<p> This study explores the psychological dynamics associated with labor and birth in order to better understand the role these experiences play in women&rsquo;s psychological development. This research study utilized interpretative phenomenological analysis as a research methodology and sought to address the following questions through the theoretical perspective of psychoanalysis and social constructionism: How does the experience of pregnancy and birth impact the subjectivity of women? How do women make sense of these experiences? What role does the body play in women&rsquo;s psychological development? Does the experience of childbirth mark a unique developmental phase in the psychological life of women? In this research study, six women were asked to describe their birth narrative in full and respond to a series of open-ended questions. The results of this study indicate that pregnancy and childbirth is a porous developmental period associated with fears about capacity and feelings of omnipotence as well as multiple losses and a new sense of self. One of the more significant findings of this study is that the experience of labor and birth is felt by many women to involve feelings associated with encountering death. This finding may lead to increased understanding of why pregnancy and childbirth results in fragmentation for some women, while it appears to be a catalyst for increased subjectivity and maternal embodiment for other women.</p>

Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. In this dissertation we show that polymeric immunoglobulin receptor-deficient (pIgRâ/â) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodeling and emphysema in pIgRâ/â mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-kappa B activation, leukocyte infiltration, and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgRâ/â mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodeling, while repetitive inhalation of bacterial products exacerbates disease. In addition, we demonstrate that p73 is required for PIGR expression in mice, and that mice lacking p73 also develop airway remodeling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodeling and emphysema. Based on this data, we propose that altered mucosal immunity due to SIgA deficiency contributes to chronic inflammation and airway remodeling in COPD.

<p> The purpose of this project was to explore the mediating effects of social and academic self-efficacy on the relations between bullying role behaviors and academic achievement. Research has primarily focused on the bully and the victim in bullying situations, which neglects to examine the experiences of those who witness or are involved in the aggressive act, including assisting bullies, defending victims, and ignoring others. As a result, research has overlooked how other bullying roles relate to academic performance. However, research has explored how various bullying role behaviors relate to self-efficacy. Additionally, self-efficacy has been associated with academic performance, such as GPA. The purpose of the current study was to add to the existing bullying role behavior literature by investigating the relations among bully participant role behaviors, self-efficacy beliefs, and GPA. This project investigated the mediational effect of social and academic self-efficacy on the relation between bullying role behaviors and GPA. The mediation models were evaluated separately by gender to differentiate this effect in males and females. In other words, does social and academic self-efficacy explain the association between bully participant role behaviors and GPA in males and females? Data were collected on 7^th-grade students (N= 348). In general, most models exploring the association between bullying role behaviors and GPA through social and academic self-efficacy had consistent results in the male and female samples; however, there were some significant results that were supported in females only (victimization experience). When exploring the mediation models, individuals who engaged in bullying, assisting, outsider behaviors or experience victimization had negative associations with social self-efficacy and academic self-efficacy; there were no significant positive associations between defending behavior and self-efficacy. Across all models, social and academic self-efficacy were significantly and positively associated. Additionally, all or most of the models found significant positive associations between academic self-efficacy and GPA and significant and negative associations between social self-efficacy and GPA. The results of the mediational model varied for each bullying role behavior to suggest that an individual&rsquo;s behavior when bullying occurs influences their self-perceptions and GPA differentially. </p>

<p> Abstract of Dissertation The Power of Peers: Do Deviant Peers Facilitate or Suppress Genetic Contributions to Externalizing Behavior During adolescence, children&rsquo;s social norms are increasingly established and enforced by peers. Affiliation with deviant peers at this time is an established risk factor for externalizing behavior, presumably because peers model, encourage, and permit antisocial behavior. What is unclear however is the degree to which deviant peers facilitate the expression of genetically influenced predispositions to externalizing behavior (contextual triggering), or whether peers socialize behavior and suppress genetic predispositions (social control). To examine these questions, a biometric moderation model was employed to examine the degree to which peer deviance moderates genetic and environmental contributions to externalizing behaviors during adolescence. </p><p> Analyses used archived data from the Nonshared Environment and Adolescent Development (NEAD) project. NEAD included a national sample of 708 same sex sibling pairs from never-divorced families and stepfamilies from the USA: monozygotic twin (N=93), dizygotic twin (N=99), and full sibling (N=95) pairs from never-divorced families, and full sibling (N=182), half sibling (N=109), and unrelated sibling (N=130) pairs from stepfamilies. The mean ages of Sibling 1 and Sibling 2 were 14.52 and 12.91, respectively. Mothers and fathers reported on their own perceptions of their adolescents&rsquo; involvement with deviant and prosocial peers (Perceptions of Child&rsquo;s Peers) and on their adolescents&rsquo; engagement in externalizing behavior (Zill Behavior Inventory). </p><p> Analyses indicated that peer deviance moderates genetic and nonshared environmental contributions to adolescent externalizing behaviors. Specifically, at higher levels of peer deviance, genetic contributions to externalizing behavior were stronger, while nonshared environmental contributions were weaker. Shared environmental contributions were significant, but not moderated by peer deviance. These findings are consistent with a contextual triggering model of gene-environment interaction: within the context of deviant peers, the heritability of externalizing behaviors was higher, while nonshared environmental contributions were lower. Therefore, deviant peers appear to enhance the expression of genetic predispositions to externalizing behaviors rather than exert social control. These findings provide insight into the process through which deviant peers affect the development of externalizing behavior.</p>

<p> Although the association between child maltreatment and non-suicidal self-injury (NSSI) has been demonstrated in the literature, additional examination is needed to investigate cognitive processes that contribute to the development of NSSI. Four early maladaptive schemas (Emotional Deprivation, Mistrust/Abuse, Social Isolation/Alienation, and Insufficient Self-Control) have been found to be related to NSSI history (Castille et al., 2007) and have also been investigated as cognitive processes associated with the development of NSSI. The aim of the current study was to test if Emotional Deprivation, Mistrust/Abuse, Social Isolation/Alienation, and Insufficient Self-Control early maladaptive schemas (EMS) statistically predict NSSI in the context of childhood emotional abuse (CEA) and also to test whether the each of the four relevant EMS mediated the association between CEA and NSSI in a community adult sample. Participants were 516 U.S. adults recruited through Amazon Mechanical Turk, aged 18 and 74. Emotional Deprivation, Mistrust/Abuse, Social Isolation/Alienation, and Insufficient Self-Control EMS and CEA severity differed significantly by NSSI history status. Although Emotional Deprivation, Mistrust/Abuse EMS did not statically predict NSSI frequency, Social Isolation/Alienation and Insufficient Self-Control EMS were found to be associated with NSSI history and frequency. As CEA was not associated with NSSI frequency, models investigating Emotional Deprivation, Mistrust/Abuse, Social Isolation/Alienation, and Insufficient Self-Control EMS as mediators of the association between CEA and NSSI frequency were not testable. However, CEA was found to statistically predict NSSI history, and Social Isolation/Alienation and Insufficient Self-Control EMS were identified as mediators of this relationship, although Emotional Deprivation and Mistrust/Abuse EMS were not. These findings can guide treatment providers by identifying relevant EMS, and informing how the related cognitive distortions may be organized, and how cognitive restructuring can be used to target the EMS and related cognitions to decrease triggers and maintenance of NSSI behaviors, especially in the context of CEA.</p>

<p>Male mammals must simultaneously produce prodigious numbers of sperm and maintain an adequate reserve of stem cells to ensure continuous production of gametes throughout life. Failures in the mechanisms responsible for balancing germ cell differentiation and spermatogonial stem cell (SSC) self-renewal can result in infertility. We discovered a novel requirement for Androgen Receptor Trapped clone-27 (ART-27) in spermatogenesis by developing the first knockout mouse model for this gene. Constitutive deletion of ART-27 is embryonic lethal between e5.5 and 7.5 due to defects in extra-embryonic tissues. Conditional knockout in the male germline results in a rapid decline in pre-meiotic germ cell number that starts around day 6-7 post-partum, eventually leading to a Sertoli cell-only phenotype that does not recover in the adult. Gene expression analysis revealed that ART-27 deletion downregulates the transcription of genes governing SSC self-renewal, differentiation, and meiosis. These data are consistent with spermatogenic arrest before meiotic entry and the total lack of germ cells after day 23. Sertoli cell-specific knockout of ART-27 also results in germ cell loss, and we hypothesize this is due to disruption of androgen receptor signaling. Our study has revealed the first in vivo function for ART-27 in the mammalian germline as a regulator of distinct transcriptional programs in SSCs and differentiating spermatogonia.

Programmed cell death (PCD) is an important process necessary for the maintenance of tissues in adult organisms and the crafting of distinct tissues in development. The two main types of PCD, apoptosis and necroptosis (i.e. programmed necrosis), are characterized through differing morphologic presentations and outcomes. Death receptor signaling is a context in which both apoptotic or necroptotic outcomes can occur. Several recent studies implicate proteins involved in apoptotic signaling in the inhibition of necroptosis including Caspase-8, FADD, and cFlipL. Bid, a member of the BCL-2 family of proteins, is cleaved by Caspase-8 which promotes its activation and translocation to the mitochondrion, promoting apoptosis. To evaluate what role Bid might play in the necroptotic arm of death receptor signaling we developed a mouse with Bid and its apoptotic arm of function (Bax and Bak) removed in hematopoietic cells. Loss of these three proteins leads to loss of restraint of necroptosis leading to increased necroptotic death, inflammatory signaling, and perturbation of tissue homeostasis in the hematopoietic and gastrointestinal organ systems. These findings in mice have implications for Myelodysplastic Syndrome, a bone marrow failure disorder characterized by increased PCD, and Inflammatory Bowel Diseases, inflammatory diseases characterized by overwhelming inflammation in the gastrointestinal system.

The Wnt pathway is a highly-conserved pathway that controls many developmental processes and is mutated in many human diseases (e.g., cancer). The tumor suppressor adenomatous polyposis coli (APC) is a critical negative regulator of Wnt signal transduction. Mutations in the APC gene resulting in constitutive activation of the Wnt pathway occur in over 80% of human colorectal cancers (CRC). Despite its critical role in the Wnt pathway, the exact mechanism of APC function in Wnt signal transduction is not clear. The lab developed a monoclonal antibody (mAb7E5) that targets the co-receptor LRP6 and inhibits Wnt signaling in APC-mutant CRC cells. Using the antibody mAb7E5, I found that APC regulates Wnt receptor activation. Furthermore, I found that, in APC-depleted cells, the co-receptor LRP6 is constitutively active in a manner independent of Wnt ligands and that LRP6 is internalized by the clathrin-dependent endocytic machinery. Finally, I demonstrate that APC, clathrin, and the AP-2 adaptor protein interact as a complex. Thus, my studies reveal a new role for APC function in Wnt signal transduction and provide insight into the development of therapeutic agents targeting APC-mutant tumors.

Type 2 diabetes is characterized by failure of pancreatic β-cells to secrete adequate insulin to meet the needs of the body. This β-cell failure is thought to be caused by increased metabolic load due to mounting insulin resistance, but the molecular mechanisms by which this dysfunction occurs are not fully understood. To better understand how β-cells fail, we took a whole-transcriptome approach, collecting RNA-sequencing datasets from purified β-cell populations from several mouse models of β-cell stress. First, we used mice lacking Abcc8, a key component of the β-cell KATP-channel, to analyze the effects of a sustained elevation in the intracellular Ca2+ concentration ([Ca2+]i) on β-cell identity and gene expression. We found that chronically elevated β-cell [Ca2+]i results in the dysregulation of over 4,200 genes, as well as modest loss of β-cell identity, characterized by decreased expression of key functional genes, increased expression of genes associated with β-cell dedifferentiation, increased β-cell transdifferentiation to PP-expressing cells, and decreased β-cell function. These studies prompted us to propose a model by which chronically elevated β-cell [Ca2+]i acts through a putative Ca2+-regulated transcription factor, ASCL1, to disrupt a network of genes, contributing to β-cell failure. In addition to exploring the effects of chronically elevated [Ca2+]i on β-cell gene expression, we analyzed β-cells from mice ectopically expressing human growth hormone (hGH), mice made insulin resistant by feeding a high-fat diet (HFD), and mice of different sexes. We found that both ectopic hGH and HFD have beneficial effects (induction of β-cell proliferation genes) as well as deleterious effects (increased expression of ER stress genes) on β-cell function. Ultimately, the collection of 17 RNA-sequencing datasets allowed us to perform weighted gene correlation network analysis (WGCNA) to generate modules of similarly-expressed genes. Several of these initial modules have meaningful correlations to specific β-cell stresses. Overall, these studies highlight the power of using whole transcriptome datasets from highly-pure cell populations and have allowed us to elucidate how stress alters the β-cell gene regulatory network.

The final steps of cell division are tightly coordinated in space and time but whether mechanisms exist to couple the actin and microtubule cytoskeletons during anaphase and cytokinesis (C phase) is largely unknown. We show here that spindle midzone microtubules are stabilized as cells initiate cleavage furrow ingression. This stabilization is dependent on actomyosin contraction, suggesting that there is active coordination between furrow ingression and microtubule dynamics during C phase. Midzone microtubule stabilization also depends on the kinase activity of Aurora B, the catalytic subunit of the Chromosomal Passenger Complex (CPC), uncovering a feedback mechanism that couples furrowing with microtubule dynamics. We further show that the CPC scaffolding protein INCENP binds actin. Interaction between actin and INCENP is important for cytokinesis, and for midzone microtubule stabilization following furrow ingression. Pharmacological stabilization of midzone microtubules rescues cytokinesis in INCENP actin-binding mutant expressing cells, demonstrating that the CPC is integral for coupling furrow ingression with midzone microtubule stabilization. We also found that actin binding is required to localize the CPC to the midzone and equatorial cortex during C phase. As the sub-cellular localization of the CPC is tied to its mitotic functions we investigated the role of actin-binding in recruiting the CPC to the equatorial cortex. The transport of the CPC from the centromeres to the cell middle is thought to depend on microtubule plus-end directed transport by the kinesin Mklp2 (Kif20a), however, we observed that in the absence of motor-based transport on MTs, the CPC can still target the cortex, in manner that depends on INCNEP-actin binding. This demonstrates that the mechanisms involving both the actin and MT cytoskeletons cooperate to precisely position CPC during C phase. We also observed that Mklp2 and the CPC remain associated throughout C phase and that the Mklp2-CPC complex diffuses once it reaches midzone MT plus ends, or the cell cortex, suggesting that motor activity does not define the bulk of the dynamic behavior we observe during anaphase. We find that cortical diffusion of Mklp2-CPC relies on F-actin, suggesting INCENP-actin binding promotes cortical recruitment and diffusion. Finally, cortically-localized CPC is sufficient to rescue furrow closure in Mklp2-depleted cells, indicating that this population is functional to promote cleavage furrow ingression. Collectively, our work demonstrates that the activities of the actin and microtubule cytoskeletons are coordinated during C phase, through both cytoskeletal cross-talk and cooperative CPC positioning, in order to ensure successful cell division.