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Src Kinase Activation in Pulmonary Arterial HypertensionPrewitt, Allison Renee 07 July 2015 (has links)
Heritable Pulmonary Arterial Hypertension (HPAH) is a rare, fatal disease of the pulmonary vasculature for which there is no cure. The majority of HPAH patients inherit mutations in the BMP type 2-receptor gene, BMPR2, but how these promote pulmonary vascular disease is unclear. In this work, we show BMPR2 mutations promote Src-kinase activation pulmonary endothelial cells (PECs) isolated from Bmpr2 mutant mice. We show increased Src activation leads to endothelial barrier defects due in part to enhanced Src-mediated caveolar endocytosis and that these defects can be rescued using Src kinase inhibitors. We go on to show that pulmonary endothelial cells and late outgrowth endothelial progenitor cells isolated from idiopathic PAH patients show similar increases in Src kinase activation suggesting that Src kinase activation may be a common disease mechanism in PAH. Therefor, these studies provide evidence for the use of Src kinase inhibitors in the treatment of pulmonary arterial hypertension.
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Tumor suppressor mechanisms of the polarity protein Par3Guyer, Richard Allen 17 July 2015 (has links)
Proteins that regulate cell polarity are fundamental for metazoan biology and are necessary for proper development of tissues and organs. In light of polarity genes fundamental role in tissue organization, disruptions in polarity networks have been suspected to promote neoplasia. Studies in Drosophila melanogaster models and correlative data from human tumor samples have supported this hypothesis, but direct experimental support for polarity genes as mammalian tumor suppressors has only recently been reported. The polarity regulator Par3 has emerged as a suppressor of growth and metastasis in mammary and skin tumors. The mechanisms by which Par3 restrains tumor progression, however, remain obscure. In the studies reported here, I show that loss of Par3 can promote activation of an oncogenic signaling pathway in mouse mammary cells by permitting aPKCι/λ to activate NF-κB signaling. These studies demonstrate that preventing aberrant aPKC activity is a key tumor suppressor function of Par3. This mechanism may be relevant to human tumors.
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Speech-language pathologists' input to toddlers in early intervention| A pilot studyWilley, Tanya 23 July 2015 (has links)
<p> Caregivers interacting with young children in natural settings have been found to provide language input that is in tune with the child's output in terms of mean length of utterance (MLU). Previous research suggests that caregivers provide language input within the child's proximal zone of language development, that is 2.0-3.0 morphemes ahead of their child's MLU. The purpose of this exploratory study was to investigate whether speech-language pathologists (SLP) working in early intervention tailor their input in the same way. </p><p> Communication interactions between six speech-language pathologists and their toddler aged clients between the ages of 28 and 33 months were audio recorded during one of their regularly scheduled speech and language intervention sessions. MLUs for the SLPs and the children were calculated for each intervention dyad via the Systematic Analysis of Language Transcripts (SALT) version 2012 computer software program. The MLU of each SLP was then compared to the MLU of her client. Data analysis revealed that three of the six SLPs directed their language input to the child at levels within the child's proximal zone of language development, between 2.0 and 3.0 morphemes greater than the child's MLU. The other three SLPs provided input at levels that exceeded the 2.0 to 3.0 morpheme range. Qualitative analysis suggest that factors other than the children's MLUs, such as their language comprehension levels, may have been a factor in the complexity levels of the SLPs input. Future research, employing larger sample sizes and careful measures of the children's language comprehension and cognitive levels, is indicated.</p>
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Identification and characterization of MAFA coregulators: MLL3/4 and its role in mouse and human islet β-cellsScoville, David William 23 July 2015 (has links)
CELL AND DEVELOPMENTAL BIOLOGY
Identification and characterization of MAFA coregulators: MLL3/4 and its role in mouse and human islet β-cells
David William Scoville
Dissertation under the direction of Professor Roland Stein
Pancreatic islet β-cells are critical regulators of glycemic control, and their dysfunction or absence leads to Diabetes Mellitus. Several transcription factors play crucial roles in the development of functional β-cells, including the transcription factor MafA. MafA expression is restricted to islet β-cells in the pancreas where it regulates postnatal β-cell maturation and function in the mouse. However, little is known about the mechanisms through which MafA regulates its target genes. The goal of this dissertation work was to identify coregulators which interact with and contribute to the function of the MafA transcription factor. Utilizing an unbiased proteomics approach in a mouse β-cell line, I identified several potential coregulators of MafA that could control the many activities associated with this protein, including β-cell proliferation and glucose-stimulated insulin secretion. Among them were the mixed-lineage leukemia 3 and 4 (Mll3/4) complexes, known for their role in histone 3 lysine 4 (H3K4) methylation and gene activation. MafA was bound to the Mll3/4 complexes in experiments performed with size fractionated β-cell extracts and by immunoprecipitation analysis. Likewise, the MLL3 and MLL4 complexes bound human MAFB, which is closely related to MAFA, important to mouse β-cell development, and co-produced with MAFA in adult human islet β-cells. Knockdown of NCOA6, a core subunit of these methyltransferases, reduced expression of only a small subset of MAFA and MAFB target genes in mouse and human β-cell lines. In contrast, a more profound effect on MafA/MafB gene activation was observed upon NCoA6 deletion specifically in embryonic β-cells using rat insulin promoter-driven Cre. We propose that this broader impact is due to the coordinated recruitment of the Mll3/4 complexes by MafB during development and MafA postnatally. Future studies may elucidate the context-dependent mechanisms involved in regulating MAFA and MAFB coregulator binding. This may allow for development of therapeutic strategies for enhancing β-cell function and mass in the treatment of diabetes.
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The Role of Retinoic Acid Signaling in Acute Kidney InjuryChiba, Takuto 05 June 2015 (has links)
Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of acute kidney injury (AKI), but little is known about whether and how this pathway is normally regulated, and what role it plays in regulating injury and repair after AKI. In these studies we show that RA signaling is activated in mouse and zebrafish models of AKI, and that these responses limit the extent of injury and promote normal repair. These effects are mediated through a novel mechanism by which RA signaling coordinates the dynamic equilibrium of pro-inflammatory M1 spectrum vs. alternatively activated M2 spectrum macrophages. According to this model, direct repression of pro-inflammatory macrophages by locally synthesized RA reduces macrophage-dependent injury post-AKI, while locally synthesized RA activates RA signaling in injured tubular epithelium, which in turn promotes alternatively activated M2 spectrum macrophages. Since RA signaling plays an essential role in kidney development but is repressed in the adult, these findings provide evidence of an embryonic signaling pathway that is reactivated after injury and plays an important role in reducing injury and enhancing repair after AKI.
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Dominant and Context-Specific Control of Endodermal Organ Allocation by Ptf1aWillet, Spencer Gaffney 10 October 2014 (has links)
CELL AND DEVELOPMENTAL BIOLOGY
Dominant and Context-Specific Control of Endodermal
Organ Allocation by Ptf1a
Spencer Gaffney Willet
Dissertation under the direction of Professor Christopher V.E. Wright
The timing and gene-regulatory logic of organ-fate commitment from within the posterior foregut of the mammalian endoderm is largely unexplored. Transient misexpression of a presumed pancreatic-commitment transcription factor, Ptf1a, in embryonic mouse endoderm (Ptf1aEDD) dramatically expanded the pancreatic gene regulatory network within the foregut. Early-stage Ptf1aEDD rapidly expanded the endogenous endodermal Pdx1-positive domain, and recruited other pancreas-fate-instructive genes, thereby spatially enlarging the potential for pancreatic multipotency. Early Ptf1aEDD converted essentially the entire glandular stomach, rostral duodenum, and extrahepatic biliary system to pancreas. Sliding the Ptf1aEDD expression window through embryogenesis revealed differential temporal competencies for stomach-pancreas respecification. The response to later-stage Ptf1aEDD changed radically towards unipotent, acinar-restricted conversion.
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Adapting Parent-Child Interaction Therapy to Train Wilderness Therapy Camp StaffSyzdek, Brian M. 29 October 2014 (has links)
<p> Wilderness therapy camps have been found to be effective for treating a number of youth issues and for generally improving youth functioning. In addition, wilderness therapy camps appear to address current treatment needs of reducing stigma in treatment and providing other benefits, such as physical and social health benefits. However, currently wilderness therapy camps lack systematic training for staff that has been deemed efficacious, utilizing evidence-based techniques. Parent-Child Interaction Therapy (PCIT) is an evidence-based therapy (EBT) for use with children with a variety of issues and backgrounds and in diverse settings, useful for reducing child problematic behaviors. Efforts have been made to expand the use of PCIT in a variety of settings, with promising results. </p><p> This dissertation proposes to describe how PCIT might be adapted to train wilderness therapy camp staff in evidence-based methods for working with youth, especially those with mental health needs, such as behavioral issues. The literature concerning PCIT and wilderness therapy camps is reviewed. A needs assessment was conducted, consisting of interviews with key informants, experts in the field of wilderness therapy, PCIT, and training methods. Based on information obtained, a full program for training camp staff, called Counselor-Camper Interaction Training (CCIT) is proposed. Finally a proposal to evaluate the efficacy of this program is put forth. As part of the proposed evaluation, a financial assessment was conducted on the program, with the results presented. </p>
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The Relationship Between Adoptive Parents Attachment and Parenting Styles on Adoption OutcomesHarkins, Courtney Amanda Ball 29 October 2014 (has links)
<p> Raising an adopted child from the child welfare system poses unique challenges because these children bring with them an increased risk for developmental and mental health problems (Simmel, 2007; Whitten & Weaver, 2010). Adoptions from Child Welfare have almost doubled in the last decade, comprising up to 41% of all adoptions (Child Welfare Information Gateway, 2012). Of these adoptions, anywhere from 10% to 25% end up disrupting (Briggs & Webb, 2004; Festinger, 2002; Rosenthal & Groze, 1994; Smith & Howard, 2000). Thus, it is important to identify and understand which factors can likely increase adoption success or which ones are more likely to create barriers. Currently, there are some studies that have identified specific adoptive child traits that increase disruption (Barth, 1997; Barth & Berry, 1988; Evan B. Donaldson Adoption Institute, 2010; Rosenthal & Grove, 1990) along with some family factors (Barth, 2000; Coakley & Berrick, 2008; Festinger, 2002). However, two important family systems aspects, involving qualities that the adoptive parent themselves bring to the process, have thus far been overlooked in the research: attachment styles and parenting styles. In order to shed more light on this neglected aspect of the adoptive process, this study investigated whether or not there was a relationship between an adoptive caregiver's own attachment style or parenting style and adoption outcomes. The logistic regression method was used in the analysis of a convenience sample of 113 adoptive parents and it was found that two parental factors were the most influential in predicting adoption outcomes: anxious attachment style and authoritative parenting style. Additionally, incidence of trauma in the parent's history was identified as a factor that negatively impacted the chance of adoption success. The implications or clinical practice and research are discussed.</p>
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The Role of Parental Involvement in the Social Development of Children with Autism Spectrum DisordersMulder, Emile Christian 06 November 2014 (has links)
<p> Autism spectrum disorders (ASD) are characterized by deficits in social interaction. Research with ASD children has dramatically underrepresented fathers, who have only recently been considered as targets for parenting interventions and research. Parenting research with typically developing (TD) children has found that parental involvement (of mothers and fathers) is associated with child social development. Extending such findings to the ASD field is important as social development is a primary concern within this population. The present study sought to do so through an internet questionnaire targeting mothers and fathers. Specifically, this study examined associations between mother involvement, father involvement and their interaction with child social skills in families of children with ASD using multilevel modeling in a multi-rater, multi-measure design. We proposed a model in which parental involvement may foster child social development, but also noted child that social skills may encourage or discourage parental involvement. Father, but not mother, involvement (quality) and engagement (time) were each found to significantly and positively predict child social skills in 101 families of children with ASD. Implications of these findings for research and intervention are discussed.</p>
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Dissecting the spatiotemporal regulation of nodal signaling and its role as a morphogenetic cueHalstead, Angela Marie 06 November 2014 (has links)
The TGF-â ligand Nodal is a key regulator of body axis formation and patterning in the developing vertebrate embryo. How the Nodal signaling pathway is activated and regulated, and how precise spatiotemporal control of the pathway is translated into morphogenetic cues for asymmetric morphogenesis is unclear. Attempts to gain insight into the dynamics of active Nodal signaling have been hindered by the inability to detect the endogenous Nodal ligand. Antibodies against the signal transducer phospho-Smad2 (pSmad2) have been used to detect active TGF-â signaling, but are of poor quality and cannot accurately depict Nodal signaling in situ. We generated a new pSmad2 antibody, with the goal of using it to create a spatiotemporal map of Nodal signaling during development. We planned to integrate such maps with our data showing increased F-actin labeling in the R LPM, and possible L vs. R cell shape differences, just prior to organ looping to aid in understanding how Nodal signaling directly translates into morphogenetic cues.
Fully understanding the role of Nodal signaling in morphogenesis fundamentally includes understanding its regulation at the transcriptional level. Current models have the winged-helix transcription factor Foxh1 bound with pSmad2 as a central transcriptional activator of Nodal. However, a conserved Engrailed-homology-1 (EH1) motif, which is recognized by Groucho co-repressors, in Foxh1 suggests that Foxh1 functions as a transcriptional switch, toggling between transcriptional on and off states via pSmad2-Grg switching, to ensure properly timed initiation and suppression, and/or amplitude, of Nodal. We minimally mutated the Foxh1 EH1 motif, creating a novel Foxh1mEH1 allele to test the contribution of Foxh1-Grgmediated repression on the transient, dynamic pattern of Nodal signaling in mice. We find that Foxh1-Grgmediated repression is not essential for Nodal expression during mouse embryogenesis. This suggests that other regulators compensate for the loss of Foxh1-Grgmediated repression, and that Nodal signaling exists within the context of a strongly buffered regulatory system that contributes to resilience and accuracy of its dynamic expression pattern.
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