VictorJuiz/thesis huggingface dataset:
Reading the Histone Code: Methyl Mark Recognition by MBT and Royal Family Proteins
Keywords: Epigenetics
Histone modifications
Royal Family Proteins
NMR, x-ray crystallography

The post-translational modifications (PTMs) of histones regulate many cellular processes including transcription, replication, DNA repair, recombination, and chromosome segregation. A large number of combinations of PTMs are possible, with methylation being one of the most complex, since it is found in three states and is recognized in a sequence specific context. Methylation of histones at key lysine residues has been shown to work in concert with other modifications to provide a Histone Code that may determine heritable transcriptional conditions in normal and disease states. On the most basic level it is pivotal to understand how and by which proteins the numerous PTMs are recognized, as well as mechanisms for downstream signal propagation. To address this need we developed a high-throughput method that allows analysis of up to 600 PTMs in a single experiment. This approach was utilized to characterize macromolecules interacting with the specific modifications on histone tails and to screen for the marks that bound to Malignant Brain Tumor (MBT) proteins, important chromatin regulators implicated in cancer. All MBTs recognized either mono- or dimethyllysine histone marks, and using structure-based mutants we identified a triad of residues that were responsible for this discrimination. These results provide the foundation for the rational design of highly selective MBT inhibitors. Additionally, this thesis describes combinatorial recognition of histone modifications, as proposed in the original Histone Code hypothesis. We demonstrate that Tudor domains of UHRF1, a protein involved in epigenetic maintenance of DNA methylation, is able to read a dual modification state of histone H3 in which it is trimethylated at lysine 9 and unmodified at lysine 4. This study provides an elegant example of the combinatorial readout of histone modification states by a single domain. Together, our findings offer mechanistic insights into the recognition of methylated histone tails by MBT domains and Royal Family in general.
Knowledge Building in Continuing Medical Education
Keywords: Knowledge Building
Continuing Medical Education
Social Network Analysis
Collaborative

Continuing medical education has been characterized as didactic and ineffective. This thesis explores the use of Knowledge Building theory, pedagogy, and technology to test an alternative model for physician engagement—one that emphasizes sustained and creative work with ideas. Several important conceptual changes in continuing medical education are implied by the Knowledge Building model—changes that extend the traditional approach through engagement in (a) collective responsibility for group achievements rather than exclusive focus on individual advancement and (b) work in design-mode, with ideas treated as objects of creation and assemblage into larger wholes and new applications, with extension beyond belief-mode where evidence-based acceptance or rejection of beliefs dominates. The goal is to engage physicians in “cultures of participation” where individual learning and collective knowledge invention or metadesign advance in parallel. This study was conducted in a continuing medical education End-of-Life Care Distance Education course, for family physicians, from 2004 to 2009. A mixed methods case study methodology was used to determine if social-mediated Knowledge Building improved physicians’ knowledge, and if so, what social network structural relationships and sociocognitive dynamics support knowledge improvement, democratization of knowledge, and a metadesign perspective. Traditional pre-/posttest learning measures across 4-years showed significant gains (9% on paired t-test = 5.34, p < 0.001) and large effect size (0.82). Social network analysis of ten 2008/2009 modules showed significant difference in density of build-on notes across groups. Additional results demonstrated a relationship between high knowledge gains and social network measures of centrality/distribution and cohesion. Correlation of posttest scores with centrality variables were all positive. Position/power analyses highlighted core-periphery sociocognitive dynamics between the facilitator and students. Facilitators most often evoked partner/expert relationships. Questions rather than statements dominated the discourse; discourse complexity was elaborated/compiled as opposed to reduced/dispersed. Themes beyond predefined learning objectives emerged and Knowledge Building principles of community responsibility, idea improvability, and democratization of knowledge were evident. Overall, results demonstrate the potential of collective Knowledge Building and design-mode work in continuing medical education, with individual learning representing an important by-product. There were no discernible decrements in performance, suggesting significant advantages rather than tradeoffs from engagement in Knowledge Building.
Meaning, Media and Dwellings: The Public Image of the High-rise Toronto Condo
Keywords: Condominium
Toronto
Marketing
Newspaper

This research examines representations of condominiums in the real estate section of the Toronto Star from 1967 through 1997, and in the Star’s Condo Living section between 1997 and 2007. I depart from conventional approaches by evaluating the articles as well as the advertisements that comprise the real estate section, based on the assumption that the context in which these texts appear is significant: a major newspaper is not a neutral vehicle, and ads and articles—consumed together, as they are in a print newspaper—will interact in creating representations of condominiums. The Condo Living section in particular is seen to perform a number of brand-like activities, most obviously in positioning the Toronto high-rise condominium as a dwelling that is particularly well-suited to young, middle-class women. This occurs partly as a function of the frequency with which women are portrayed as condominium owners. Beyond this, however, I show how the advertisements and articles in Condo Living help remake the public image of the condominium by countering existing stigmas attached to high-rise living. The section also helps to differentiate the condominium from other dwelling types by emphasizing elaborate amenities and making claims to urbanity through high-profile cultural and entertainment events. Perhaps most importantly, I demonstrate how the leading present-day design aesthetic—a reworking of midcentury modernisms—came to thoroughly dominate the image and the built form of the recent-era condominium. Positioning the condominium as a design-led dwelling type had profound implications: due to the links between design and high-end fashion, health and beauty items, the condominium immediately became a member of an aspirational product category associated with women, wealth, style and glamour. In addition to positioning the condominium as ‘naturally’ suited to young single, women, it removed the condo from direct competition with the single-family house, allowing it to be perceived as a desirable and distinct—rather than denigrated—dwelling type.
Characterization of Tumour-initiating Cells in Human Colorectal Cancer
Keywords: colorectal cancer
stem cell biology

It has been hypothesized that tumours are caricatures of normal tissue organization, where a minority cell population, the ‘stem cell’ of cancer, holds the exclusive ability for tumour propagation. These cancer stem cells (CSCs), or tumour-initiating cells, possess extensive self-renewal ability, through which they ensure maintenance of the tumourigenic clone. Such cells have been identified in various cancers, including colorectal, and have been proposed to be the source of tumour re-initiation following therapy. An important and currently unanswered question in solid tumours is whether all CSCs are equal or whether there is a gradient of potency within the CSC compartment. Using primary human colon tumour cells and sensitive in vivo functional assays, we have determined that colon CSCs are not uniform; rather, they vary with respect to their proliferative capacity, which is also linked to their response to chemotherapy. These findings hold therapeutic implications for colorectal cancer treatment since all types of CSCs must be eradicated to remove the risk of tumour relapse. While the CSC model may provide attractive answers to some challenging questions, it remains controversial. Ascertaining the importance of CSCs will come from targeted CSC therapies. Here we demonstrate that human colorectal CSC function is dependent on the self-renewal regulator BMI-1. Down-regulation of BMI-1 inhibits the ability of colorectal tumour-initiating cells to self-renew resulting in the abrogation of their tumourigenic potential. Treatment of primary colorectal cancer xenografts with small molecule BMI-1 inhibitors resulted in colorectal tumour-initiating cell loss with long-term and irreversible impairment of tumour growth. Targeting the BMI-1 related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer. Collectively, we have advanced the CSC field in two areas of importance. We show for the first time that the CSC pool encompasses a gradient of proliferative potential linked to chemotherapeutic response. Second, we provide critical proof for the clinical relevance of CSCs by inhibiting tumour growth through targeting of the self-renewal machinery. This body of work significantly advances our understanding of colorectal tumour-initiating cells.
Epigenetic Silencing of Novel Tumour Suppressor Genes in Medulloblastoma
Keywords: medulloblastoma
epigenetics

Medulloblastomas (MB) are the most common pediatric nervous system malignancy. Known mutations account for only a subset of MB cases. We hypothesized that CpG island methylation-mediated tumour suppressor gene (TSG) silencing contributes to MB pathogenesis, either alone, or in combination with genetic events such as loss of heterozygosity (LOH). We performed a microarray-based genome-wide screen of MB cell lines treated with 5-aza-2’deoxycytidine, identifying genes exhibiting increased expression following treatment. Using this strategy, we identified inhibitors of WNT signalling (SFRP1, SFRP2, and SFRP3) and an inhibitor of the HGF/MET signalling pathway (SPINT2) as putative TSGs silenced by promoter region methylation in MB. Methylation of the WNT signalling inhibitors SFRP1, SFRP2, and SFRP3 was identified using bisulfite sequencing and methylation-specific PCR (MSP). Stable re-expression of SFRP1, SFRP2, and SFRP3 reduced proliferation, impaired anchorage-independent growth, and limited WNT signalling activity. SFRP1 re-expression reduced tumour growth in vivo in xenograft models. Aberrant WNT signalling plays a role in the pathogenesis of a subset of sporadic human MB, as well as MB in cases of Turcot syndrome with germline mutations of APC. Activating mutations of β-catenin are also implicated in a subset of MB. We have identified for the first time an additional mechanism – loss of normal pathway inhibition by SFRP gene silencing – that contributes to MB pathogenesis. SPINT2 methylation was confirmed with bisulfite sequencing and MSP. Stable re-expression of SPINT2 reduced proliferation, impaired cell migratory ability, and decreased the capacity for anchorage-independent growth. In vivo, re-expression of SPINT2 reduced tumour formation in xenograft models. This study identified for the first time SPINT2 as a putative TSG in human MB, and further implicated aberrant HGF/MET oncogenic signalling in the pathogenesis of this disease. The efficacy of targeting the HGF/MET pathway as a novel therapeutic strategy was tested in vitro using the small molecule MET kinase inhibitor PHA665752. Treatment of MB cell lines with PHA665752 reduced cell proliferation, anchorage-independent growth, migration, and limited downstream signalling via the MAPK and PI3K/AKT pathways.
Geometric Analysis on Solutions of Some Differential Inequalities and within Restricted Classes of Holomorphic Functions
Keywords: Several complex variables
Unique continuation

Pars 1 and 2 are devoted to study of solutions of certain differential inequalities. Namely, in Part 1 we show that a germ of an analytic set (real or complex) admits a Gagliardo-Nirenberg type inequality with a certain exponent s>=1. At a regular point s=1, and the inequality becomes classical. As our examples show, s can be strictly greater than 1 even for an isolated singularity. In Part 2 we prove the property of unique continuation for solutions of differential inequality |\Delta u|<=|Vu| for a large class of potentials V. This result can be applied to the problem of absence of positive eigenvalues for self-adjoint Schroedinger operator -\Delta+V defined in the sense of the form sum. The results of Part 2 are joint with Leonid Shartser. In Parts 3 and 4 we derive the basic elements of complex function theory within some subalgebras of holomorphic functions (including extension from submanifolds, corona type theorem, properties of divisors, approximation property). Our key instruments and results are the analogues of Cartan theorems A and B for the `coherent sheaves' on the maximal ideal spaces of these subalgebras, and of Oka-Cartan theorem on coherence of the sheaves of ideals of the corresponding complex analytic subsets. More precisely, in Part 3 we consider the algebras of holomorphic functions on regular coverings of complex manifolds whose restrictions to each fiber belong to a translation-invariant Banach subalgebra of bounded functions endowed with sup-norm. The model examples of such subalgebras are Bohr's holomorphic almost periodic functions on tube domains, and all fibrewise bounded holomorphic functions on regular coverings of complex manifolds. In Part 4 the primary object of study is the subalgebra of bounded holomorphic functions on the unit disk whose moduli can have only boundary discontinuities of the first kind. The results of Parts 3 and 4 are joint with Alexander Brudnyi.
Elucidating the Interaction between the Molecular Chaperone Hsp104 and the Yeast Prion Sup35
Keywords: Hsp104
Sup35

Hsp104 is a protein remodeling factor that is crucially important for induced thermotolerance and prion propagation in yeast. Recent work demonstrates that Hsp104 is able to directly recognize and interact with synthetic polypeptide substrates, and that this interaction is dependent on the amino acid composition or sequence (Lum et al., 2008). Here this concept is applied to the in vivo substrate Sup35. Sup35, a translation termination factor, also forms the yeast prion [PSI+]. The maintenance of the prion is critically dependent on the expression levels of Hsp104. Over-expression of Hsp104 leads to the loss of prions, as does inhibition of this protein remodeling factor. As part of this thesis, an in vitro assay was established in which spontaneous nucleation, the event preceding of fiber formation, was suppressed. Fibrilization itself then becomes strictly dependent on the chaperones Hsp104, huHsp70p and Ydj1. In line with in vivo observations, Hsp104 mutants that fail to propagate [PSI+] also fail to overcome nucleation inhibition in this assay. Following this, the next part of this work established that the middle (M) domain of Sup35 inhibited this process, while not affecting spontaneous fibrilization under non-inhibitory conditions. This finding was reproduced in vivo, as middle domain over-expression also led to curing of weak [PSI+]. This suggested that the M-domain contains an Hsp104 binding site. This hypothesis is supported by data presented in this thesis which show that a small segment 129-148 within the Middle domain has enhanced Hsp104 binding properties. Deletion of this 20-mer peptide also reduced the Hsp104 ability to interact with this prion substrate; it also results in the destabilization of the prion and enhanced curing by the prion curing agent guandidinium hydrochloride. This represents the first ever Hsp104 binding site identified within a natural substrate.
Iterative, Interactive Analysis of Agent-goal Models for Early Requirements Engineering
Keywords: Requirements Engineering
Goal Modeling
Interactive Analysis
Model Analysis
Software Modeling
Iterative Analysis
Early Requirements Engineering

Conceptual modeling allows abstraction, communication and consensus building in system development. It is challenging to expand and improve the accuracy of models in an iterative process, producing models able to facilitate analysis. Modeling and analysis can be especially challenging in early Requirements Engineering (RE), where high-level system requirements are discovered. In this stage, hard-to-measure non-functional requirements are critical; understanding the interactions between systems and stakeholders is a key to system success. Goal models have been introduced as a means to ensure stakeholder needs are met in early RE. Because of the high-level, social nature of early RE models, it is important to provide procedures which prompt stakeholder involvement (interaction) and model improvement (iteration). Most current approaches to goal model analysis require quantitative or formal information that is hard to gather in early RE, or produce analysis results automatically over models. Approaches are needed which balance automated analysis over complex models with the need for interaction and iteration. This work develops a framework for iterative, interactive analysis for early RE using agent-goal models. We survey existing approaches for goal model analysis, providing guidelines using domain characteristics to advise on procedure selection. We define requirements for an agent-goal model framework specific to early RE analysis, using these requirements to evaluate the appropriateness of existing work and to motivate and evaluate the components of our analysis framework. We provide a detailed review of forward satisfaction procedures, exploring how different model interpretations affect analysis results. A survey of agent-goal variations in practice is used to create a formal definition of the i* modeling framework which supports sensible syntax variations. This definition is used to precisely define analysis procedures and concepts throughout the work. The framework consists of analysis procedures, implemented in the OpenOME requirements modeling tool, which allow users to ask “What if?” and “Is this goal achievable, and how?” questions. Visualization techniques are introduced to aid analysis understanding. Consistency checks are defined over the interactive portion of the framework. Implementation, performance and potential optimizations are described. Group and individual case studies help to validate framework effectiveness in practice. Contributions are summarized in light of the requirements for early RE analysis. Finally, limitations and future work are described.
Beyond Acculturation: Cultural Constructions of Immigrant Resilience and Belonging in the Canadian Context
Keywords: immigrant
resilience
culture
belonging
adaptation
adversity
acceptance
attachment

The psychological literature on immigrants has identified numerous challenges of resettlement. Research on acculturation indicates that adaptive functioning is characterized as a bicultural prospect in which individuals balance their heritage and the dominant culture within the receiving society. This conceptualization of positive adaptation typically relegates culture to a broad-based and static property circumscribed within ethnicity, neglecting diverse cultural representations and the way specific mechanisms affect the process of adaptation. The current research sought immigrants’ subjective accounts of resilience. The aim of this study was to identify specific markers of significant adversity and corollary positive adaptation that intersect with diverse mechanisms of culture to develop a theory of cultural adaptation. A constructivist grounded theory approach was implemented in data collection and analysis. Eighteen first-generation immigrants, who represented a range of cultural backgrounds and geographic regions, each participated in one semi-structured interview. The overarching theme that emerged from data analysis, Belonging, was found to explicate the meaning of resilience for immigrants in terms of their cultural adaptation. Belonging indicated a process by which immigrants gained a sense of identification with and inclusion in Canadian society. Immigrants’ perception of Belonging was affected by two mid-level themes, Forming Attachments and Feeling Acceptance. Forming Attachments was contextually driven and highlighted a personal process of developing cultural attachments. The advancement of attachments, interpersonally, occupationally and to the larger sociocultural environment, was meaningful to recovery and had implications for Belonging. The second mid-level theme identified a reciprocal process of acceptance that revealed a struggle to accept cultural changes as well as the significance of feeling accepted as an equal member of society. Taken together, Forming Attachments and Feeling Acceptance had a significant effect on immigrants’ sense of Belonging and were contextualized within a range of cultural domains. This study highlights the dynamic role of culture in immigrant adaptation and contributes to both research and health care professionals by offering a framework of immigrant resilience that may promote healthy forms of functioning.
Investigating a College Computer Course Delivered in Both Online and Face-to-face Classes
Keywords: Distance education
Comparative studies

The purpose of this study is to investigate a college computer course delivered in both online and face-to-face classes. As more online courses and programs emerge, concerns about the quality and comparability of online instruction with face-to-face instruction have arisen. Questions about the relative effectiveness of each mode of instruction are important both at the stage of course development and at the stage of course delivery. Earlier comparative studies have shown that online courses were equal to face-to-face courses. These studies evaluated student services and technological infrastructure, student satisfaction, and learning outcomes. However, few studies have been conducted on computer applications at the community college level. This study seeks to fill in this gap by providing students’ perceptions of computer education for a business program at the three-year diploma level. This study has examined the learning environment and informed practice by presenting differentiation and diversity mainly due to different mode of delivery in a college computer course. This study aims to provide a detailed understanding of the similarities and differences of college students attending online class versus face-to-face class taught by the same professor. It examines students’ perceptions of course design and delivery, their attitudes and beliefs about acquisition of computer applications, and their academic achievement as measured by the test scores. Mixed methods are employed to investigate the research questions both in depth and in breadth. In the Fall of 2009, 60 out of 89 eligible participants filled out the online questionnaire resulting in the response rate of 67% and six students participated one-on-one in-person interviews. Results from both quantitative and qualitative studies show that there is no significant difference between the face-to-face and online students with respect to their perceptions, attitudes, motivation, and learning outcomes. The findings demonstrate that there was no evidence showing difference between online learning and face-to-face learning. The different learning modes provide students with positive learning experiences. This study provides stakeholders such as students, college administrators, and professors with a detailed and meaningful understanding of the important learning environments for the online and face-to-face classes. The implications from the findings will help to enhance, advance, and expand face-to-face and online education at both the theoretical and practical level.