VictorJuiz/thesis huggingface dataset:
Nanoparticles for Cancer Detection and Therapy: Towards Diagnostic Applications of Quantum Dots and Rational Design of Drug Delivery Vehicles

This thesis describes observations, techniques and strategies, which contribute towards the development of nanoparticle based detection and treatment of cancer. Quantum dots and biorecognition molecules were studied towards applications in detection and microgels were used in the rational design of a targeted drug delivery vehicle. The fluorescence intensity of quantum dots was examined in buffers commonly used in molecular biology. The fluorescence intensity of ZnS-capped CdSe quantum dots (QDs) was found to vary significantly, depending on the amount of ZnS capping on the QDs or the concentration, pH and type of buffer the QDs were in. Since fluorescence cannot reliably be used to quantify QDs, an alternative quantification method was developed, which does not rely on their fluorescence. This method employs phage display to identify nanoparticle-specific bacteriophage which were then applied in an assay to quantify QDs in environments where absorbance or fluorescence spectroscopy are ineffective. Biorecognition molecules, which can direct nanoparticles to a molecular target, were also identified through phage display. Phage display on whole cells was used to identify a peptide, which was conjugated with QDs to stain HeLa (cervical cancer) cells. A high-throughput phage display screening strategy was also developed, which could enable the simultaneous identification of multiple biorecognition molecules from a single library. QD-encoded microbead barcodes were conjugated to protein targets and then used to screen a phage display library. The beads and the binding phage were then separated using flow cytometry and fluorescence assisted cell sorting. Finally, biorecognition molecules were combined with nanoparticles to create drug delivery vehicles, which were designed to protect, deliver and then release chemotherapeutic drugs through an intracellular pH trigger. PolyNIPAAm and chitosan hydrogels, under 200 nm in diameter, were loaded with chemotherapeutic drugs, conjugated to transferrin and tested in vitro on HeLa cells. These projects demonstrate the great potential in this growing field as well as some of the many challenges that have yet to be overcome.

Keywords: nanoparticles
cancer detection
cancer therapy
targeted drug delivery
quantum dots
phage display
Advisor: Chan, Warren C. W.
GSK-3 Inhibition: A Novel Approach to Sensitization of Chemo-resistant Pancreatic Cancer Cells

The aggressive nature of pancreatic cancer, characterized by invasiveness, resistance to treatment, rapid progression, and its high prevalence in the population urges the need for developing more effective treatments. Many studies have attributed resistance to therapeutics of pancreatic cancer to activity of the transcription factor nuclear factor kappa B (NF-kB). NF-kB is regulated by the serine/threonine kinase glycogen synthase kinase-3 (GSK-3). GSK-3 is a key mediator of pathways such as insulin, wnt, and PI3K/Akt and has roles in proliferation, glucose metabolism, apoptosis, motility and neuroprotection. Depending on the cellular context, GSK-3 activity can promote or inhibit cell survival. GSK-3 inhibition was recently reported to have anti-cancer effects against pancreatic cancer cells. This effect was in part attributed to suppression of NF-kB. In this thesis, I showed that while blocking GSK-3 disrupts NF-kB, and has anti-survival effects on pancreatic cancer cells, it does not sensitize to the chemotherapeutic drug gemcitabine. NF-kB inhibition by curcumin also resulted in similar effects. These results questions previous reports that NF-kB activation plays a major role in chemo-resistance of pancreatic cancer. The inhibition of NF-kB by genetic disruption of GSK-3 was previously reported to sensitize mouse embryonic fibroblasts and hepatocytes to TNF-alpha cytotoxicity. I therefore tested whether GSK-3 inhibition could sensitize pancreatic cancer cells to apoptosis induced by the clinically applicable member of the TNF-alpha family, TNF-alpha related apoptosis inducing ligand (TRAIL). In contrast to the results obtained with gemcitabine, the combination of genetic or pharmacological inhibition of GSK-3 and TRAIL was found to be highly synergistic in apoptosis induction. Analysis of the apoptotic mechanisms, point towards effects of GSK-3 inhibition on caspase-8 activation, consistent with inhibition of the death receptor signalling pathway. It was found that not only caspase-8 but also mitochondrial anti-apoptotic proteins such as Bcl-XL and Mcl-1 were mediating the TRAIL sensitization. Furthermore, for the first time the in vivo effects of GSK-3 inhibition in combination with TRAIL treatment was investigated. The results indicate a significant enhancement of apoptosis in pancreatic cancer xenografts with minimal toxic effects. Together, these studies provide a rationale for developing combination treatments based on GSK3 inhibition and TRAIL death receptor activation to treat pancreatic cancer.

Keywords: Oncology
Molecular therapeutics
Pancreas
GSK-3
Advisor: Hedley, David
Girls' Education as a Means or End of Development? A Case Study of Gender and Education Policy Knowledge and Action in the Gambia

Girls’ education has been promoted by the international development community for over two decades; however, it has proven harder to promote gender equality through education than it has been to promote gender parity in education. Of significance is the global circulation and co-existence of two competing rationales for the importance of girls’ education: economic efficiency and social justice. The cost of ignoring how and why Southern governments and their development partners choose to promote girls’ education is high: an over-emphasis on economic efficiency can mean that the root causes of gendered inequalities in society remain unchallenged, and more social justice-oriented reforms become marginalized. This thesis uses a critical feminist lens to qualitatively investigate the role and significance of human capital, human rights, and human capabilities policy models in the context of the production and enactment of gender equality in education policy knowledge in The Gambia, a small, aid-dependent Muslim nation in West Africa. The purpose of the study was to assess the scope education policies provide for positive change in the lives of Gambian women and girls. Towards illuminating relations of power in and the politics of gender equality in education policy processes, the study compares and contrasts written texts with the perspectives of state and non-state policy actors. The study is based on data drawn from interviews, participant observation, and documentary analysis. The findings suggest that different gender equality in education ideas and practices have been selectively mobilized and incorporated into education policy processes in The Gambia. At the level of policy talk, girls’ education is framed as important for both national economic growth, and “women’s empowerment”. However, the policy solutions designed and implemented, with the support of donors, have tended to work with rather than against the status quo. Power and politics was evident in divergent interpretations and struggles to fix the meaning of key concepts such as gender, gender equality, gender equity, and empowerment. Religious beliefs, anti-feminist politics, and the national feminist movement were identified as important forces shaping gender equality in education knowledge and action in the country.

Keywords: girls' education
gender equality
policy transfer
policy borrowing
public policy
feminism
development
social justice
transformative education
human capabilities
human rights
knowledge
sub-Saharan Africa
meaning
qualitative
ethnography
policy analysis
Advisor: Mundy, Karen
Effects of Enteroendocrine Hormones on Beta-cell Function and Glucose Homeostasis

Mechanisms to augment the cellular function and mass of beta-cells may be effective means of treating type 2 diabetes. Important in the physiological control of beta-cell function and nutrient disposal are factors released from gut enteroendocrine cells during nutrient digestion. In enteroendocrine L-cells, post-translational processing of proglucagon gives rise to a number of proglucagon-derived peptides. One such peptide, glucagon-like peptide-1 (GLP-1), acts via its own receptor (GLP-1R) to stimulate beta-cell insulin secretion, proliferation and survival. Another, oxyntomodulin (OXM), weakly activates the GLP-1R and inhibits food intake in a GLP-1R-dependent manner in rodents, which led us to hypothesize that OXM modulates GLP-1R-dependent glucoregulation. While OXM did not mimic the inhibitory effect of GLP-1 on gastric emptying in mice, OXM stimulated insulin secretion, beta-cell survival and improved glucose tolerance in a GLP-1R-dependent manner. In a similar manner to GLP-1, glucose-dependent insulinotropic polypeptide (GIP), secreted from enteroendocrine K-cells, physiologically stimulates insulin secretion via a distinct GIP receptor (GIPR) in beta-cells. Beyond the beta-cell, GIP and GLP-1 appear to exert divergent actions for the control of glucose homeostasis. Moreover, I illustrate that physiological and pharmacological GLP-1R signalling may be comparatively more important for the preservation of beta-cell mass and glucose homeostasis in murine streptozotocin-induced diabetes. Lastly, studies in rodents and humans have showed that metformin increases circulating levels of GLP-1, leading us to hypothesize that GIP and GLP-1 may be involved in the glucoregulatory effects of metformin. Interestingly, transcripts for the Glp1r and Gipr were significantly increased within islets of metformin-treated mice, and metformin treatment enhanced the sensitivity of cultured beta-cells to GIP and GLP-1. In summary, these studies illustrate mechanisms by which enteroendocrine peptides compare and contrast with respect to beta-cell survival and function and the control of glucose homeostasis.

Keywords: diabetes
beta-cell
incretin
GLP-1
GIP
Advisor: Drucker, Daniel J.
Essays on Empirical Dynamic Games and Imperfect Information

This thesis collects three papers that study applied problems in economics dealing with dynamic strategic behavior and imperfect information. In the first chapter I study the relationship between participation in United Nations Human Rights Treaties (HRT), foreign aid receipts and domestic human rights institutions. I provide empirical evidence that countries with relatively high HRT participation rates receive more foreign aid. Further, countries with high quality institutions are more likely to participate in HRTs, but that high levels of HRT participation leads to a decline in the quality of domestic human rights institutions. Based on these findings, I propose and estimate a dynamic game of HRT ratification. The estimates show that economic factors play an important role in HRT ratification and that the ratification costs countries incur vary significantly across treaties and country regime types. I use the estimated model to evaluate the effects of counterfactual policies on HRT ratification decisions, human rights behavior, and the distribution of foreign aid. The second chapter considers environmental regulation under imperfect information and political constraints. We compare the value of two types of information to a regulator: the cost of pollution and the profitability of firms in the economy. We find that in environments where small increases in the losses to regulated firms greatly affect the regulator's ability to implement the policy, it is most valuable to learn the types of firms, while it is most valuable to learn the cost of pollution when small increases in losses are relatively ineffectual. The third chapter deals with the identification and estimation of dynamic games when players maximize expected payoffs given beliefs about other players' actions, but their beliefs may not be in equilibrium. First, we derive conditions for point-identification of structural parameters and players' beliefs, and propose a simple two-step estimation method and sequential generalization of the method that improves its asymptotic and finite sample properties. We also present a procedure for testing the null hypothesis of equilibrium beliefs. Finally, we illustrate our model and methods with an application of a dynamic game of store location by retail chains.

Keywords: Economics
Advisor: Aguirregabiria, Victor
Victimhood and Socio-legal Narratives of Hate Crime Against Queer Communities in Canada, 1985-2003

This dissertation analyzes personal and institutional narratives that shape the Canadian phenomenon of anti-LGBT violence as hate crime and locate queers within and without the discursive figure of the responsible, legitimate and undeserving victim of hate crime. These socio-legal narratives were taken from interviews with LGBT community activists involved in anti-violence projects, mainstream and gay print news media reportage of two notable homicides, Parliamentary debates of the enhanced sentencing provision that sought to include ‘sexual orientation’ to the list of biased motivating factors, Senate witness testimony on the amendment to Canada’s hate propaganda statutes which sought to include ‘sexual orientation’ to the list of protected groups, interviews with police officers who had direct experience with anti-hate crime initiatives, and judicial reasons for sentence. Utilizing an interdisciplinary analysis and drawing on hate crime scholarship and victimology, this dissertation asks: how is legitimate and, consequently, illegitimate LGBT hate crime victimization being represented and constituted through Canadian socio-legal narratives? In revealing how socio-legal actors and institutions have positioned LGBT individuals discursively within or without legitimate victimhood, that is, within and without the status of innocent victim deserving of social empathy and socio-legal institutional response, my dissertation illustrates how the spectre of illegitimate victimization is repeatedly invoked in socio-legal narratives of anti-LGBT hate crime. My analysis of these narratives about queer victimization and hate crime suggests that the figure of the responsible, legitimate and undeserving victim of hate crime remains an elusive and unstable identity for the queer victim of hate crime. Insofar as hate crime scholars have argued that the mobilization of hate crime activism has produced a victim whose hate crime status ensures its legitimacy, I contribute to this scholarship by arguing that this status is particularly challenging for the queer victim of hate-motivated violence. I demonstrate that the resiliency of the figure of classic victimology’s self-endangering and risky ‘homosexual’ and the sustained ideological resistence to LGBT individuals as full citizens, despite their notable legal gains, positions LGBT individuals, particularly gay men, ambiguously, situating them conceptually both without and within legitimate victimhood.

Keywords: hate crime
victimhood
LGBT
gay/lesbian
psychoanalysis
narrative
Advisor: Gartner, Rosemary
Identification of Genetic Loci that Contribute to the Immunopathogenesis of Systemic Lupus Erythematosus using Congenic Mouse Strains

Systemic lupus erythematosus (SLE) is an autoimmune disorder that is characterized by the production of antibodies directed against self-antigens, such as nuclear components. Genetic analyses of lupus patients have consistently demonstrated a complex genetic basis for disease susceptibility that involves multiple genes. Identifying genes and pathways that promote disease genesis has been aided by murine studies. In particular, congenic mouse studies that examine the role of chromosomal intervals from inbred lupus-prone mouse strains on a non-autoimmune background have been useful in dissecting the genetic contribution of novel susceptibility loci in lupus pathogenesis. In this thesis, the role of New Zealand Black (NZB) chromosomes 4 and 13 are examined in non-lupus prone C57BL/6 (B6) congenic mouse strains, denoted B6.NZBc4 and B6.NZBc13, respectively. Although repeatedly mapped to contain disease augmenting alleles,NZBc4 alone was not sufficient to initiate disease, despite an expansion of NKT and B1a cells–both with controversial pathogenic roles in lupus. Instead, by crossing the B6.NZBc4 mouse with another congenic mouse strain that develops fatal lupus autoimmunity, NZBc4 was unexpectedly found to contain a suppressor locus; disease suppression was mediated by a shift away from pathogenic immunoglobulin isotypes and associated with changes in the NKT and B1a cell compartments. In contrast to the NZBc4 locus, the NZBc13 locus is sufficient to initiate polyclonal B cell activation, ANA production and mild GN, similar to NZB mice. A B cell intrinsic defect was found to be responsible for initiating the abnormal cellular phenotype in B6.NZBc13 mice. Functional analyses of the B cell subset in B6.NZBc13 mice revealed normal BCR-signaling responses and tolerance mechanisms; however, they were hyper-responsive to TLR3 stimulation, resulting in increased survival and proliferation. Thus, the study of these NZB congenic mouse strains has been instrumental in confirming the presence of loci on NZB chromosomes 4 and 13 that modulate the development of disease and highlights that disease onset is mediated by a balance of both susceptibility and suppressor alleles. Collectively, these findings contribute to the current field of lupus immunogenetics and confirm the power of congenic mouse models in understanding the genetic basis of SLE.

Keywords: Lupus
Congenic
Advisor: Wither, Joan
El bildungsroman en el Caribe hispano

This dissertation examines the bildungsroman genre in Cuba, Puerto Rico, and the Dominican Republic. A close examination of the development of this genre demonstrates that it has ideological implications that link the young protagonists’ development with that of the nation. The authors on whom I focus—Ángela Hernández, Rita Indiana Hernández, René Marqués, Pedro Juan Soto, Magali García Ramis, Severo Sarduy, and Jesús Díaz—do not merely imitate the European model but revise, adapt, and often subvert it thematically and, in some cases, aesthetically. I argue that these bildungsromane differ, for the most part, from the European prototype due to their openly political themes, such as the establishment of the Estado Libre Asociado in Puerto Rico, the 1959 Revolution in Cuba, and, in the case of the Dominican Republic, Trujillo’s dictatorship. I claim that Dominican bildungsromane do not propose national projects or models but rather question the purported homogeneity of identity of the country as a normalized political body. On the other hand, in Cuba and Puerto Rico the genre has been used to promote absolute discourses of nationality as well as political projects that must be questioned due to their discriminatory and sometimes racist and violent nature.

Keywords: Bildungsroman
Coming of age narratives
National identities
Puerto Rican Literature XXth Century
Cuban Literature XXth Century
Dominican Literature
Hernández, Ángela
Hernández, Rita Indiana
Marqués, René
García Ramis, Magali
Martínez Maldonado, Manuel
Díaz, Jesús
Sarduy, Severo
Soto, Pedro Juan
Spanish Caribbean Literature
Advisor: Rodríguez, Néstor E.
Charge Transfer Processes in the Excited Dynamics of II-VI Semiconductor Nanocrystals

In large molecular systems such as DNA, supramolecular complexes and dendrimers, functional groups located at different parts of the molecular structure can act as charge donors or acceptors, and photoinduced intramolecular charge transfer can occur. An analogous scenario can be found in colloidal semiconductor nanocrystals, most evident in type-II heterostructures, where the relative band-alignment of the constituent materials are in a stagger configuration. Such a configuration, provides an energetically favourable situation for an photo-generated electron to be transferred from one material to the other, confining the electron and the hole in different domains of the nanostructure. A less obvious scenario in nanocrystals is when the core is thought of as the donor group, and the surface as the acceptor group. In such a scenario, the localization of electron or hole at surface defect sites, a process that occurs in every nanocrystal, can be thought of as an ``intramolecular" charge transfer. The studies presented in this dissertation are an attempt to further understand charge transfer processes in semiconductor nanostructures, in particular, those occurring within the same nanocrystals. This is carried out by a combination of spectroscopic techniques and modelling. First, time-resolved fluorescence measurements are used to investigated surface trapping/de-trapping dynamics in CdSe and CdSe/CdS/ZnS core/shell/shell quantum dots. A kinetic model, in which trapping/de-trapping is described with Marcus' classical electron transfer theory, is used to analyzed our results, yielding excellent agreement between model and experiment. Second, the influence of temperature and solvent environment in the optical spectra of CdSe/CdTe nanorods are examined. Solvatochromic shifts in these heterostructures are found to be larger than those observed in core-only quantum dots. Finally, ultrafast dynamics and biexciton states in CdSe/CdTe quantum dots are probed using two-dimensional optical spectroscopy. The fine structure of the lowest exciton and biexciton states are calculated for a model system with type-II band-alignment and simulations of 2D spectra are performed.

Keywords: Nanocrystal
Type-II
Spectroscopy
Charge Transfer
Advisor: Gregory, Scholes
William James and the Force of Habit

By paying attention to the habitual register of politics this dissertation has sought to contribute to the theoretical literature on democratic citizenship. More precisely, I offer a more complex account the moral psychology of political agency presumed by the turn to ethics within democratic theory. The central question of this dissertation is how do citizens come to feel empowered to act on their convictions in politics? Political theorists often celebrate civic action as spontaneity and willfulness, and at the same time lament the agency-foreclosing complexity and fragmentation of late-modern politics. Drawing out this tension in Michel Foucault’s analysis of docility and transgression I argue that a middle path between disembodied autonomy and docile passivity is articulated in the moral psychology found in William James’s account of habit. The study makes this case by looking at three episodes of the foreclosure and recovery of action in James’s thinking: his engagement with Darwinian science and his nervous breakdown in the 1870’s and 80’s; his critique of democratic docility and debate on strenuousness with Theodore Roosevelt during the Spanish-American war; and the cynical adaptation of James’s psychology by the democratic realism of Walter Lippmann in the 1920’s. In each case I argue that James’s lively account of habit as a force of unruly spontaneity functions as a therapy of action against feelings of powerlessness, docility, and incompetence constrain democratic conviction. The result is at once a novel continuation of the American tradition of democratic individualism and a contribution to the contemporary debates on the democratic ethics of self-making.

Keywords: James, William
habit
agency
democracy
Advisor: Chambers, Simone