Blended Learning Versus the Traditional Classroom Model

The purpose of this action research project was to determine the effectiveness of blended learning in the classroom compared to the traditional, direct instruction approach. Two sections of sixth grade math went through the same unit with one section using the blended learning model and the other section participating in the direct instruction model. Data was collected quantitatively using a pre-assessment and post-assessment, as well as, qualitatively using informal questioning and observations. Analysis of the data suggested that students in the blended classroom increased their learning more than the direct instruction classroom. Also, students participating in blended learning were observed collaborating with their peers more often, engaging with the material and taking ownership of their learning, and asking deeper, more thoughful questions

Functions of the Mineralocorticoid Receptor in the Hippocampus.

In the central nervous system, glucocorticoids influence neuroendocrine function, cognition, neurogenesis, neurodegeneration, and cell survival. Glucocorticoid hormones signal through the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), closely related members of the steroid hormone receptor superfamily. Their expression profiles and modes of action suggest both overlapping and distinct functions in mediating glucocorticoid effects. As GR function has been widely examined, research in this thesis focuses on the roles of MR action in the central nervous system using both in vivo and in vitro approaches. First, we generated a transgenic mouse model that overexpresses MR in the forebrain (MRov). Relative to wild-type littermate controls, MRov mice display reduced anxiety-like behaviors and exhibit suppressed HPA axis activity in response to stress. These data demonstrate that functions of forebrain MR can both overlap (regulation of neuroendocrine function) and oppose (modulation of anxiety-like behavior) GR-mediated actions. Second, we utilized the mouse hippocampal cell line, HT-22, to address corticosteroid receptor-mediated effects on both cell survival and regulation of transcription in an in vitro system. HT-22 cells express GR but not MR, and have been shown to be sensitive to glutamate toxicity in a manner that is exacerbated by activation of GR. To address the role of MR in this “glucocorticoid endangerment”, we generated stable clones of HT-22 cells that express MR in addition to GR. Using these cell lines, we confirmed that while GR activation enhanced glutamate toxicity, the co-activation of MR and GR in the HT-22/MR clone attenuated the glucocorticoid endangerment of the cells. Finally, MR- and GR-mediated regulation of glucocorticoid responsive genes was monitored at the transcriptome level in HT-22/Parent and HT-22/MR cells. This research demonstrated that co-activation of MR and GR resulted in the regulation of a substantially larger set of genes relative to GR activation alone, including classes of genes known to regulate cell survival and proliferation, suggesting that changes in the balance of receptor levels may result in functionally significant alterations in global transcriptome regulation. Together, these data reveal important overlapping and distinct roles for hippocampal MR and GR.Ph.D.Cellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/58376/1/arozebo_1.pd

Extracellular Heparan 6-<i>O</i>-Endosulfatases SULF1 and SULF2 in Head and Neck Squamous Cell Carcinoma and Other Malignancies

Pan-cancer analysis of TCGA and CPTAC (proteomics) data shows that SULF1 and SULF2 are oncogenic in a number of human malignancies and associated with poor survival outcomes. Our studies document a consistent upregulation of SULF1 and SULF2 in HNSC which is associated with poor survival outcomes. These heparan sulfate editing enzymes were considered largely functional redundant but single-cell RNAseq (scRNAseq) shows that SULF1 is secreted by cancer-associated fibroblasts in contrast to the SULF2 derived from tumor cells. Our RNAScope and patient-derived xenograft (PDX) analysis of the HNSC tissues fully confirm the stromal source of SULF1 and explain the uniform impact of this enzyme on the biology of multiple malignancies. In summary, SULF2 expression increases in multiple malignancies but less consistently than SULF1, which uniformly increases in the tumor tissues and negatively impacts survival in several types of cancer even though its expression in cancer cells is low. This paradigm is common to multiple malignancies and suggests a potential for diagnostic and therapeutic targeting of the heparan sulfatases in cancer diseases

Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM