, and cooperates with the actin polymerization protein, Enabled. Strikingly, overexpression of Step induced ectopic actin-based protrusions and epithelial breakdown in more severe cases. By antagonizing actomyosin networks and promoting actin protrusions, Step is a critical regulator of epithelial morphogenesis.
Montesquieu's Moderation: Commercial Innovation and Public Responsibility in Eighteenth-century Britain and France
Keywords: Commercial Honour
John Law
Liberty
Montesquieu
Political Moderation
Scottish Enlightenment Political Thought

The dissertation considers Montesquieu’s conception of moderation in the context of John Law’s economic system in France. In considering the institutional and intellectual context of Law’s ‘System’, the first part casts light upon the unsavoury effects of unfettered commerce in Bourbon France, and examines their formative influence upon Montesquieu’s political thought. It explains that Law’s System threatened to produce a despotism of the most pernicious sort. Unlike traditional threats to moderate government that stemmed from absolute princely rule or clerical power, the form of despotism that concerned Montesquieu most came from a fusion of financial and political power. He moreover feared that Law’s financial system fed into an emerging commercial culture of the time, which perceived money and personal wealth as the greatest arbiter of social standing. As a corrective, Montesquieu provides an elegant theory of moderate government, which reinvigorates institutions of honour to foster a hierarchy of value in the public mind that privileges civic engagement over wealth and commercial success. In comparing the political thought of Montesquieu, David Hume, Adam Smith, and Adam Ferguson, the second part of the project unearths a conceptually distinct idea of eighteenth-century political moderation, which paradoxically relies on pre-modern institutions to preserve liberty and political order in a modern commercial context. These themes will help illuminate post-Cold War attempts at dealing with the explosion of liberal capitalism as the de facto global standard. Francis Fukuyama, who famously proclaimed that there is no viable alternative to this dominant ideology, examined its deep roots to discover sources for taking advantage of it while counteracting its pathologies. The subsequent third-way politics of the 1990s and centrist attempts to counteract the recent wave of populism in the West each aim to protect the existing liberal economic order from more debased forms. Their attempts at moderating the excesses of liberal capitalism in some ways mirror the moderate compromises that Montesquieu and his Scottish counterparts deemed necessary for guaranteeing a free and stable order. The dissertation carefully reconstructs their visions of free and moderate government so that the limits and potential of this analogy can be fully understood.
Subcutaneous Islet Delivery for Diabetes Therapy
Keywords: CLARITY
Islet Transplantation
Modular Tissue Engineering
Subcutaneous
Vascularization

Pancreatic islet transplantation into the portal vein remains as one of the only approaches to achieve insulin independence in type I diabetics. However, due to the instant blood mediated inflammatory response, many islets are lost upon transplantation and multiple donors are required. Pancreatic islet transplantation into the subcutaneous space is being pursued as an alternative because it can support a large transplant volume, and is minimally invasive, but the subcutaneous space is poorly vascularized and cannot support cell transplantation without modification. Here I focus on developing strategies to deliver pancreatic islets into the subcutaneous space to engraft, re-vascularize and integrate with the host. Firstly, modular tissue engineering was adopted to subcutaneously deliver pancreatic islets and was sufficient to return streptozotocin-induced diabetic SCID/bg mice to normoglycemia. We then formed size-controlled and tuneable pseudo-islets using deaggregated islets within endothelialized collagen rods to enable enhanced islet transplants, which were superior to native islets. Pseudo-islets regenerated their intrinsic vasculature when subcutaneously transplanted as confirmed by three-dimensional whole implant imaging. Finally, two strategies were developed to pre-vascularize the subcutaneous space and reduce the therapeutic dosage of pancreatic islets in both mouse and rat models. This work highlights strategies to re-vascularize pancreatic islets within the subcutaneous space – a feature that has not been previously been shown. In addition, this work provides several platforms that can be developed to incorporate immune modulation and improve clinical translation.