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Owing to the presence of muscle stem cells (MuSC), adult skeletal muscle is capable of regenerating after injury. Quiescent muscle stem cells become activated and proliferate into myoblasts which undergo myogenic differentiation to repair damaged tissue. The transcription factor (TF) Six1 is a known regulator of muscle stem cells which potentially plays a role in the early stages of MuSC activation. When bound to the appropriate cofactor, Six family transcription factors are capable of activating or repressing transcription. Previous work suggests that Six1 establishes the accessibility landscape required for the myogenic regulatory factor (MRF) MyoD to bind to DNA. It was hypothesized that Six1 recruits p300 to acetylate Histone H3 lysine 122 which then renders DNA more accessible and facilitates gene transcription. The objective of this research was to investigate the role of Six1 in regulating the epigenetic and accessibility state of DNA in myoblasts. It was found that Six1 and the histone acetyltransferase p300 coincide at many gene enhancers. In addition, Six1 knock-down is associated with reduced DNA accessibility at a large number of loci in C2C12 myoblasts and with gene downregulation. In this research, we determined that recruitment of p300 by Six1 alters chromatin accessibility and gene expression in proliferating myoblasts, providing evidence of Six1 pioneer factor activity.

<p>  </p> <p>The purpose of this research was to understand: (1) how students perceive a polytechnic high school model in relation to students’ college and career readiness, as well as (2) the challenges and successes that this type of school model presents, from the student perspective, after attending a semester of higher education at the model's collaborating university. To address these two research objectives, the authors conducted a case study of a novel public-charter high school developed by a state’s flagship research-intensive university in partnership with community, industry, and academic leaders. What makes this polytechnic high school model unique is its focus on supporting urban youth to pursue passions through science, technology, engineering, and mathematics (STEM) focused experiences, that are situated within industry-driven, hands-on projects, and a personalized learning environment. More specifically, this study examined the perceptions of this polytechnic high school model from its active senior class as well as its first graduating class after matriculating to the collaborating university. This study was conducted to better comprehend the model in relation to students’ college and career readiness (defined here as 21st century skills [creativity, communication, and collaboration], sense of belonging, and college/career intent). This was achieved by analyzing beginning of the year survey results from one school’s current seniors, as well as administering pre- and post-surveys to graduates of the unique polytechnic high school as students began and ended their first semester of post-secondary education at the collaborating university. In addition, data were obtained from a focus group with the alumni after completion of the first semester at the collaborating university. The resulting data were then analyzed to identify the participants perception of the innovative school model in relation to students’ 21st century skills, sense of belonging, college/career intent, as well as determining the challenges and successes encounter after transitioning to the collaborating university. While this research discusses the outcomes of a case study specifically focused on a polytechnic high school that is an innovative school-university collaborative model, the resulting data can be used to provide more information surrounding innovative educational approaches so that schools, educators, and other educational stakeholders have the necessary information needed to make informed decisions as they attempt to transform secondary learning experiences in response to societal changes.</p>

<p>I want delay publication of my dissertation until April 30 2013. Thanks.</p> / <p>Strontium titanate (SrTiO₃) has a wide range of applications in the electronic industry and attracts growing world-widely interest recently because of novel discoveries at its surfaces, interfaces and with selected dopants. The understanding of some of the structural properties of SrTiO₃ and its optical properties have been lagging due to limited characterization techniques available to study single monolayers and dopants in this material.</p> <p>In the present thesis, pure SrTiO₃ single crystals with (2x1) and c(4x2) surface patterns were synthesized and samples (Pr, Al) doped SrTiO₃ were prepared through ion implantation. The atomic and electronic structures of these samples were investigated by various high-resolution imaging and spectroscopic techniques available in an aberration-corrected transmission electron microscope. Particularly, the direct imaging of individual light atoms and vacancies within a bulk material containing heavier elements was demonstrated for the first time via the STEM-annular dark-field (ADF)/annular bright-field (ABF) images. In addition, the first electron energy-loss spectroscopy (EELS) 2-dimensional maps of dopants located in a lattice were obtained. These results provided a solid foundation regarding the mechanism of red light emission in doped SrTiO₃. More importantly, a new experimental approach allowing the effective extraction of weak EELS signals from low-dimensional defects was developed and successfully applied to understand the chemical state and coordination of Ti cations within a single monolayer on a reconstructured SrTiO₃surface and the local defect configurations of injected Pr⁺ and Al⁺ ions within SrTiO₃ single crystals.</p> / Doctor of Philosophy (PhD)

The study of cardiac regeneration can have many forms in which it is defined. It can not only be the ability to add new myocardium to dead or dying tissues, but also include the prevention of cardiac tissue degeneration, reversal of tissue remodeling, and the maintenance of systolic and diastolic function in the incidence of tissue damage, which can lead to subsequent heart failure progression. The use of stem cells for cardiac regeneration represents a growing field of new therapies for patients with end stage cardiac disease. Various studies have noted promising results in the recovery and reparation of these tissues. Cumulatively, their goals have become the identification of the most suitable cell type, as well as how to maximize functional efficiency and cost effectiveness for practical application. Many protocols simply do not ensure adequate cell engraftment, viability, and ultimately the return of normal tissue function. Investigators seek to determine how these processes can be enhanced or manipulated to promote cardiac regeneration in hopes of eventually making their clinical use a standard practice. / Physiology

Pluripotent stem cells (PSCs) are unique in their capability to self-renew and differentiate into cell types of all three embryonic germ layers. Since their discovery, PSCs have become an indispensable tool for modeling development, disease onset/progression, and drug discovery. The pluripotent state is known to be regulated by a core network of transcription factors including Oct4, Sox2, and Nanog. However, the roles of other contributing transcription factors remain understudied. Our research focused on defining the roles and molecular mechanisms of Rex1, a zinc finger transcription factor whose expression is strongly correlated with the pluripotent state. Attempts by our lab to elucidate the role of Rex1 in embryonic stem cells (ESCs) revealed the presence of two smaller protein products that result from the initiation of translation at downstream start codons within the REX1 open reading frame. We hypothesized that the full-length Rex1 protein and its shorter alternative translation isoforms were acting to regulate the expression of lineage-determining genes in PSCs. To evaluate this hypothesis, we generated mouse embryonic stem cell (mESC) lines expressing FLAG-tagged versions of the full-length Rex1 protein, and its isoforms, from the endogenous locus. Through the use of these lines, we demonstrated the formation of multiple Rex1 isoforms by alternative translation, a novel observation that has yet to be reported. Furthermore, our results indicate that Rex1 is a negative regulator of differentiation-related genes and endogenous retroviral elements, suggesting Rex1 is acting to maintain the tightly regulated transcriptional network of pluripotency, while also maintaining genomic integrity through the repression of repetitive elements. / Thesis / Master of Science (MSc)

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Out of the four molecular subgroups (WNT, SHH, Group 3 and Group 4), Group 3 patients face the highest incidence of leptomeningeal spread and overall patient survival of less than 50%. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naïve tumors, provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumors. The paucity of patient matched primary and recurrent MB samples has contributed to the lack of molecular targets specific to medulloblastoma recurrence, limiting relapsing MB patients to palliation. Our previous in silico analyses revealed enriched expression of many stem cell self-renewal regulatory genes in Group 3 MB. In this work, I have set out to investigate whether by identifying genes contributing to self-renewal of Group 3 MB cells, we can characterize a population of cells responsible for therapy evasion and subsequent tumor relapse. Initially, we have adapted the existing COG (Children’s Oncology Group) protocol for children with newly diagnosed high-risk MB for treatment of immuno-deficient mice intracranially xenografted with human MB cells. Cell populations recovered separately from brains and spines mice during the course of tumor development and therapy were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy. Additionally, we have investigated therapeutic potential of small molecules targeting BMI1, a known self-renewal regulating gene. In the setting of recurrent Group 3 MB, pharmacological inhibition of BMI1, led to a remarkable decrease in cell proliferation and self-renewal in vitro as well as reduction of local and spinal metastatic disease in vivo. Finally, by combining the established therapy-adapted patient-derived xenograft mouse model and BMI1 inhibitor, PTC-596, we have demonstrated an additive effect of two modalities and provided the pre-clinical data for the upcoming Phase I trial. Biological investigations into the drivers of MB recurrence will lead to development of new therapeutic options for children who are frequently limited to palliation. Clinically relevant mouse models of MB recurrence can serve as platforms for pre-clinical testing and validation of new treatments aimed to provide therapeutic intervention rather than palliation. / Thesis / Doctor of Philosophy (PhD) / Medulloblastoma is the most common type of brain cancer that affects children. Out of the four main subgroups of medulloblastoma, tumors in Groups 3 and 4 are the most aggressive and are associated with a low overall survival in children diagnosed with this type of brain cancer. These two subtypes of medulloblastoma also account for the largest number of patients in which gold standard therapies fail and no additional therapies are available. Several studies have shown the existence of few cells within the tumor that alone can drive tumor growth. The aggressive behavior of these cells has in part been attributed to dysregulation of genes involved in cell replication and division. Further studies that will focus on understanding the significance of genes that regulate cell growth and replication can help discover a population of cells that is capable of evading therapy and contribute to tumor relapse. The identification and characterization of such population can lead to development of novel treatments for the children affected with aggressive medulloblastoma. In my thesis, I have developed a mouse model that replicates the aggressive therapy given to the medulloblastoma patients in order to study cells capable of escaping the harsh treatment and drive tumor comeback. Next, by profiling the gene expression and functional attributes of those cells, we identified genes that contribute to regulation of cell division and growth. The effects of both increasing and decreasing the activity of those genes were then tested in cells grown in the dish. Subsequently, the most promising results were verified in the established mouse models. The main objective of my thesis was to discover new opportunities in treatments the most aggressive type of brain cancer affecting children, and thus not only improve the quality of treatment but also the overall survival of patients with medulloblastoma.

Chapter 1: The pluripotent state is maintained by a network of “core” transcription factors (TF). REX1 (Reduced Expression-1) is a pluripotency related TF derived from retrotransposon-mediated duplication of the zinc finger TF Yin Yang 1 (YY1). Furthermore, expression of REX1 and YY1 induces changes in genes regulated by endogenous retroviral elements (ERV), suggesting an evolutionary origin of REX1 for ERV regulation. Studies suggest that murine REX1 may act in epigenetic regulation of gene expression and ERVs, but the precise mechanism remains unelucidated, so we generated FLAG-tagged REX1 pluripotent stem cell (PSC) lines, as well as a series of truncation mutants to explore the REX1 function. Our studies indicate the presence of previously undescribed isoforms of the full-length REX1 protein, suggesting that regulation by REX1 may be more complex than initially appreciated. We hypothesize that REX1 regulates the expression of a sub-set of ERVs and REX1 isoforms regulate REX1 target genes in pluripotent stem cells. Previously, we performed REX1 ChIP-seq and found enrichment for REX1 binding at specific ERVs. Here, we show that differential expression of REX1 isoforms do not change the expression of ERVs. Furthermore, our REX1 KO lines show changes in expression of ERV family members and together with the ChIP data, suggest that REX1 may act as a negative regulator of some retroviral elements. However, further experiments reveal a potential compensation of REX1 KO, possibly by the homologous factors YY1 and YY2. Due to the limited nature and time constrain of our study, we did not find conclusive evidence to further elucidate the potential compensation mechanism and the characteristics of the REX1 isoforms. Our work provided a new avenue for exploring the functional importance of REX1 isoforms and the potential, YY1 and YY2 independent, regulatory role REX1. Chapter 2: Mitotic bookmarking describes a potential mechanism involved in the stable propagation of cellular identity through the cell cycles. Candidate based studies have identified mitotic bookmarking factors (MBFs) that are retained on the mitotic chromatin and preserve the transcriptional memory of the cell. Nevertheless, there is a poor understanding of which proteins can serve as MBFs, as well as the chromatin dynamics of bookmarked sites during mitosis and the start of G1 phase. Previously, we designed a chromatin immunoprecipitation followed by mass spectrometry (ChIP-MS) assay to develop a global unbiased approach for identifying and characterizing novel MBFs. Using ChIP-MS, we identifed putative MBFs associated with the mitotic chromatin in pluripotent stem cells (PSCs) and used ATAC-seq to identify subsets of pluripotency-associated accessible gene regions that appear to be bookmarked by a variety of transcription factors, including PARP1, PSIP1, and HDGF. Here, we characterize the interaction of a putative MBF, not found in our ChIP-MS screen, NFYa, with PARP1 and, inconclusively, another putative MBF, DNMT1. Furthermore, we found that PWWP containing putative MBF, HDGF, has a potential role in pluripotency maintenance but it is not mitosis-specific. Due to the limited nature and time constrain of our study, we did not find conclusive evidence to establish the role of PSIP1 in PSC mitotic bookmarking. Our work provided a new avenue for exploring the functional importance of mitotic bookmarks in pluripotent maintenance. / Thesis / Master of Science (MSc)

Persistently high attrition rates from STEM majors present a stubborn challenge for researchers, administrators, and faculty alike. To approach this problem, my dissertation examined the socialization processes by which students develop a sense of belonging to both their institution and their discipline. Previously identified as an important factor in students' persistence and overall satisfaction with their undergraduate experience, belonging is a critical piece of the retention puzzle. However, not every student experiences or develops belonging in the same way. This dissertation applied the theoretical lens of socialization to deepen the understanding of how social interactions help or hinder students' belonging to their university and chosen major alike. My dissertation work was grounded in the synthesis of two theoretical frameworks: Conrad et al.'s (2006) model of socialization and Strayhorn's (2018e) conceptualization of sense of belonging. The study took the form of an embedded case study of two similar disciplinary contexts within a large public land-grant Research 1 institution, with four students from each context for a total of eight participants. By leveraging four years of interview data from each participant, supported by institutional documentation, I addressed the question: In what ways does a student's socialization experience influence, if at all, their sense of belonging to both their chosen discipline and their university? Data analysis included qualitative coding, trajectory mapping, and thematic analysis. Trajectories were produced for each participant before expanding the analysis to examine patterns across and between the contexts. My findings addressed the mechanisms of socialization at the undergraduate level and how they evolved over time. The primary outcome of my work was a set of three distinct socialization trajectories, named the Anchored, who built strong socializing relationships early and maintained them throughout their undergraduate years; Independents, who neither sought nor wanted such relationships; and Wanderers, whose socializing relationships tended to be short-lived and inconsistent, although desired. Fourteen unique groups of socializing agents were identified, along with five common drivers for intentionally engaging with specific agents: personal and academic support, research and industry aspirations, and finding a path. Pre-college socialization experiences were salient for developing anticipatory belonging, as students who were exposed to their discipline or institution prior to arriving as students had an easier time becoming integrated to their communities. Once students arrived, their socialization trajectories tended to shape their feelings of belonging to the institution, with close ties forming for the Anchored, appreciation for general support among the Independents, and a mix of happiness and frustration for the Wanderers. By contrast, disciplinary belonging was more reliant on the individual participant's goals and interests. Disciplinary differences between the two contexts were identified but were limited in scope and generally linked to the career outcomes students associated with their chosen major rather than their experiences in the major. Finally, my research revealed that a strong sense of belonging in one domain of undergraduate life could be sufficient for a student to persist to degree completion despite weak or absent feelings of belonging in other areas. / Doctor of Philosophy / For decades, students have been leaving STEM majors at alarmingly high rates despite the efforts of researchers, administrators, and faculty. To approach this problem, my dissertation examined how social interactions and relationships can help students feel like they belong in their chosen major and university. Previous research identified such feelings of belonging as an important factor in helping students persist to the completion of their degrees, and my work added onto this body of work by specifically examining the role of students' social connections. My dissertation utilized data from eight total students. Four of the students were chemical engineering students, with the remaining four from chemistry and biochemistry, together called the "chemical sciences." The data for this work included four years of interview data supported by institutional documents. Such documents provided information like curricular requirements, demographic and population information, and course information, which helped provide background for the students' interviews. Leveraging these data, I addressed the aforementioned interaction of students' social interactions and their feelings of belonging on campus and in their major. My data analysis was based around the creation of trajectories that would capture the evolution of a student's experiences over the course of their undergraduate career. Once trajectories were generated for each student, I was then able to look across the trajectories and identify patterns between and within them. The primary finding of my dissertation work was the emergence of three distinct patterns of how students' social interactions evolved over time, labeled the Anchored, who built strong and consistent networks that they maintained over two or more years; the Independents, who neither sought nor wanted such relationships; and the Wanderers, who had relationships and interactions that were often short-lived or inconsistent, but wanted more. Fourteen unique groups with whom students interacted were identified, along with the respective impacts said groups could have on students' feelings of belonging. Additionally, five drivers for seeking out interaction with these groups were identified: personal and academic support, research and industry aspirations, and finding a path. The experiences students had with their university or major prior to enrolling were found to be important for shaping the way students perceived their future, and those with greater exposure to their institution or discipline had an easier time seeing themselves fitting in and finding a place for themselves on campus once they enrolled. Once students arrived, their trajectory of interaction tended to shape how they felt about their institution, with close ties forming for the Anchored, appreciation for general support among the Independents, and a mix of satisfaction and frustration for the Wanderers. By contrast, belonging within the discipline was more reliant on the individual participant's goals and interests. Disciplinary differences between the two contexts were identified but were limited generally linked to the career outcomes students associated with their chosen major rather than their experiences in the major. Finally, my work revealed that when students felt like they belonged in one area of their undergraduate life, those feelings could support lacking feelings in other areas, helping them to persist to graduation.

Improving chemical transport models for atmospheric simulations relies on future developments of mathematical methods and parallelization methods. Better mathematical methods allow simulations to more accurately model realistic processes and/or to run in a shorter amount of time. Parellization methods allow simulations to run in much shorter amounts of time, therefore allowing scientists to use more accurate or more detailed simulations (higher resolution grids, smaller time steps). The state-of-the-science GEOS-Chem model is modified to use the Kinetic Pre-Processor, giving users access to an array of highly efficient numerical integration methods and to a wide variety of user options. Perl parsers are developed to interface GEOS-Chem with KPP in addition to modifications to KPP allowing KPP integrators to interface with GEOS-Chem. A variety of different numerical integrators are tested on GEOS-Chem, demonstrating that KPP provided chemical integrators produce more accurate solutions in a given amount of time than the original GEOS-Chem chemical integrator. The STEM chemical transport model provides a large scale end-to-end application to experiment with running chemical integration methods and transport methods on GPUs. GPUs provide high computational power at a fairly cheap cost. The CUDA programming environment simplifies the GPU development process by providing access to powerful functions to execute parallel code. This work demonstrates the accleration of a large scale end-to-end application on GPUs showing significant speedups. This is achieved by implementing all relevant kernels on the GPU using CUDA. Nevertheless, further improvements to GPUs are needed to allow these applications to fully exploit the power of GPUs. / Master of Science