No description available.

<p> ABSTRACT The nervous system comprises more diverse and intricately specialized cell types than any other tissue in the body. Understanding the developmental mechanisms that generate cellular diversity in the nervous system is a major challenge in neuroscience. The nematode <i>C. elegans</i> offers the opportunity to study neuronal development at the molecular level with extraordinary resolution.</p><p> My dissertation focuses on the elucidation of genetic mechanisms required for the proper development of the chemosensory BAG neurons, which are specialized for detecting the respiratory gas carbon dioxide (CO₂). Analogs of these neurons play diverse roles in animals from different phyla. CO₂-sensing neurons in the mammalian brainstem are critical regulators of the respiratory motor program, and their dysfunction has been linked to fatal apneas such as Sudden Infant Death Syndrome. In nematodes, CO₂-sensing neurons mediate an avoidance behavior, but their ethological function was not known.</p><p> In my initial studies of BAG neuron development, I demonstrated that a conserved ETS-family transcription factor directly regulates genes required for CO₂-sensing, including the receptor-type guanylate cyclase, GCY-9, which likely functions as a CO₂ receptor. To uncover other genes that function together with <i>ets-5,</i> I carried out a large-scale chemical mutagenesis screen for mutants with improper BAG neuron differentiation. From this screen I identified two new genes required for BAG neuron development: the Pax6 homolog <i>vab-3</i> and the p38 Mitogen-Activated Protein (MAP) kinase <i>pmk-3</i>.</p><p> VAB-3 likely acts during embryonic development to pattern the expression of ETS-5 in head neurons of <i>C. elegans</i>. In loss of function <i> vab-3</i> mutants, ETS-5 protein is misexpressed in hypodermal cells and a motor neuron, in addition to its expression in BAG. VAB-3 likely represses transcription of ETS-5 in some lineages, such as those that give rise to hypodermal cells.</p><p> I next demonstrated that the p38 MAPK PMK-3 functions in a Toll-like receptor (TLR) signaling pathway. This discovery revealed an unexpected role for TLR signaling in neuronal differentiation. Because TLR signaling was known to be required for behavioral responses to microbes, I tested whether BAG neurons were required for pathogen avoidance. I found that this was the case and propose that TLR signaling functions in pathogen avoidance by promoting the development and function of chemosensory neurons that surveil the metabolic activity of environmental microbes.</p><p> Because ETS-5, VAB-3 and TOL-1 are members of gene families that are conserved between nematodes and vertebrates, a similar mechanism might act in the specification and differentiation of CO₂-sensing neurons in other phyla.</p>

<p> If society recognizes that it is mutually beneficial for individuals and communities to invest in school interventions that will lead to a more productive society, then early investment in intentional self-regulation (ISR) attributes may be a cost-beneficial strategy in regard to subsequent secondary-, post-secondary, and career successes, especially when early investment is complimented by continued investment in ISR through secondary school. In Chapter 1, I explain why ISR attributes should be a focus of educational curricula and interventions. I review several studies that have identified measures and tools that can be used to evaluate and improve ISR attributes among elementary school-aged youth, and how ISR attributes relate to academic success in elementary school students. In Chapter 2, I discuss the rationale for using longitudinal data from 959 participants in the Character and Merit Project (CAMP) to analyze the characteristics of ISR, as operationalized by Selection, Optimization, and Compensation (SOC) factors, and the outcome of interest, self-perceived academic success. I describe the findings of longitudinal analyses aimed at evaluating the utility of the Chase (2014) two-factor model of SOC, and how this two-factor model related to self-perceived academic success across the elementary school years. I used growth mixture models, cross-tabulation analyses, and tests of the equality of means to determine how SOC factors related to self-perceived academic success trajectory class membership. Chapter 3 explains the implications of the findings, as well as potential limitations. I conclude with a discussion of the possibilities for future studies of ISR and academic success, as well as the implications for educational policy and practice, within and after the elementary school years.</p>

<p> Short-term longitudinal study of mother-infant feeding interactions is rare in the infant obesity, growth, eating disorder, and attachment research. Beginning at birth through 3 months of age, this case-study replication series utilized archival data of 12 mother-infant pairs videotaped during weekly bottle-feeding sessions in their homes. Measures included infant weight and length and amount of food ingested. Videotapes were scored according to five infant and nine maternal observed feeding behaviors scaled on the Interaction Rating Scale - Feeding Ratings, a global measure of mother-infant feeding interactions. Study hypotheses proposed that the more optimal the mothers&rsquo; or infants&rsquo; behaviors, the larger the weight or BMI of the infant or the more food the infant ingested at a feeding session. Spearman rank-order correlation time-point analyses on 69 feeding observations showed statistically significant relationships. All combined infant behavior ratings as well as specific infant behavior ratings of State Rating, Physical Activity, and Gaze Behavior were significantly related to larger infant weight or infant BMI. Regarding maternal behavior ratings, statistically significant negative correlations were found between Persistence in Feeding and infant weight, Contingent Vocalization and BMI, and Gaze Behavior and amount of food ingested. These results have implications for further theorizing about the early antecedents of pediatric obesity in particular, but also for the development of caregiver-infant attachment in general.</p>

Two processes influence the success of mitosis, the process by which eukaryotic cells divide their replicated genome into two new daughter cells. First, the cell must build a bipolar array of microtubules called the mitotic spindle, which is accomplished by microtubule sliding by the Kinesin-5 Eg5; second, a subset of those microtubules, called kinetochore-microtubules (K-MTs), must attach correctly to each chromosome. The stability of these K-MT attachments to the chromosome influences whether chromosomes will segregate correctly in anaphase, but an influence of K-MT stability on the ability of cells to build or maintain bipolar spindles had not been recognized. Here we show that human cell lines with high K-MT stability are better able to maintain bipolar spindles when Eg5 is inhibited compared to cell lines with low K-MT stability. Artificially stabilizing K-MTs promoted bipolarity maintenance, while destabilizing K-MTs undermined the maintenance of bipolarity. In addition, inhibition of the mitotic master-regulator cyclin-dependent kinase-1 (CDK-1) in the G2 phase of the cell cycle stabilized K-MTs after CDK-1 inhibition was relieved, which promoted bipolar spindle maintenance without Eg5 but undermined mitotic fidelity. These results indicate that the dynamics of K-MTs play a previously unappreciated role in determining the overall geometry of the mitotic spindle.

<p> Mothers&rsquo; socialization has been shown to impact prosocial tendencies in children. Discussions during joint book reading may provide a context to observe mothers&rsquo; strategies for evoking emotions. More specifically, mother-child talk about emotions, cognitive states, and inductive reasoning may enhance children&rsquo;s perspective taking about characters experiencing diversity. However, mothers may differ in their amount and type of talk if the characters in the story are from an in-group or out-group. While not all mothers may engage in these strategies during book reading, evoking sympathy in children has been shown to predict children&rsquo;s prosocial attitudes and behaviors toward others in need. The goal of this study was to explore mothers&rsquo; discourse strategies during a joint book reading task with first and second graders. Moreover, this study aimed to test whether reading and discussing a story about an in-group or out-group member differed and whether certain differences increased donating behavior and prosocial attitudes and from pre- to post-tests. In the main results, children&rsquo;s donations did not significantly increase from pre-test to post-test as hypothesized nor did donations differ between the in-group or out-group story condition. However, children&rsquo;s prosocial attitudes toward both in-group and out-group children improved equally from pre-test to post-test. Also as hypothesized, maternal discourse differed between story conditions. More specifically, there was an interaction between child gender and story condition where mothers with daughters used more emotion talk and cognitive state talk when discussing out-group members than did mothers with sons. Exploratory analyses revealed that mothers who used more emotion talk and inductive reasoning had children with lower prosocial attitudes when averaged across time of measurement toward both the in-group and out-group. Alternatively, children&rsquo;s trait sympathy predicted higher average donations and prosocial attitudes. Finally, children&rsquo;s civic identity scores predicted children&rsquo;s average prosocial attitudes and maternal discourse variables (i.e., emotion words, cognitive state words, and number of inductive sequences). Future research should continue to investigate the relationship between children&rsquo;s civic identity and maternal discourse, as this was the first study to explore the two. In conclusion, inducing sympathy in children may be an effective strategy for fostering more favorable attitudes toward other people in need regardless of their group identification. Additionally, individual child characteristics may predict children&rsquo;s inclination to help others in need; however, aspects of mothers discourse may hinder such prosocial tendencies with children if they induce personal distress.</p>

Myocardial infarction (MI) causes irreversible tissue damage, leading to heart failure. Our laboratory found canonical Wnt signaling and the Wnt10b ligand are strongly induced in mouse and human hearts after MI. Wnt10b regulates cell fate in various organs, yet its role in the heart is unknown. To investigate the effects of Wnt10b gain-of-function on cardiac repair mechanisms and functional outcomes after injury, we generated αMHC-Wnt10b transgenic (TG) mouse line that overexpresses Wnt10b in adult cardiomyocytes. Following acute myocardial injury, the TG mice displayed improved recovery of cardiac function, accompanied by enhanced neovascularization and attenuated scar fibrosis. Wnt10b stimulated expression of vascular endothelial growth factor receptor 2 in endothelial cells and angiopoietin-1 in vascular smooth muscle cells through nuclear factor-κB activation to promote stabilized blood vessel formation. Wnt10b also reduced the number of myofibroblasts to mitigate fibrosis. My findings may lead to novel strategies to optimize the inherent repair capacity of the heart and prevent the onset of heart failure.

Diabetic Retinopathy (DR) is a leading cause of blindness worldwide, and its prevalence is growing. Current therapies for DR address only the later stages of the disease, are invasive and are of limited effectiveness. Retinal pericyte death is an early pathologic
feature of DR. Though it has been observed in diabetic patients and in animal models of DR, the cause of pericyte death remains unknown. A novel pro-apoptotic pathway initiated by the interaction between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the E3 ubiquitin ligase, seven in absentia homolog 1 (Siah1), was identified to play a significant role in human retinal pericyte apoptosis. Inhibition of the GAPDH/Siah1 pro-apoptotic complex blocks diabetes-induced pericyte apoptosis, widely considered a hallmark feature of DR.

<p> This dissertation seeks to formulate an integral psychology framework to better understand the nature and unfoldment of postformal, or postconventional, characterizations of individual consciousness evolution. To this end, an extensive critical evaluation and problematization of the disparate theoretical literatures indicated that while the egocentric and cosmocentric dimensions have been taken into account by various models, the psychocentric, or more specifically, the evolutionary soul dimension and its role in postconventional development has been largely overlooked. </p><p> With this background, there appeared to be hardly any substantial signs of agreement in the extensive and rapidly expanding literatures on human development. Such division has resulted in increasingly heated disagreements and debates concerning controversies of shape, goals, and, particularly, direction (e.g., structural-hierarchical versus spiral-dynamic models). Further, it was found that egocentric and cosmocentric biases bring to the fore a related set of problems that, in present-day formulation, can be summarized as the issue of epiphenomenalism along with the problem of identifying a facilitative agent (an ontological reference point that might help explain the how and why of stage change), which has apparently all but escaped developmental psychologists. </p><p> As a dialogue partner, the study adopts Sri Aurobindo and the Mother&rsquo;s rich integral acumen concerning the psychic being as an alternative assumption ground to both reveal and challenge some of the taken-for-granted assumptions found to underlie much of the ongoing theoretical debate. The guiding purpose of this dissertation, then, has been to advance the fields of both Western and integral yoga psychologies by contributing new and unique pathways to postconventional development&mdash;an integral psychology framework that places the deeper inmost source of evolution at the very center of a comprehensive whole person vision of human growth and development.</p>

The Wnt signaling pathway plays essential roles in a wide variety of biological processes including early animal development, cell fate determination, cell proliferation, organogenesis, and stem-cell renewal. Deregulation of the Wnt pathway can lead to human disease (e.g. developmental defects and cancers). Our lab had previously demonstrated that X-linked Inhibitor of Apoptosis (XIAP) is required for Wnt signaling via a mechanism that involves XIAP-facilitated dissociation of Gro/TLE from TCF/Lef. We had shown that XIAP is recruited onto TCF/Lef complexes upon Wnt pathway activation and ubiquitinates Gro/TLE-bound TCF/Lef. Ubiquitinated Gro/TLE has decreased affinity for TCF/Lef, allowing beta-catenin to bind. Inhibition of GSK3 by lithium causes XIAP to be recruited to TCF/Lef, although the precise mechanism was unknown. We found that XIAP is phosphorylated by GSK3, a known component of the Wnt pathway. Using mass spectrometry analysis with purified proteins, we identified two GSK3 phosphorylation sites on XIAP that are strongly phosphorylated. Mutational analysis of these two sites indicate that they are required by XIAP to fully activate Wnt signaling, as assessed by reporter assays in cultured mammalian cells and axis duplication assays in Xenopus embryos. Using purified proteins, we found that the XIAP phosphomutants have similar ubiquitination activity as wild-type XIAP. In cultured mammalian cells, however, the XIAP phosphomutants have a markedly decreased capacity to ubiquitinate Gro/TLE. We also showed that the phosphomutants also have a decreased affinity for Gro/TLE. We propose a model in which phosphorylation is necessary for the interaction between XIAP and Gro/TLE to activate Wnt signaling. GSK3 phosphorylates XIAP at T180 and S239 to facilitate its binding to Gro/TLE. XIAP can then ubiquitinate and remove Gro/TLE for subsequent binding of beta-catenin to form the transcriptionally active complex.