VictorJuiz/thesis huggingface dataset:
Evaluation of a Family of Elastin-like Polypeptide Coatings for Blood Contacting Devices

Blood contacting devices are frequently limited by complications such as surface-induced thrombosis. This thesis investigated the feasibility of using a family of recombinant elastin-like polypeptides (ELPs), namely ELP1, ELP2 and ELP4 that differ by molecular weight and sequence length, as potential thromboresistant coatings. The ELP coatings were prepared by physical adsorption onto the surface of Mylar, with surface modification confirmed by goniometry, X-ray photoelectron spectroscopy (XPS), and chemical force microscopy (CFM). Both surface wettability and hydrophilic adhesion force increased as the ELP sequence length decreased. The ELP adsorption process monitored by using quartz crystal microbalance with dissipation (QCM-D) showed that the ELPs adsorbed within a monolayer. Additionally, ELP surface coverage was found to increase with the polypeptide sequence length. The QCM-D studies also revealed that the longer polypeptides (ELP2 and ELP4) exhibited higher specific dissipation values indicating that they established adsorbed layers with greater structural flexibility and associated water content compared to ELP1. Exposure of the ELP coatings to flowing reconstituted blood demonstrated that both the ELP2 and ELP4 coatings reduced the quantity of adsorbed fibrinogen (Fg), with the ELP4 coating resulting in the lowest levels of adherent platelets. Energy dissipation versus frequency shift plots obtained from QCM-D studies indicated that adsorbed Fg on the ELP4 coating maintained a softer, more flexible film then on the other ELPs. The ELP4 coating also demonstrated an altered binding activity for GPIIb/IIIa where only the AGDV motif in the adsorbed Fg gamma-chain appeared to be exposed and bioactive. Conversely, on the other ELP coatings both the AGDV and RGD motifs (found within the Fg alpha-chain) were available for binding, suggesting that a different Fg conformational state exists on the ELP1 and ELP2 coatings. Moreover, both the ELP2 and ELP4 coatings displayed minimal bulk platelet reactivity following extended whole blood shear exposure (up to an hour) compared to Mylar. This was not observed with the ELP1 coating. Overall, the results suggest that the structural flexibility and associated water content of the ELP coatings appear to be important criteria influencing their thrombogenicity, with ELP4 displaying the most favourable blood-material response compared to ELP1 and ELP2.

Keywords: biomaterial
elastin-like polypeptides
hemocompatibility
surface properties
Advisor: Woodhouse, Kimberly A.
Simmons, Craig Alexander
Inhibition of Mitochondrial Translation as a Therapeutic Strategy for Acute Myeloid Leukemia

Inhibition of mitochondrial translation as a therapeutic strategy for acute myeloid leukemia Marko Škrtić Doctor of Philosophy Institute of Medical Science University of Toronto 2012 Abstract Intro: Acute myeloid leukemia (AML) therapies have remained unchanged for 20 years, and thus new therapies are needed. Objective: To identify FDA-approved agents with anti-leukemia stem cell activity, we performed a screen and identified the antimicrobial tigecycline (TIG). Methods: Primary AML mononuclear cells were isolated by Ficoll centrifugation from peripheral blood. Flow cytometry dye; JC-1, Carboxy-H2DCFDA, Mitotracker GreenFM. Leukemia stem cell activity was assayed by human AML engraftment in NOD/SCID mice. Results: TIG induced cell death in primary AML patient samples (LD50, 3-6μM n=14), preferentially over normal hematopoietic cells. Likewise, in colony assays, TIG (5μM) reduced the clonogenic growth of AML samples (n=7) by 93%, demonstrating an effect on leukemia progenitor cells, but not normal hematopoietic cells (34% reduction, n=5). A yeast genome-wide screen identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated cell death in eukaryotic cells. TIG decreased the expression of mitochondrial peptides, enzyme activity and membrane potential preferentially in AML cells over normal hematopoietic cells. ShRNA knockdown of TuFM mitochondrial translation factor in leukemia cells reproduced TIG anti-leukemia target effects previously described. We discovered that primary AML CD34+/CD38- stem cells have greater mitochondrial mass (3-fold, n=5) than normal CD34+ cells (n=4). Higher baseline mitochondrial mass in primary AML samples was predictive for tigecycline sensitivity in vitro (r=-0.71, p<0.05). We assessed the effect of TIG on primary AML stem cells defined by their ability to initiate leukemic engraftment in vivo. NOD/SCID mice treated with TIG had decreased human AML engraftment (n=3 AML patients) compared to control. Conclusions: We identified mitochondrial translation inhibition as a novel therapeutic strategy for AML. Currently, a Phase I clinical trial of tigecycline in hematological malignancies is underway.

Keywords: Leukemia
Mitochondria
Advisor: Schimmer, Aaron D.
Teacher-centred Classrooms and Passive Resistance: Implications for Inclusive Schooling

This thesis is based on an ethnographic study conducted in a split grade five and six classroom in Toronto during the 1985/86 academic year. Data were collected through participatory observation, as well as through individual and focus group interviews. A group of eight activist African-Canadian high school students, as well as 26 Euro- Canadian “drop-backs” were also interviewed. The time during which I conducted the study was a period of intensive education activism of parents and the community in Toronto. I was interested in determining whether or not, and this activism was reflected at the school level, and if it was reflected, how. I also wanted to examine whether or not the historically supportive auxiliary role that parents played during this period was elevated to more substantive and meaningful active involvement in the education of their children during the last half of the 1980s. This study shows that activities in the classroom were driven by pre-packaged curriculum materials and were implemented with very few modifications. Coupled with teacher-centred practice, this closed the door for any diversifying opportunities that could have found their way into the classroom, not only from the homes of the children and the school community, but also from critics of the use of prepackaged material and, most importantly, from the students themselves. Furthermore, teacher-centred classroom discourse pushed students to develop a cynical attitude towards schooling. Having no say in what or how they were taught provided the children with few choices but to develop a coping mechanism of passive resistance. Their short-term survival strategies included appearing as though they were striding along, but not embracing their school experiences fully. By the same token, they were not challenged to think critically, to evaluate or to problem-solve. A link was also established between the students’ passive resistance at the elementary level with ‘fading out’ or ‘dropping out’ and successful resistance at the high school level.

Keywords: Discrimination in education
Cause of gun violence
Advisor: Dehli, Kari
Grassroots Governance: Domestic Violence and Criminal Justice Partnerships in an Immigrant City

My dissertation is a critical ethnography of grassroots feminist agencies and immigrant organizations involved in the governance of gender violence in Toronto, Ontario. Along with examining the agencies operating on the outskirts of the law, I also observe the organizations that contract directly with the provincial government to counsel abusers prosecuted through the city’s specialized domestic violence courts. Drawing on the methodological and theoretical insights of socio-legal studies, postcolonial feminism, and governmentality scholarship, my research explores the governance of domestic violence through the community. Specifically, I examine how the voluntary sector performs the state’s work of prosecuting domestic violence, punishing offenders and building citizens. My research reveals the significant influence that community organizations exert on the prosecution of gender violence and in defining the conditions of punishment for offenders. Through court observation of Toronto’s domestic violence plea court, I show how grassroots administrative workers transform into hybrids of the prosecutor and defense within governance networks. In addition, based on interviews with service providers delivering counseling to offenders, I document how non-profit organizational habits add distinctive flavors to the administration of punishment, materializing in governing regimes that emphasize care in some contexts and discipline in others. Finally, I also explore the dual constructions of immigrant counselors as both the experts and the “others” to the nation with regards to gender violence. In contrast to assumptions of ignorance amongst the immigrant “other” in the liberal imaginary, my findings indicate that the notion of women’s empowerment is nothing new or unfamiliar within Toronto’s diasporic communities; several of the immigrant anti-violence experts involved in this research credit their politicization and training “back home” as foundational to their involvement in feminist and the anti-violence movement. These findings challenge liberal assumptions of the East as a space devoid of the cultural material of women’s empowerment, which form the backbone of Western performances of modernity.

Keywords: Domestic Violence Courts
Community Organizations
Immigration
Criminal Justice Partnerships
Post-colonial Feminism
Governmentality
Advisor: Valverde, Mariana
A Follow-up Study of Boys with Gender Identity Disorder

This study provided information on the long term psychosexual and psychiatric outcomes of 139 boys with gender identity disorder (GID). Standardized assessment data in childhood (mean age, 7.49 years; range, 3–12 years) and at follow-up (mean age, 20.58 years; range, 13–39 years) were used to evaluate gender identity and sexual orientation outcome. At follow-up, 17 participants (12.2%) were judged to have persistent gender dysphoria. Regarding sexual orientation, 82 (63.6%) participants were classified as bisexual/ homosexual in fantasy and 51 (47.2%) participants were classified as bisexual/homosexual in behavior. The remaining participants were classified as either heterosexual or asexual. With gender identity and sexual orientation combined, the most common long-term outcome was desistence of GID with a bisexual/homosexual sexual orientation followed by desistence of GID with a heterosexual sexual orientation. The rates of persistent gender dysphoria and bisexual/homosexual sexual orientation were substantially higher than the base rates in the general male population. Childhood assessment data were used to identify within-group predictors of variation in gender identity and sexual orientation outcome. Social class and severity of cross-gender behavior in childhood were significant predictors of gender identity outcome. Severity of childhood cross-gender behavior was a significant predictor of sexual orientation at follow-up. Regarding psychiatric functioning, the heterosexual desisters reported significantly less behavioral and psychiatric difficulties compared to the bisexual/homosexual persisters and, to a lesser extent, the bisexual/ homosexual desisters. Clinical and theoretical implications of these follow-up data are discussed.

Keywords: Gender Identity Disorder
Advisor: Zucker, Ken
Determination of Molecular Regulators of Anoikis Resistance

As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighbouring cells. This cell death process has been termed “anoikis”. Tumour cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems. The understanding of the molecular regulators of anoikis resistance will allow for a better understanding of the metastatic process and the development of novel anti-metastatic therapeutics. To better determine the molecular underpinnings of anoikis resistance, we have used both chemical biology and genetic approaches. Using chemical biological approaches such as small molecule screens, we determined that both FLIP and Na+/K+ ATPase could modulate a cell’s response to anoikis. Through the use of a shRNA genome wide lentiviral screen we determined that ABHD4 was able to inhibit a cell’s response to anoikis. We also showed the importance of anoikis resistance in the ability of malignant cancer cells to survive in circulation. By decreasing a cell’s ability to resist anoikis, one is able to decrease the ability of a cancer cell to survive in circulation and form tumours in distant organs. Taken together, we have identified novel regulators of anoikis resistance and demonstrated the importance of anoikis in metastatic progression, which may lead to the development of novel treatments for metastatic cancers.

Keywords: Anoikis
Chemical Biology
Metastasis
Screening
Advisor: Schimmer, Aaron D.
Politics of Diaspora

The intention of the study is to come into a better understanding of the way in which the Diasporic body comes to know and understand its subjectivity within the governing contemporary public sphere. I suggest that this knowledge is diverse and that it can assist us to re-conceptualize learning in the context of schooling and education. I am interested in this seemingly mundane thing of ‘blackness’ and the way in which the signifying power of ‘blackness’ has come to constitute the conditions of possibility for the formation of a certain humanism. I trace somewhat abstract historical trajectories in order to better understand how contemporary everyday Diasporic life comes to be classified, organized, self-regulated and inscribed through particular intersections of race by way of gender, ableism, class, and sexuality. I seek to ascertain ways in which race is interpreted as the ‘Truth’ in order to impute the ethic of colonialism onto the Diasporic body. With this study my interest concerns understanding my lived experiences within the context of Diaspora and about how I come to make sense of race/racism/blackness through the cultural location of the colonial West. I am seeking to understand how, at certain moments, abject bodies of the Diaspora become predisposed to socialize in specific ways through these protean subjectivities. My interest involves coming to know critical pedagogies immanent to African Diasporic spaces that are germane for re-imagining schooling and education. I am interested in the school as a Diasporic space, the pedagogical and instructional implications for the teacher/educator, and about the ways in which meaning is made of Diaspora. I am suggesting writing Diaspora for schooling and education presents alternative ways of making sense of one’s subjectivity, citizenry, identity, about coming to know and understand how belonging, power and privilege come to be inscribed within the governing nation-state.

Keywords: Diaspora and modernity
race and ethnicity
culture and subjectivity
nation-state and citizenry
Advisor: Dei, George Jerry Sefa
NAViGaTing the Micronome: A Systematic Study of both the External Effects of MicroRNAs on Gene Repression networks, and the Contribution of microRNA Terminal Loops to MicroRNA Function

The first aim of this thesis is to examine relationships between microRNAs targeting gene networks, combining knowledge from microRNA prediction databases into our microRNA Data Integration Portal (mirDIP). Modeling the microRNA:transcript interactome – referred to as the micronome – to build microRNA interaction networks of signalling pathways, we find genes within signalling pathways to be co-targeted by common microRNAs suggesting an unexpected level of transcriptional control. We identify two distinct classes of microRNAs; universe microRNAs, which are involved in many signalling pathways; and intra-pathway microRNAs, which target multiple genes within one signalling pathway. We find universe microRNAs to have more targets, to be more studied and more involved in cancer signalling than their intrapathway counterparts. The second aim was to undertake a more focused view, analyzing the characteristics of microRNAs within the micronome itself beginning with a focus on the under-examined microRNA terminal loop across the micronome to determine if this region of the microRNA structure might contribute to microRNA functioning. We have identified 2 main classes of microRNAs based on loop structure – perfect and occluded, which show biological relevance. We found regulatory motifs within microRNA terminal loops and found a large number of Frequently Occurring Words (FOWs) significantly overrepresented across the micronome. Set analysis of in vitro secreted microRNAs, microRNA expression across a panel of normal tissues, and microRNAs shown to be secreted in lung cancer shows that specific microRNA loop motifs within these groups are significantly overreperesented – suggesting that microRNA terminal loops harbour sequences bearing microRNA processing and localization signals.

Keywords: MicroRNA
Computational Biology
Interaction Networks
Terminal Loops
mirDIP
Advisor: Jurisica, Igor
Overlay Neighborhoods for Distributed Publish/Subscribe Systems

The Publish/Subscribe (pub/sub) model has been widely applied in a variety of application scenarios which demand loose-coupling and asynchronous communication between a large number of information sources and sinks. In this model, clients are granted the flexibility to specify their interests at a high level and rely on the pub/sub middleware for delivery of their publications of interest. This increased flexibility and ease of use on the client side results in substantial complexity on part of the pub/sub middleware implementation. Furthermore, for several reasons including improved scalability, availability and avoiding a single point of failure, the pub/sub middleware is commonly composed of a set of collaborating message routers, a.k.a. brokers. The distributed nature of this design further introduces new challenges in ensuring end-to-end reliability as well as efficiency of operation. These challenges are largely unique to the pub/sub model and hence absent in both point-to-point or multicast protocols. This thesis develops solutions that ensure the dependable operation of the pub/sub system by exploiting the notion of overlay neighborhoods in a formal manner. More specifically, brokers maintain information about their neighbors within a configurable distance in the pub/sub overlay and exploit this knowledge to construct alternative forwarding paths or make smart forwarding decisions that improves efficiency, bandwidth utilization and delivery delay, all at the same time. Furthermore, in the face of failures overlay neighborhoods enable fast reconstruction of forwarding paths in the system without compromising its reliability and availability. Finally, as an added benefit of overlay neighborhoods, this thesis develops large-scale algorithms that bring the advantages of the pub/sub model to the domain of file sharing and bulk content dissemination applications. Experimental evaluation results with deployments as large as 1000 nodes illustrate that the pub/sub system scales well and outperforms the traditional BitTorrent protocol in terms of content dissemination delay.

Keywords: Publish/Subscribe
Reliability
Fault-Tolerance
Middleware Systems
Multipath forwarding
Bulk content dissemination
Advisor: Jacobsen, Hans-Arno
Essays on International Trade, Productivity, and Growth

This thesis investigates the role of institutions and firm behaviours in international trade. Chapter 1 estimates a dynamic general equilibrium model of entry, exit, and endogenous productivity growth. Productivity is endogenous both at the industry level (firms enter and exit) and at the firm level (firms invest in productivity-enhancing activities). Three key findings emerge. First, there is no evidence of learning by exporting: the observed positive correlation between exporting and productivity operates entirely via the impact of exporting on productivity-enhancing investments. Restated, exporting decision raises productivity, but only indirectly by making investing in productivity more attractive. Second, there is evidence of learning by producing multiple products: product-mix raises productivity directly in addition to the investment channel. Third, there are strong complementarities among the product-mix, exporting and investment decisions. Finally, we simulate the effects of reductions in foreign tariffs. This increases exporting, investing, and wages. Productivity rises at the economy-wide level both because of the between firm reallocation effect and because of within firm increases in productivity. Chapter 2 incorporates credit constraints into amodel of global sourcing and heterogeneous firms. Following Antras and Helpman(2004), heterogeneous firms decide whether to source inputs at arm’s length or within the boundary of the firm. Financing of fixed organizational costs requires borrowing with credit constraints and collateral based on tangible assets. The party that controls intermediate inputs is responsible for these financing costs. Sectors differ in their reliance on external finance and countries vary in their financial development. The model predicts that increased financial development increases the share of arm’s length transactions relative to integration in a country. The effect is most pronounced in sectors with a high reliance on external finance. Empirical examination of country-industry interaction effects confirms the predictions of the model. Chapter 3 examines whether financial development facilitates economic growth by estimating the effect of financial development on reducing the costs of external finance to firms. The data reveal substantial evidence of decreasing returns to the benefit of financial development in industries that are more dependent on external finance and countries with less financial frictions.

Keywords: productivity
heterogeneous firms
exports
complementarity
international trade
growth
Advisor: Trefler, Daniel