VictorJuiz/thesis huggingface dataset:
The Effect of Pre-eclampsia and HIV on the Expression and Regulation of Drug Transporters in Placenta
Keywords: BCRP
HIV
Placenta
Pre-eclampsia
Transporters

Disease-mediated changes in the expression and activity of placental ABC and SLC drug transporters have been extensively studied in animal models resulting in altered transplacental passage of their substrates. While these transporters are likely also dysregulated in human placental tissues, translational studies are lacking and thus little is known about expression and regulation of these clinically important drug transporters in patients with Pre-eclampsia (PE) and Human Immunodeficiency Virus (HIV). Moreover, statistics indicate that prescription drug use in pregnancy is on the rise and is likely higher in these two conditions. In two separate studies, we used placental tissues obtained at birth from women with PE and HIV, to investigate the effect of these two diseases on the expression of highly expressed and clinically relevant drug transporters. We further used in vitro cultured placental cells and cultured placental villous explants to further understand the effects of angiogenic factors in the context of PE and ARVs in the context of HIV on the expression of several drug transporters. Our studies demonstrated that both PE and HIV resulted in widespread dysregulation of several placental uptake and efflux transporters from women with clinically diagnosed disease. Additionally, within our PE group, placental angiogenic factor sFlt-1 was significantly induced while VEGF and PLGF were significantly downregulated in PE placentas compared to non-PE controls. These were further investigated in vitro where they were found to play a role in the regulation of BCRP and OATP2B1 expression. Within our HIV group, many women were on prescribed antiretroviral regimens, some of which were found to significantly induce PGP and downregulate OAT4 expression in vitro in human placental explants. Our findings suggest that the protective function of the placenta is compromised in women with PE and HIV with significantly altered expression of clinically important transporters. These translational studies provide key insight and real-world evidence of disease-mediated changes in placental transporter expression. As this may impact fetal health and increase in utero exposure to prescription medications, further studies and closer clinical investigation are needed to determine the impact of disease-induced changes on placental drug transporters and the possible impact on maternal drug-disposition and fetal drug exposure.
Making Welfare Work for Autocracy: Wealth, Will Woes in the Politics of Welfare in China
Keywords: Authoritarian Survival
China
Single-party Regime
Social Policy
Welfare Development
Welfare State

China’s recent welfare expansion demonstrates a puzzling case. The welfare expansion has been broad-based, benefiting almost every sector of the society in one way or another, which is rare considering past authoritarian regimes often made welfare expansion exclusive to its loyal-support base. A wide degree of variation also exists in how welfare policies are prioritized in the shortterm and how welfare provision is made in the long-term. To address these puzzles, the study examines welfare expansion at the city-level, covering 114 cities from 2006 to 2016. The main arguments are three-fold. First, local leaders prioritize different welfare policies with different motivations. They prioritize education spending strategically, ensuring human development for the local economy’s productive purpose while enhancing prospects for personal promotion. By contrast, annual social security and total welfare spending are determined by the local state sector’s size. Second, the state sector also plays a critical role in determining long-term welfare provision. Cities with a large state sector tend to have a high level of welfare provision in the long-term. Finally, the state sector gained more than any other sector from the expansion of social security even though the general population experienced a relative improvement in their welfare. The findings underscore the importance of the state sector for regime survival. The expansion of the state sector is a culmination of past policies. While the state sector’s expansion had the goal of establishing its commanding presence in the market economy, on the political level, it became a vehicle for advancing the Party’s socialist agenda and establishing social stability. Moreover, the mixed-welfare system made the fiscal burden of welfare expansion bearable through standardization of social security, creating a large pool for contribution by socializing risk. Privileged benefit and coverage helped strengthen the Party’s patronage relation with the state sector, while the relative improvement in welfare provision for all helped gain broader legitimacy. As a result, the Party-regime made the welfare expansion work for its own survival interest by instrumentalizing welfare for mass-cooptation while making it affordable. The study establishes a clear link between welfare expansion, mass cooptation, and authoritarian-regime survival.
Towards the Controlled Synthesis of Conjugated Polymers
Keywords: conjugated
material
organic
polymer
semiconductor

Organic semiconductors with varying physical and optoelectronic properties are readily obtained by incorporating different functional groups in conjugated polymers. While controlled chain-growth polymerization routes have been developed for a handful of these conjugated polymers, most conjugated polymers are still synthesized through step-growth methods that allow little to no control over the resulting polymers. Robust and versatile synthetic methodologies are needed to access conjugated polymers with unprecedented control and optimized properties. In Chapter 2, I describe a rapid and selective synthetic route to thionated naphthalene diimides (NDIs). Thionated NDIs exhibit improved electron mobilities and ambient stabilities. Thionation procedures, however, are lengthy, unselective, and low yielding. Polymeric analogues had not previously been reported due to incompatibilities between sulfur atoms and prevalent palladium catalysts. I illustrate that the rate and selectivity of thionation is drastically improved using steric control and highly efficient microwave irradiation. This methodology is readily applied to synthesize NDI-based polymers with varying degrees of thionation through post-polymerization modification. In Chapter 3, I investigate the anion-radical polymerization of parent and thionated, thiophene- and selenophene-flanked NDIs. Although NDI-based polymers exhibit among the highest electron mobilities for n-type conjugated polymers, their existing synthetic routes are still largely uncontrolled. Anion-radical polymerization provides a promising alternative, wherein thiophene- flanked NDIs have been shown to exhibit chain-growth polymerization. I show that thiophene- and selenophene-flanked NDIs undergo anion-radical polymerization, albeit through step-growth mechanisms. While thionated NDIs form anion-radical complexes and exhibit signs of catalyst insertion, they do not undergo further polymerization. In Chapter 4, I present the templated oxidative synthesis of conjugated polymers. Templated synthesis is a prevalent route to accessing biological and bioinspired polymers but has only sparingly been applied to the synthesis of conjugated polymers. I illustrate that well-defined macromolecular templates synthesized through ring-opening metathesis polymerization undergo subsequent oxidative coupling to form well-defined conjugated polymers. I apply this methodology to synthesize soluble, poly(3,4-ethylenedioxythiophene)-based polymers with controlled molecular weights and low dispersities. In Chapter 5, I summarize the main conclusions and outlook of this thesis work. Further optimization and expansion of the methodologies described herein could greatly impact the fields of conjugated polymers and organic electronic materials.
Ergativity on the Move
Keywords: ergativity
Inuktitut
linguistic theory
syntax
variationist sociolinguistics

This thesis investigates changes associated with the ergative morphosyntactic alignment of the Inuit language. All these changes have been argued to signal an alignment shift from ergative to accusative, though none of them has ever been confirmed with detailed quantitative evidence. The most important change involves the rise of the antipassive construction in Inuktitut dialects at the expense of the ergative construction as the new default transitive construction (see Johns 1999, 2001a, 2001b, 2006, 2017; Spreng 2005; Carrier 2012, 2017; Yuan 2018). Other reported changes are 1) the elimination of overt transitive objects in the most innovative varieties, which would make the ergative construction a ‘marked’ transitive construction (see Johns 2017; Yuan 2018), and 2) the loss of the ergative case on transitive subjects in favor the absolutive case, which also marks intransitive subjects (see Tersis 2004; Langgård 2009; Carrier 2012). Using a variationist sociolinguistic approach to analyze data from North Baffin Inuktitut and a formal syntactic one to interpret the results, this study is the first to provide statistical evidence confirming that the ergative construction and the ergative case have been used progressively less and that they correlate with each other. I also posit that the general ongoing alignment change from ergative to accusative was first initiated by a neutralization in transitive subject number agreement, and that a series of changes has then successively triggered one another. Building on Brook (2018), I thus argue that these distinct changes constitute increasingly bigger envelopes of variation nested in one another and have in turn triggered one another after reaching a certain level of completion. One clear theoretical implication of these successive changes affecting distinct forms that display the traditional ergative alignment of the Inuit language is that ergativity is not a single concept but a macroset of many different properties (e.g., Dixon 1994; Johns 2000; Deal 2015a; Haig 2017).
Novel in vitro Microfluidic Platform for Studying Osteocyte Mechanobiology
Keywords: bone remodelling
intercellular signalling
microfluidic
osteoclast
osteocyte

Osteocytes are the major mechanosensing cells during bone remodeling. Current bone mechanotransduction research use macro-scale devices such as flow chambers; however in vitro microfluidic devices provide an optimal tool to better understand this biological process with its flexible design and high-throughput capabilities. Our recent work on co-culture platform has demonstrated the feasibility of building more complex microfluidic devices for osteocyte mechanotransduction studies. However, there still lacks a robust system where multi-physiological flow conditions are applied to bone cells during intercellular communication. I aim to improve the in vitro experimental platform for osteocyte mechanotransduction studies by 1) designing a novel multi-shear stress co-culture microfluidic device to study osteocyte intercellular communication; 2) testing the novel OCY454 osteocyte cell line to enable in vitro studies of osteocyte-osteoblast cross-talk; and 3) investigate magnetically actuated beams as a new method for in vitro fluid flow stimulation of osteocytes. I demonstrated that osteocytes seeded in the novel microfluidic device respond to different levels of fluid shear stress in each channel by varying amount of secreted RANKL. Furthermore, co-cultured osteoclast precursors had suppressed differentiation when next to osteocytes stimulated with high fluid shear stress. This microfluidic device can provide a new platform for researchers to further understand how mechanically stimulated osteocytes affect the bone remodelling process without complicated in vivo models. I also validated the response of OCY454 osteocytes to fluid shear stress, demonstrating changes in key indicators such as extracellular sclerostin level and intracellular calcium response, as well as capability to drive effector cell differentiation. This new cell line can help unlock further understanding of the role sclerostin plays in bone remodelling, and potentially give rise to novel pharmaceutical targets that can be used for treatment of bone diseases. Using novel magnetically actuated micro-beams, I experimented with a new method of generating localized fluid shear stress on osteocytes. This novel magnetic actuator can help us better understand how intercellular communication propagates within an osteocyte network when stimulated with localized shear stress. With development of new in vitro technical approaches to study osteocyte mechanotransduction, a better understanding of the bone remodeling process can be obtained.
Apolipoprotein A1 and High-density Lipoprotein as a Cargo and Regulator of Endothelial Transcytosis
Keywords: Apolipoprotein A1
Endothelium
High Density Lipoprotein
Internalization
Low Density Lipoprotein
Scavenger Receptor B1

Lipoproteins are circulating lipid carriers that regulate lipid homeostasis; low density lipoprotein (LDL) provides cholesterol, while high density lipoprotein (HDL) removes cholesterol from peripheral tissue. An imbalance of these processes leads to dyslipidemias and atherosclerosis, the accumulation of LDL in the arteries. To reach the target tissue, lipoproteins cross a protective monolayer of endothelial cells through transcytosis. Current understanding of transcytosis is limited and further complicated because endothelial cells vary depending on the tissue and vessel of origin. Indeed, brain endothelial cells are the most impermeant due to limited endocytic trafficking. In this dissertation, I investigate the relationship of HDL with the endothelium under physiological and pathophysiological states. Specifically, I aimed to elucidate the mechanism of HDL internalization in the brain endothelium in one study while determining the role of HDL in atherosclerosis in the other. In the brain endothelium, I found that HDL internalization is partially mediated by Scavenger receptor B1 (SR-B1) in a cholesterol-dependent, caveolae- and clathrin- independent manner. Furthermore, HDL internalization is independent of PDZK1 and the production of nitric oxide, which belong to the signaling pathway stimulated by the association of HDL with SR-B1. Together this suggests that HDL internalization is dependent on SR-B1 and cholesterol through brain- specific mechanisms. Given that atherosclerosis is also due to SR-B1-mediated transcytosis of LDL across coronary endothelial cells, I aimed to determine whether ApoA1, the protein found in HDL can prevent LDL transcytosis and how this is affected by the lipid state of ApoA1 as well as the natural mutant called Milano ApoA1. The Milano mutation results in half the plasma HDL levels, yet carriers do not develop atherosclerosis - the mechanism of which is not clear. I observed that ApoA1 can decrease LDL internalization and transcytosis by competition for SR-B1, while lipid-associated ApoA1 is more effective in inhibiting LDL internalization. The Milano protein is a slightly better inhibitor of LDL internalization but is comparable to wild-type ApoA1 in inhibiting LDL transcytosis and associating with SR-B1. Together this suggests that HDL is athero-protective by also inhibiting LDL transit across the endothelium, a process not affected by the Milano mutation.
Public Shaming of Professional Athletes on Social Media
Keywords: athlete behaviour
fan-athlete relationship
gender
online behaviour
public shaming
social media

The overarching purpose of this dissertation was to explore the nature and extent of public shaming of professional athletes on social media in response to perceived legal, social, and sport-specific norm violations and the potential reasons that fans engage with athletes in this manner on social media. The methods employed were two-fold: for studies one and two, a qualitative content analysis of 7,700 fan comments on Facebook, Twitter, and Instagram directed at eleven male and female professional athletes from six different sports was conducted. To analyse these data, I implemented methodological pluralism by engaging in a semantic and subsequent latent thematic content analyses. For study three, guided by a narrative methodology, I conducted five semi-structured in-depth interviews with sport fans (three males, two females) who engaged regularly with professional athletes and teams on Twitter, Facebook, and Instagram. Findings cumulatively revealed that fans engage in public shaming of male and female professional athletes in response to the athletes’ perceived legal, social, and sport-specific violations. Public shaming on social media was evident with each athlete violation I examined, regardless of sport or experience level, and occurred across all platforms (Twitter, Facebook, and Instagram). Acts of shaming were illustrated by fans’ explicit withdrawals of support and descriptions of desired physical, psychosocial and career-related consequences for the athletes. In addition, there were undercurrents of gender and sexism observed across fans’ public shaming, which were exemplified through fans’ objectification of females, promotion of hyper-masculinity, and victim blaming. Fans proposed that public shaming acts occur in response to the threats that norm violations pose to fans’ sense of identification and belonging that have been cultivated through fandom and enhanced through the relationships perceived to be developed with athletes via social media. Specifically, fans suggested public shaming might be provoked when the integrity of fan-athlete relationships are challenged by legal, social, or sport-specific norm violations. Based on the collective findings, I explained the theoretical, methodological, and applied contributions of this dissertation to the existing literature, proposed ethical considerations for research of this nature, and discussed recommendations for future directions in this area of scholarship.
The Design of Playful and Intelligent Creative Tools
Keywords: artificial intelligence
color
creativity support
human computer interaction
interface design

While ample research demonstrates the importance of concepts such as flow, playfulness and exploration for creative tasks, practical application of these principles leaves more to be desired, as evidenced by the prevalence of cumbersome creative interfaces. The goal of this thesis is to address the problem of designing playful, expressive and delightful creative interfaces for a number of concrete creative tasks, including interaction with color and 2D animation. To this end, I explore a number of approaches for establishing artist needs, develop digital representations that are amenable to both machine learning and user interaction, and design novel digital media that amplify, not stifle, creativity. This practical application of intelligence, including domain understanding and AI, and playfulness to the design of creative interfaces is meant to inspire future work in interaction design that adopts the same spirit.
Numerical Simulation of the Stick-slip Instability for Laboratory Earthquakes using a Discrete Element Model
Keywords: earthquake nucleation
machine learning
numerical simulation
Particle Flow Code (PFC)

The fractal nature of earthquakes allows the study of their mechanisms in controlled laboratory environments. At the field scale, studies on earthquake nucleation mechanisms are dominated by two end-member theories––cascade triggering and preslip triggering. However, at the laboratory scale, very few studies have focused on the nucleation mechanism. This study aimed to discover the key factors that trigger stick-slip instability at the laboratory scale using numerical simulation.Numerical simulation provides a unique advantage in that it is capable of generating a large quantity of data at very little cost. Utilizing this advantage, a stick-slip experiment conducted by Goebel et al. was reproduced 27 times by employing a distinct element method (DEM) code, analogous to repeating the experiment on multiple Westerly granite samples. In particular, a dynamic-weakening pulse-slip model was built into the DEM framework, provided by Particle Flow Code (PFC), to promote rupture along the laboratory-scale fault. A data pipeline was constructed to collect, transform and analyze the numerical simulation data. New insights on the nucleation mechanism were derived from the data. The results rejected the hypothesis that mainshocks are directly caused by foreshocks. Instead, it was found that there was a strong correlation between a fault’s tendency to slip and the foreshock-induced acceleration of grain-scale normal and shear forces, which led to the idea that foreshocks indirectly prepare the nucleation zone to reach a state that allows a few acoustic emissions to cascade up into stick-slip instability. These results support the latest findings in the field, and could potentially resolve the disagreement surrounding the nucleation mechanism at the field scale.
Advances in Risk Parity Portfolio Optimization
Keywords: Asset allocation
Convex optimization
Factor modelling
Portfolio optimization
Quantitative finance
Robust optimization

Risk parity is an asset allocation strategy that seeks to equalize the risk contributions of the constituent assets in a portfolio. The resulting portfolio is fully diversified from a risk perspective. However, like other asset allocation strategies, risk parity is susceptible to estimation errors. Moreover, its mathematical formulation imposes some fundamental limitations. This thesis aims to modernize risk parity by addressing all of the aforementioned issues. We address the susceptibility to estimation errors through three different frameworks. First, we introduce a robust framework that quantifies estimation error and embeds this information during optimization to construct a robust risk parity portfolio. Our second framework takes a different approach, introducing robustness during the parameter estimation step. This is formulated as a game-theoretic minimax problem to make an optimal investment decision against the most adversarial estimate of our parameters. Our third framework improves the quality of our estimated parameters before optimization takes place. We posit that we can embed the cyclical information of financial markets directly into our estimates, resulting in risk parity portfolios aligned with the current market regime. The result is a Markov regime-switching factor model of asset returns from which we can naturally derive regime-dependent parameters for use during optimization. The final component of this thesis addresses the fundamental limitations of risk parity: its lack of accountability for the investor's risk and reward appetite and its prohibition of short sales. We propose a generalized risk parity framework where the investor's risk and reward appetite define our objective, while still enforcing a desirable degree of risk-based diversification. Moreover, we propose an algorithm that allows us to consider portfolios with short positions. Thus, our generalized framework addresses the fundamental limitations of risk parity while retaining the desirable property of risk-based diversification. The frameworks proposed in this thesis can be used independently or in tandem, depending on the investor's needs and goals. The unifying subject of this thesis is to advance risk parity by addressing its fundamental weaknesses. This is achieved by proposing different frameworks and algorithms, with the overarching property of preserving the interpretability and computational tractability of our solutions.