VictorJuiz/thesis huggingface dataset:
La théorie de la lecture chez Marcel Proust

The abstract of the dissertation « La théorie de la lecture chez Marcel Proust », submitted in partial fulfillment of the requirements for PhD to be awarded in June 2010. L’écriture en tant que forme de communication se prête à une analyse bipartite : (1) l’auteur dans son rapport au texte – le côté rhétorique ; (2) le lecteur dans son effort interprétatif face à ce même texte – le côté herméneutique. Face à la multitude de réflexions traitant les particularités génétiques et poétiques de la Recherche, il y a une pénurie de critiques qui, au lieu de privilégier une des parties susmentionnées, posent le regard sur les deux à la fois dans un but d’en observer des interactions. L’entre-croisement des stratégies d’écriture et des effets de lecture s’inscrit bien dans le cadre de la théorie de communication. Ma thèse se place dans la lignée tracée par Serge Doubrovsky, Michael Finn et Julia Kristeva qui se sont interrogés sur les façons dont la composante rhétorique d’un texte littéraire influence sa lecture. Le maintien de cette double perspective simultanée permet de suivre la construction du pont liant les pôles rhétorique et herméneutique. Je développe une approche apte à saisir les observations provenant du côté de production et de celui de réception et à en offrir une synthèse. Cette approche consiste en une hybridation entre la rhétorique, en tant qu’art de persuader, et la psychanalyse pour en arriver à l’herméneutique, ou à un produit de l’effort interprétatif. La psychanalyse justifie et délimite l’enquête sur les processus rhétoriques de la production de l’énoncé. De l’autre côté, l’impact de la rhétorique sur l’herméneutique se facilite par la subversion. Cette notion herméneutico-rhétorique emprunte à la théorie des horizons d’attente de Jauss et s’inspire de l’argumentum ad hominem de la rhétorique classique. J’utilise cette notion synthétique pour étudier l’implication du lecteur dans la diégèse et pour explorer la manière dont une telle implication intéressée influence l’interprétation. L’application de cette méthode de travail au texte de la Recherche se fait le long les trois axes. Le premier s’interroge sur la communication, cherchant à l’expliquer à partir des obstacles qui l’empêchent. Le résultat de ce parcours est l’observation que la communication se réalise lorsqu’un sujet communiquant devient aussi un objet. Le deuxième axe place les défis communicatifs dans le contexte des enjeux entre le particulier et le général – contexte du problème herméneutique. Sur le troisième axe se range la discussion de la prise de possession à laquelle est censée aboutir la résolution du problème herméneutique. J’explique que, par l’entremise de l’introjection et de l’incorporation, la quête de la possession devient névrotique et impossible à réaliser. Je conclus en remarquant que la communication efficace doit commencer par la problématisation du sujet et par sa transformation en objet.

Keywords: Marcel Proust
reader's response, communication through art.
Advisor: Michelucci, Pascal
Investigations into the Biological Roles of the E3 ligase Ariadne 2/TRIAD1

The process of ubiquitination plays an essential role in numerous cell functions, including apoptosis and the induction of immune responses. Ariadne 2 is a RING finger E3 ligase and is part of the highly conserved RBR (RING-B-Box-RING) superfamily, however, little is known of its function in mammalian systems. To further examine the physiological role, Ariadne 2 deficient mice were generated. In a mixed background, Ariadne 2 deficient (Arih2-/-) mice die prematurely after birth however lethality is not fully penetrant. Adult mice that escape lethality have lower body weight and reduced viability due to an apparent lymphoproliferative disorder. In a C57BL/6 background, Ariadne 2 deficiency leads to a fully penetrate embryonic lethality, occurring after embryonic day 16.5. Arih2-/- foetal liver have reduced cellularity and increased apoptosis, however haematopoietic cells are capable of differentiating into myeloid and granulocytic progenitors and can fully reconstitute lethally irradiated Rag1-/- recipient mice. These Rag1-/-Arih2-/- chimeras recapitulate the lymphoproliferative disorder observed in the mixed background Arih2-/- mice. Further analysis show Rag1-/-Arih2-/- chimeras display increased number of lymphocytes, granulocytes, macrophages and dendritic cells, increased serum immunoglobulin levels and pro-inflammatory cytokines, and dramatic heterogeneous cellular organ infiltration, consisting mainly of T cells. T cell homeostasis is also altered, as seen by increased activated and ‘memory-like’ T cells, elevated TH1 and TH2 cytokines, increased regulatory T cells (Treg), and increased T cell proliferation. This may be due to an observed premature maturation of Arih2-/- dendritic cells. Arih2-/- foetal liver derived dendritic cells (FLDC) express high levels of maturation markers CD80/B7.1, CD86/B7.2, CD83, CD40 and MHCII and are capable of activating T cells in the RIP-GP model of induced diabetes. This may be linked to modulation of the NFκB and ERK pathways, in particular increase in nuclear p65/RelA and phospho-p65/RelA leading to an increase in NFκB and AP-1 binding to DNA and sustained and hyperactive NFκB response in Arih2-/- dendritic cells. Overall, Ariadne 2 is shown to be a negative regulator in the activation of immune cells, in particular dendritic cells, and is a novel regulator in the maintenance of peripheral tolerance and the pathogenesis of autoimmunity.

Keywords: E3 ligase
Ariadne 2
Advisor: Mak, Tak Wah
Role of Microornas in Tumroigenesis and their Modulation by Versican 3' Untranslated Region

MicroRNA is a single-stranded RNA molecule of about 22 nucleotides in length and is expressed endogenously. It functions as a gene regulator by pairing imperfectly with 3’ untranslated region (3’UTR) of target mRNAs, leading to translational inhibition. MicroRNA is implicated in many regulatory pathways and hence affects various cellular activities. In the development of cancer, genetic alterations occurred at miRNA locus and its expression level is dysregulated in various cancers versus normal tissue counterparts. It is thus important to find the targets of dysregulated microRNAs contributing to progression of cancer. To facilitate long term functional studies, a microRNA expression construct with unique futures was generated. Stable expression of miR-378 enhanced cell survival, reduced caspase-3 activity, and promoted tumor growth and angiogenesis. By algorithmic predictions and proteomic analysis, two tumor suppressors, SuFu and Fus-1, were found to be translationally regulated by miR-378. Target validation was confirmed by co-transfection experiments and luciferase activity assays, reassuring its oncogenic role by regulating two tumor suppressor genes simultaneously. Conversely, microRNA can also function as a tumor suppressor by modulating expression of Versican, an extracellular matrix protein known to facilitate tumorigenesis and angiogenesis. By a novel PCR method, more than one microRNA were found to bind to Versican 3’UTR. iii Among these microRNAs, targeting of Versican and Fibronectin by miR199a-3p was validated. Expression of a fragment of Versican 3’UTR was expected to antagonize the function of miR-199a-3p. Stable expression of Versican 3’UTR resulted change in cell morphology and increased cell-cell adhesion. Analysis of primary tissues from transgenic mice expressing versican 3’UTR showed an increase expression of Versican and Fibronectin, and organ adhesion was found between liver and its surrounding tissues. In addition, 3’UTR also modulated the level of miR-199a-3p and miR-136, alleviating translation of negative cell cycle regulators, PTEN and Rb1. This resulted in reduced cell proliferation and hence diminished tumor growth. These findings suggest a role of microRNA in tumor growth, providing a valuable target for therapeutic intervention.

Keywords: microRNA
Advisor: Yang, Burton B.
The Regulation of Integrin-mediated Cell Adhesion and Spreading by the Actin-binding Protein Filamin A

Cell adhesion and spreading are regulated by complex interactions between the cytoskeleton, matrix adhesion receptors and extracellular matrix proteins, but the molecular determinants of these interactions in early events in cell spreading are not defined. I found that the actin-binding proteins cortactin, vinculin and filamin A were enriched in the earliest formed extensions of HEK-293 cells spreading on collagen. Knockdown of filamin A by short hairpin RNA reduced spreading and the number of cell extensions. Antibody blockade of collagen binding sites on ß1 integrin reduced (p<0.05) cell spreading and the localization of filamin A at cell extensions. Knockdown of filamin A reduced ß1 integrin occupancy by collagen as measured by 12G10 antibody, suggesting a functional co-dependence of filamin A and ß1 integrin. Based on mass spectrometry screening of potential filamin A interacting proteins I examined the interaction of filamin A with the intermediate filament protein vimentin. Filamin A and vimentin-expressing cells were well-spread on collagen and exhibited numerous cell extensions enriched with filamin A and vimentin. By contrast, knockdown of filamin A or vimentin inhibited spreading, cell adhesion, cell surface ß1 integrin expression and ß1 integrin activation. Knockdown of filamin A reduced vimentin phosphorylation and blocked recruitment of vimentin to cell extensions while knockdown of filamin A and/or vimentin inhibited the formation of cell extensions. Inhibition of cell spreading, vimentin phosphorylation and ß1 integrin surface expression and activation were all phenocopied in cells treated with the protein kinase C inhibitor bisindolylmaleimide; cell spreading was also reduced by siRNA knockdown of protein kinase Cє. By immunoprecipitation of cell lysates and by pull-down assays using purified proteins I found an association between filamin A and vimentin. Filamin A also associated with protein kinase Cє, which was enriched in cell extensions. In vitro pull-down assays using deletional mutants of purified filamin A showed that both vimentin and protein kinase Cє bound to a region of filamin A that included repeats 1-8. Reconstitution of filamin A-deficient cells with full-length filamin A or filamin A repeats 1-8 restored cell spreading, vimentin phosphorylation and the cell surface expression of ß1 integrins. I conclude that interactions of filamin A with vimentin and protein kinase Cє may be important for the trafficking and activation of ß1 integrins and cell spreading on collagen.

Keywords: actin
cell adhesion
Advisor: McCulloch, Christopher
Characterization of the Physiological Role of PDZ-RhoGEF in Drosophila and Mice

Biological outputs of insulin/IGF signaling are regulated through essential mediators, such as IRSs, PI3-kinase, and PKB/Akt. These mediators serve critical roles in signal propagation, feedback, and as junctions for crosstalk with other pathways. Abnormal insulin/IGF signaling results in disease, such as obesity, diabetes, and cancer. Given the vital role of this signaling pathway to human health, unraveling its regulatory mechanisms is crucial. Components of this pathway are highly conserved throughout evolution. PTEN, one of the well-defined regulators of this pathway, functions as a lipid phosphatase that negatively regulates insulin/IGF-1 signaling at the PIP3 level, a phosphoinositol that is upregulated by activated PI3-kinase in both Drosophila and mammals. To discover genetic modulators of PTEN in Drosophila, we performed a loss-of-function genetic screen to identify molecules that modify the phenotype elicited by PTEN overexpression in the Drosophila eye. From this screen, we identified a member of the Dbl-family, the guanine nucleotide exchange factor DRhoGEF2, which suppresses the PTEN-overexpression eye phenotype via its effects on dPKB/dAkt activation. By conducting a genetic rescue, we established that PDZ-RhoGEF, a member of the regulator of G-protein signal (RGS)-like domain containing Rho GEFs (RGS-RhoGEFs) subfamily of Dbl-family GEFs, is the mammalian counterpart of DRhoGEF2. PDZ-RhoGEF is essential for cell proliferation and survival through ROCK-dependent activation of IRS/PI3-kinase signaling cascade, which has a major impact on adipose tissue homeostasis. Through an integrative approach, we have demonstrated that DRhoGEF2/PDZ-RhoGEF-dependent signaling has tissue-specific effects on insulin/IGF-signaling throughput in both Drosophila and mammals. Particularly, we have demonstrated the role played by PDZ-RhoGEF in diet related pathology, provides an alternative therapeutic opportunity in disease intervention.

Keywords: PDZ-RhoGEF
DRhoGEF2
Drosophila
Mice
Advisor: Mak, Tak Wah
Elucidating the Role if Integrin-extracellular Matrix Protein Interactions in Regulating Osteoclast Activity

Millions of people around the world suffer from the debilitating effects of inflammatory bone diseases characterized by excessive bone loss due to an increase in osteoclast formation and activity. Osteoclasts are multinucleated cells responsible for bone resorption in health and disease. Arthritic joints also have elevated levels of extracellular matrix proteins affecting the disease progression. The interaction between osteoclasts and the external milieu comprised of extracellular matrix proteins through integrins is essential for modulating the formation and activity of osteoclasts. The focus of this thesis was to elucidate how the interaction between the extracellular matrix proteins and osteoclasts regulates osteoclast formation and activity and the role of alphavbeta3 in this process. In primary rabbit osteoclast cultures, blocking the integrin alphavbeta3 using Vitaxin, an anti-human alphavbeta3 antibody, decreased osteoclast resorption by decreasing osteoclast attachment. Vitaxin’s inhibitory effect on osteoclast attachment was enhanced when osteoclasts were pretreated with M-CSF, a growth factor known to induce an activated conformation of the integrin alphavbeta3. Using the RAW264.7 cell line, the effects of the matrix proteins fibronectin and vitronectin on osteoclast activity were compared to those of osteopontin. Both fibronectin and vitronectin decreased the number of osteoclasts formed compared to osteopontin. Fibronectin’s effect on osteoclastogenesis was through decreasing pre-osteoclast migration and/or fusion but not through inhibiting their recruitment. In contrast, fibronectin induced resorption through increasing resorptive activity per osteoclast in comparison to vitronectin and osteopontin. These stimulatory effects were accompanied by an increase in the pro-inflammatory cytokines nitric oxide and IL-1beta Crosstalk between the signalling pathways of nitric oxide and IL-1betawas suggested by the ability of the nitric oxide inhibitor to decrease the level of IL-1beta which occurred exclusively on fibronectin. Osteoclasts on fibronectin also had a compact morphology with the smallest planar area while vitronectin increased the percentage of osteoclast with migratory morphology and osteopontin induced osteoclast spreading. The increase in compact morphology on fibronectin was associated with a decrease in extracellular pH. Low extracellular pH was found to increase the total time osteoclasts spend in a compact phase. These results show that matrix proteins differentially regulate osteoclast formation, activity and morphology.

Keywords: Osteoclast
Bone
Extracellular matrix proteins
Advisor: Manolson, Morris Frank
In-line Extrusion Monitoring and Product Quality

Defects in polyethylene film are often caused by contaminant particles in the polymer melt. In this research, particle properties obtainable from in-line melt monitoring, combined with processing information, are used to predict film defect properties. “Model” particles (solid and hollow glass microspheres, aluminum powder, ceramic microspheres, glass fibers, wood particles, and cross-linked polyethylene) were injected into low-density polyethylene extruder feed. Defects resulted when the polyethylene containing particles was extruded through a film die and stretched by a take-up roller as it cooled to form films 57 to 241mm in thickness. Two off-line analysis methods were further developed and applied to the defects: polarized light imaging and interferometric imaging. Polarized light showed residual stresses in the film caused by the particle as well as properties of the embedded particle. Interferometry enabled measures of the film distortion, notably defect volume. From the images, only three attributes were required for mathematical modeling: particle area, defect area, and defect volume. These attributes yielded two ”primary defect properties”: average defect height and magnification (of particle area). For all spherical particles, empirical correlations of these properties were obtained for each of the two major types of defects that emerged: high average height and low average height defects. Analysis of data for non-spherical particles was limited to showing how, in some cases, their data differed from the spherical particle correlations. To help explain empirical correlations of the primary defect properties with film thickness, a simple model was proposed and found to be supported by the high average height defect data: the “constant defect volume per unit particle area” model. It assumes that the product of average defect height and magnification is a constant for all film thicknesses. A numerical example illustrates how the methodology developed in this work can be used as a starting point for predicting film defect properties in industrial systems. A limitation is that each prediction yields two pairs of primary defect property values, one pair for each defect type. If it is necessary to identify the dominant type, then measurement of a length dimension of sufficient defects in the film is required.

Keywords: low density polyethylene
film casting
defect
in-line monitoring
extrusion
Advisor: Balke, Stephen Thomas
Sayad, Saed
Cellular and Molecular Architecture of the Human Hematopoietic Hierarchy

The blood system is organized as a developmental hierarchy in which rare hematopoietic stem cells (HSCs) generate large numbers of immature progenitors and differentiated mature blood cells. In this process, at least ten distict lineages are specified from multipotent stem cells, however the cellular and molecular organization of the hematopoietic hierarchy is a topic of intense investigation. While much has been learned from mouse models, there is also an appreciation for species-specific differences and the need for human studies. Blood lineages have been traditionally grouped into myeloid and lymphoid branches, and the long-standing dogma has been that the separation between these branches is the earliest event in fate specification. However, recent murine studies indicate that the progeny of initial specification retain the more ancestral myeloid potential. By contrast, much less is known about the progenitor hierarchy in human hematopoiesis. To dissect human hematopoiesis, we developed a novel sorting scheme to isolate human stem and progenitor cells from neonatal cord blood and adult bone marrow. As few as one in five single sorted HSCs efficiently repopulated immunodeficient mice enabling interrogation of homogeneous human stem cells. By analyzing the developmental potential of sorted progenitors at a single-cell level we showed that earliest human lymphoid progenitors (termed LMPs) possess myelo-monocytic potential. In addition to B-, T-, and natural killer cells, LMPs gave rise to dendritic cells and macrophages indicating that these closely related myeloid lineages also remain entangled in lymphoid development. These studies provide systematic insight into the organization of the human hematopoietic hierarchy, which provides the basis for detailed genetic analysis of molecular regulation in defined cell populations. In a pilot study, we investigated the role of a zinc finger transcription factor (ZNF145), PLZF, in myeloid development. We found that PLZF restrained proliferation and differentiation of myeloid progenitors and maintained the progenitor pool. Induction of ERK1/2 by myeloid cytokines, reflective of a stress response, leads to nuclear export and inactivation of PLZF, which augments mature cell production. Thus, negative regulators of differentiation can serve to maintain developmental systems in a primed state, so that their inactivation by extrinsic signals can induce proliferation and differentiation to rapidly satisfy increased demand for mature cells. Taken together, these studies advance our understanding of the cellular and molecular architecture of human hematopoiesis.

Keywords: hematopoietic
stem cell
cord blood
Advisor: Dick, John E.
Examining the Complexities of Fostering Social Inclusion in Elementary Classrooms

The purpose of this 1-year case study was to understand how 5 elementary school teachers in an inner-city school foster social inclusion. Through classroom observations and interviews, the study examined the variations of classroom practices the teachers used to create inclusive environments, the challenges they faced in the process, and the strategies they developed to address these challenges. How their work in the classroom interacted with the school's organizational structures was also explored. Three concepts frame the study: a broad conception of social inclusion that addresses multiple aims for creating an environment of belonging and takes students of all social identities into account; a detailed conception of the practice of social inclusion from a range of theoretical perspectives and teachers' experiences; and a situated conception of context that interrelates the classroom with the school and the community. Three dimensions of pedagogy—content-based practices, relations, and structures—are used to identify and compare principles of inclusive practice. The study portrays the interactions of daily classroom life through cross-case analysis and reveals the complex decision-making processes that teachers use to foster social inclusion. This study builds on growing scholarship in the field of social inclusion in education (Ainscow et al., 2006; Dei, 1996a; Kosnik & Beck, 2009; Kumashiro, 2002; Topping & Maloney, 2005) and on the increased interest in inclusive pedagogical practices. The in-depth portraits of the teachers’ classroom practices are compared to literature in 4 areas: citizen-based pedagogy, culture-based pedagogy, race-based pedagogy, and anti-oppression pedagogy. The teachers’ practices are analyzed in relation to 2 principles of social inclusion: connecting content to students’ lives and creating mutually supportive social spaces. The study revealed that the participants' practices were mainly associated with pedagogies based on citizenship and culture, with some connections to race-based and anti-oppression pedagogies. What differentiates this study from most other studies in this area is its detailed attention to the dynamic complexity of applying principles of social inclusion to practice. The portraits offer insights into inclusive work in classrooms that will benefit teachers, teacher educators, and researchers interested in expanding the field of social inclusion in education.

Keywords: social inclusion
pedagogy
elementary schooling
inner city schooling
Advisor: Thiessen, Dennis