VictorJuiz/thesis huggingface dataset:
When the Mighty Fall: Moral Outrage Toward Powerful Perpetrators
Keywords: morality
perception

Past work demonstrates that powerful individuals are more inclined to act unethically (e.g., Gruenfeld et al., 2008). As a result, people are routinely confronted with powerful transgressors. Power is a potent force in perception (e.g., Keltner et al., 2008) and, therefore, I investigate how a perpetrator’s power will impact people’s moral outrage towards bad behavior. Powerful transgressors, due to their control over valued resources and social influence, can cause greater harm to victims and are more likely to encourage unethical group norms, compared to less powerful transgressors. Therefore, across six studies, I hypothesized that powerful perpetrators would elicit greater moral outrage than less powerful perpetrators. Participants reported greater moral outrage toward powerful transgressors who acted unethically in hypothetical scenarios (pre-registered Study 1 and Study 2), real stakes economic games (Study 3), live interactions in a laboratory (Study 4), and recalled events (Study 5). This robust effect held in contexts when the perpetrator’s power was not directly relevant, regardless of the victim’s power, and generalized across a variety of unethical acts. It was mediated by perceptions that powerful transgressors inflicted greater harm to victims and encouraged unethical group norms (Studies 2 and 3). However, this effect was moderated by important individual differences and contextual variables. Specifically, this effect was eliminated or reversed for participants who heavily endorse system-justifying ideologies (Study 5) and towards admired leaders within one’s own group (Study 6). My findings highlight the importance of social features like power in influencing moral judgment, suggesting that moral perception does not occur in a social vacuum.
Investigating the Impact of FGFR5 Expression on β-cell Metabolism, Maturity and Intracellular Signaling
Keywords: Beta cell
Diabetes
FGFR
FGFR5
Islet
Metabolism

Pancreatic β-cells exist in an incredibly dynamic microenvironment that impacts cell metabolism, maturity, and function. Our research group previously showed that pancreatic β-cells plated on laminin matrix express reduced levels of FGFR1, a kinase receptor linked to β-cell metabolism. Due to recent evidence that adult β-cells also express FGFR5, a co-receptor for FGFR1, we hypothesize that laminin would impact FGFR5 expression with consequent effects on β-cell metabolism. Using a genetically encoded sensor for NADPH/NADP+ redox state (Apollo-NADP+), we show overexpression of FGFR5 enhances glucose-stimulated NADPH metabolism in β-cell lines as well as mouse and human β-cells. This enhanced response was accompanied by increased expression of transcripts for glycolytic enzymes (Glucokinase/Gck, Pyruvate kinase M2/Pkm2) and the functional maturity marker Urocortin 3 (Ucn3). Culturing β-cells on laminin matrix also stimulated upregulation of endogenous FGFR5 expression, and similarly enhanced β-cell glucose-stimulated NADPH-metabolism as well as Gck and Pkm2 transcript expression. Collectively these data reveal that β-cells respond to laminin by increasing FGFR5 expression to enhance β-cell glucose metabolism. We next examined changes to intracellular signaling pathways activated by FGFR5 expression. Using live cell imaging and qPCR we showed that the FGFR5-induced changes to metabolism are due to activation of the MEK/ERK signaling pathway. We then examined if the metabolic changes induced by MEK/ERK activation, specifically increased glucose consumption, had subsequent effects on nutrient sensing pathways. Using Western immunoblot and a variety of live cell imaging techniques, we showed FGFR5-induced metabolism increased activation of the nutrient sensing mTOR pathway. Lastly, we used data mining to uncover gene correlations to FGFR5 based on a human online β-cell database. Findings from the data mining analysis were validated using qPCR and identified the gene Rcc2 (Regulator of chromosome condensation 2) as being upregulated by FGFR5 in β-cell lines. We then expanded our data mining approach to better understand changes associated with late-stage β-cell maturation by centering our analysis on UCN3, a β-cell maturity marker. Our UCN3 focused analysis allowed us to construct a “late-stage maturation map” for β-cells which identified correlation to notable integrin subunits and solute carrier genes.
Characterization of Duplex-Tetraplex Equilibria in DNA
Keywords: G-quadruplex
i-motif
Nucleic Acid
Volumetric Study

The four-stranded non-canonical structures G-quadruplexes and i-motif are formed by G-rich and C-rich DNA strands, respectively. These tetrahelical structures form in biologically important loci of the genome and are the essential regulator of genomic events. For this reason, tetrahelical structures have become an important target for developing anti-cancer strategies. To design drugs that control the formation of tetrahelical structures at specific genomic loci, it is important to understand the forces controlling the conformational preferences of potentially tetraplex-forming DNA strands. This doctoral thesis aims to characterize the distribution of conformational states adopted by G- and C-rich DNA strands and molecular forces that modulate their conformational equilibria. The first part of this dissertation describes the use of volumetric methods to characterize the hydration properties and the ionic atmosphere of an i-motif from the promoter region of the c-MYC oncogene. Our study reveals that changes in volume, ΔV, and adiabatic compressibility, ΔKS, accompanying i-motif formation are nearly zero. The DNA releases its counterions to the bulk upon i-motif formation thereby ceasing to be a polyelectrolyte. In the second part of the dissertation, we employ a CD-based analytical approach to determine the conformational preferences of equimolar mixtures of complementary G-rich and C-rich DNA strands from the promoter regions of c-MYC, VEGF, and Bcl-2 oncogenes. The conformational distribution is sequence-specific and is modulated by environmental factors such as temperature, salt, and pH. Under physiological conditions, the G-quadruplex and duplex coexist in all three DNAs although in different proportions. In the final part of the dissertation, we report changes in volume and compressibility accompanying interconversions between the G-quadruplex, duplex, and coil conformations adopted by the G-rich DNA strand from the c-MYC promoter. We rationalized our data in terms of the hydration and intrinsic properties of DNA. In addition, we further use our data to construct the first pressure-temperature phase diagram of G-quadruplex stability. Taken as a whole, our studies provide insights into the formation of tetrahelical structures within the genome.
Doctors' Efforts to Reform Medical Practice in England for Climate Change Mitigation: Insights for Implementing Medical Education and Training Reforms
Keywords: Climate Change
Education Reform
Medical Education
Professional Education
Reflective Practice
Socio-Cultural Theories of Learning

In this study, I explore how the ideas and experiences of doctors who have attempted to reform medical practice in England for climate change mitigation can enhance the implementation of similar reforms in medical education and training. I draw upon theories of climate justice, the social responsibility of medicine, critical reflective practice, and learning as a socio-cultural process to frame and investigate the research problem. I draw upon the critical-interpretive paradigm and the methodological recommendations of the phronetic social science framework to design the study. Applying these ideas, I conducted an interview study with 18 English doctors representing diverse clinical specialties, official designations, career stages, and social backgrounds. I documented how these doctors conceptualized reform problems and solutions, and attempted to enact change between 2006 and 2020. I also inquired into what enabling conditions and barriers they encountered in the process, and how they regard the consequences of their efforts, and envision future action. I then analyzed how their reflections and insights can improve the implementation of ongoing efforts to reform medical education and training in England to address climate change mitigation. My analysis shows that doctors’ efforts to reform professional practice can be adapted and applied to reform medical education and training in a variety of ways. Significant among these are: exercising/leveraging formal authority and leadership to drive top-down change, seeking new job roles to work on climate change mitigation, securing sustained sources of funds for reforms, building alliances in and outside the health system, creating networks for collaboration, generating new socio-environmentally informed ways of conceptualizing and practicing illness prevention and healthcare, and pursuing professional learning to develop additional capabilities to enact change. The scaling-up and wider application of reform initiatives such as these can have significant impacts in mitigating the threats and harms of climate change in England. They can inspire similar action in health systems in other global contexts as well.
Traumatic Brain Injury: Sex and Gender Considerations Relevant to Rehabilitation
Keywords: biological sex
education
gender role
rehabilitation
traumatic brain injury
work

Traumatic brain injury (TBI) is a global cause of disability. Effects of TBI include cognitive, physical, and psychosocial disabilities. Although sex and gender considerations in research are considered important for good science, there is limited information on the extent to which sex and gender effects in TBI are recognized in rehabilitation. Further, the extent to which an educational tool targeted at persons with TBI and caregivers, can serve to improve knowledge, attitude, and skill on the topic for future integration within clinical practice has not been explored. Information is further lacking on differences in sex- and gender-based needs for men and women in the community specifically while transitioning to work and during the COVID-19 pandemic. As such, this thesis aimed to address these knowledge gaps by (1) understanding clinicians’ perspectives on the clinical impact of sex and gender in TBI rehabilitation, (2) exploring the effectiveness of education on sex and gender impacts in TBI for persons with TBI and caregivers, and (3) investigating differences in support service and workplace accommodation needs of men and women with TBI for transitioning into the community. The added impact of COVID-19 on employment status and mental health was also explored. The thesis was based on three studies. The first study, a qualitative descriptive design with semi-structured interviews with diverse rehabilitation clinicians highlighted limited attention on sex and gender topics in TBI rehabilitation and a need for resources that consider psychosocial factors. Results from the second study, a pilot pre-test/post-test randomized control-group trial revealed the potential for education to improve knowledge, attitudes, and skills on sex and gender effects in TBI, furthering the need for tools to help persons with TBI and caregivers address daily barriers post-injury. Finally results from the third study, an observational cross-sectional survey, demonstrated differences between men and women with TBI in transitioning to work and because of the pandemic, based on respective gender roles and behaviours. Findings from each study furthered the knowledge base on sex and gender considerations in TBI rehabilitation, with future attentions needed on developing sex- and gender-sensitive tools for clinical and non-clinical benefits.
Tracking the Continuity of the Leviticus Laws of Genital Fluids in the Dead Sea Scrolls and Rabbinic Literature
Keywords: Dead Sea Scrolls
Hebrew Bible
Jewish Law
Rabbinic Texts
Second Temple Period

This comparative study explores Leviticus’ rules on the impurity caused by genital fluxes as attested in the Dead Sea Scrolls and rabbinic literature to shed light on the state of halakhah in the pre-rabbinic stage. Using the five impurity categories of genital fluxes outlined in Lev 15 and 12, this study demonstrates the Dead Sea Scrolls' relevance as a textual product of the Second Temple period for tracking the antiquity of some rabbinic halakhic rulings. As a starting point, an analysis of the biblical exposition of each impurity category is undertaken, noting hermeneutical, textual, and text-critical difficulties in the text but selectively limiting the detailed examination to problems that have implications in the attestation of these rules in the Dead Sea Scrolls or other Second Temple period texts in comparison with their attestation in the rabbinic literature. The study pays particular attention to variant readings found in ancient translations (the LXX and the Targumim) and the Samaritan Pentateuch, and to cases of word choices in the DSS and other Second Temple period texts. It contends that these variants and word-choices are hermeneutically pertinent to our understanding of the state of halakhah in the Second Temple period when verified by their conformity with a particular position on a halakhic issue for which rabbinic opinions diverge. The investigation leads to the conclusion that difficulties in the biblical text are responsible for many divergences or innovations in later attestations of the biblical rules, and that many rabbinic rulings can be linked to the innovations or polemical texts in the Dead Sea Scrolls or to variant readings in ancient translations or versions of the Hebrew Bible. This study stands out from other comparative approaches to the DSS and rabbinic texts which tend to have broader perspectives by narrowing down the scope of the investigation to one type of impurity to demonstrate from that standpoint how a textual, text-critical, and hermeneutical analysis of the Dead Sea Scrolls texts can yield valuable pieces of evidence on the state of halakha in the Second Temple period, and thus shed light on the trajectory of halakhic development.
Insights on the Xenobiotic Barrier Function of the Caenorhabditis elegans Pharynx Cuticle
Keywords: C elegans
crystal
cuticle
drug resistance
model organism
pharynx

Cuticles are specialized extracellular matrices that prevent water loss and provide a barrier to external, harmful chemical and infectious agents. In the model nematode C. elegans, I report the serendipitous discovery that certain lethal molecules accumulate in the heads of worms as crystalline and spherical objects. Using DIC microscopy, transmission electron microscopy, pulse-chase, RNA interference and fluorescent dyes, I confirmed that the crystalizing molecules preferentially accumulate in the non-luminal side of the anterior pharynx cuticle. A chemical screen of 2560 molecules revealed that crystal formation can be suppressed by 85 small molecules as well as the amyloid dyes Congo Red and Thioflavin S, but not by chitin dyes. Many crystallizers and suppressors have highly similar core scaffolds and are enriched for aromatic rings, with the ability to form hydrogen, halogen and π-π bonds. Interestingly, 43% of the substructures that are ≥1.5X enriched in crystallizing molecules compared to molecules that do not form objects and/or a random set of molecules, are known to bind amyloids. 33% of the core scaffolds of the crystal suppressors are found in known amyloid-interactors. Bioinformatic analysis of the C. elegans pharynx proteome revealed that during molting, the pharynx secretes in the cuticle large amounts of proteins/peptides with phase-separation ability, a property shared by amyloidogenic proteins. Through a genetic screen, I found that loss of components of a novel sphingomyelin synthase, SMS-5, or an ABC transporter, PGP-14, which are both expressed in the pharynx, abolishes crystal formation in the pharyngeal cuticle but also drastically alters the worm's overall sensitivity to xenobiotics/ This indicates that the proteins play a critical barrier function. Taken together, my Ph.D. work identifies the pharynx cuticle as a critical determinant of drug sensitivity, and implicates sphingomyelin, an ABC transporter and potentially phase-separated proteins/peptides as novel determinants of xenobiotics accumulation in C. elegans.
Antenatal Synthetic Glucocorticoid Programming of Post-natal Blood-brain Barrier Drug Transporters
Keywords: blood-brain barrier
breast cancer resistance protein
glucocorticoid
p-glycoprotein
preterm birth

The blood-brain barrier (BBB) is essential in protecting the developing brain from neurotoxins, through high expression of drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). However, external stimuli such as xenobiotic exposure may disrupt BBB protection. Antenatal synthetic glucocorticoid (sGC) therapy is a life-saving treatment administered to pregnant women at risk for delivering preterm, to aid in the maturation of several fetal organ systems, notably the lungs. The purpose of the studies described in this thesis were to investigate the long-term effects of antenatal sGC on the levels and function of BBB drug transporters. We investigated drug transporter levels and function in brain endothelial cells (BECs) of postnatal day (PND) 14 male and female offspring prenatally exposed to multiple or single course betamethasone (BETA) treatment. We have identified a reduction in the levels and function of P-gp in male offspring only, as well as sex differences in baseline P-gp function in BECs derived from juvenile guinea pigs. Importantly, we found a single course did not impact P-gp function. Recently miRNAs have had increased attention as a regulatory mechanism for drug transporter expression. As we observed decreased P-gp protein and function independent of changes in mRNA levels, we investigated miRNAs as a potential mechanism underlying these effects. Our targeted analysis of 7 miRNAs did not reveal differences after antenatal sGC. However, these initial studies have laid the groundwork for future investigations into miRNA regulation of BBB transporters. Finally, while levels of P-gp mRNA/protein, and function were unaltered in BECs derived from female offspring, once exposed to a challenge (infection mimic ssRNA, P-gp activity was markedly reduced. This is in-line with previous research that the long-term effects of antenatal sGCs do not always manifest themselves at baseline. The findings from this thesis have implications as decreased P-gp function can result in increased transfer of neurotoxic P-gp substrates into the brain of infant (e.g., bilirubin in hyperbilirubinemia) and pediatric (e.g., colchicine poisoning) populations. Additionally, long-term changes in drug transporter activity can have consequences for central nervous system (CNS) exposure to harmful agents across the entire life-course.
Genetically Engineering Microbes for Detecting and Treating Inflammatory Bowel Disease
Keywords: Escherichia coli Nissle
Genetic engineering
Genetically engineered microbes
Inflammatory bowel disease
Saccharomyces boulardii
Synthetic Biology

Inflammatory bowel disease (IBD) is a chronic medical condition characterized by inflammation in the intestine. Treating the patients starts by appropriately diagnosing the disease, followed by administering therapeutic drugs to reduce the symptoms and induce tissue repair that can help the patient achieve remission. However, as there are no definitive cures, treatment of IBD requires long-term management that involves periodically monitoring the extent of inflammation within the intestine and several treatment courses. Traditional methods for detecting the disease are highly intrusive, and the therapies are not entirely effective, often leading to relapse and sometimes even requiring surgical interventions. Therefore, there is a need for better diagnostic tools and treatment options to improve the outcomes and quality of life of IBD patients. Small, single-celled organisms, such as bacteria or yeast, have the unique ability to travel through the gastrointestinal tract and into the intestine- a natural habitat for microbes. Once inside this area, they come in close contact to the sites of inflammation, priming them for disease intervention. As these microbes are living organisms, they can also be genetically re-programmed to accomplish desired functions such as sensing molecular or environmental cues, or to deliver molecules with therapeutic properties. With the advances in genetic engineering tools and strategies, microbes can be engineered into diagnostic tools to monitor the inflammation within the patient’s intestine and as therapeutic delivery systems to provide targeted therapies at the source of the disease. The goal of this project was to contribute to the development of engineered microbes for detecting and treating IBD. These contributions include developing and validating genome editing tools, therapeutic protein expression systems, biosensors to detect reactive oxygen species, and a colorimetric yeast-based assay to detect biomarkers of IBD using a probiotic yeast strain Saccharomyces boulardii. I also discovered novel transcriptional markers of colitis within a probiotic bacteria strain, E. coli Nissle, that could be used to monitor intestinal inflammation. Overall, the results of this project should prove valuable for engineering microbial devices for medical applications.
Allosteric Regulation of the Helicobacter pylori NikR Transcription Factor in Response to Nickel and pH
Keywords: Acid Adaptation
Allostery
Helicobacter pylori
Metal Homeostasis
Nickel
Transcription Factor

Survival of the Helicobacter pylori pathogen within the acidic environment of the human stomach requires the nickel enzyme urease, which makes nickel an essential nutrient for this bacterium. Due to its inherent toxicity and limited availability, nickel homeostasis is maintained through a network of pathways that are coordinated by the nickel-responsive transcription factor, NikR. Nickel binding to H. pylori NikR (HpNikR) allosterically activates binding to several target promoters encoding genes involved in nickel homeostasis and acid acclimation to either activate or repress their transcription. HpNikR can also respond to a drop in pH and bind target promoters independently of nickel to regulate their transcription. In this work, the allosteric mechanisms by which nickel, and acidity activate DNA binding by HpNikR were explored using biochemical, spectroscopic, and computational methods. The results demonstrate that HpNikR adopts an equilibrium between an open conformation and more DNA-binding competent cis and trans states, regardless of nickel binding or increased acidity. The response to nickel involves an increase in protein rigidity that is propagated from the nickel-binding sites to the DNA-binding domains through a network of residues linked to the inter-domain interface. This response allows nickel binding to slow down conformational exchange and shift the equilibrium toward the DNA binding-competent states. The protein then becomes stabilized in a cis conformation upon binding a target promoter, in a manner consistent with conformational selection. In addition, the DNA sequence was found to play an important role in tuning the allosteric response. Experiments at lower pH levels revealed that the histidine residues of the nickel-binding sites are involved in the allosteric response to acidity. However, the mechanism of pH-responsive DNA binding is quite distinct compared to the response to nickel, and results in a unique DNA-bound cis conformation. Overall, this work provides novel insights into how HpNikR is able to respond to two important environmental cues for H. pylori – nickel and pH. This knowledge advances our understanding of the allosteric mechanisms employed by metalloregulators, and contributes to our understanding of how HpNikR helps this bacterial pathogen thrive in the harsh environment of the human stomach.