Directed differentiation of human pluripotent stem cells (hPSCs) has the potential to produce human cell types that can be used for disease modeling and cell transplantation. Two key challenges in the differentiation from hPSCs to \(\beta\) cells are the specification from pancreatic progenitors to insulin-expressing \((INS^+ )\) cells and the maturation of \(INS^+\) cells into glucose responsive β cells. To address the first, two high-content chemical screens identified PKC inhibitors as inducers of \(INS^+\) cells from pancreatic progenitors. PKC inhibition generated up to tenfold more \(INS^+\) cells while PKC agonists blocked differentiation into \(INS^+\) cells. Transplantation of \(PKC\beta\) inhibitor-treated pancreatic progenitors, containing higher proportions of endocrine progenitors and endocrine cells, resulted in mature \(\beta\) cells showing higher levels of glucose-stimulated human c-peptide production in vivo. This indicates that in vitro derived \(INS^+\) cells might be competent to mature into functional \(\beta\) cells. To address the second challenge, we first studied mouse and human \(\beta\) cell maturation in vivo. Postnatal mouse \(\beta\) cell maturation was marked by an increase in the glucose threshold for insulin secretion and by expression of the gene urocortin 3. To study human \(\beta\) cell maturation, a Method for Analyzing RNA following Intracellular Sorting (MARIS) was developed and used for transcriptional profiling of sorted human fetal and adult \(\beta\) cells. Surprisingly, transcriptional differences between human fetal and adult \(\beta\) cells did not resemble differences between mouse fetal and adult \(\beta\) cells, calling into question inter-species homology at the late stages of development. A direct comparison between hPSC-derived \(INS^+\) cells, and \(\beta\) cells produced during human development is essential to validate directed differentiation and provide a roadmap for maturation of hPSC-derived \(INS^+\) cells. Genome-wide transcriptional analysis of sorted \(INS^+\) cells derived from three hPSC-lines suggest that different lines produce highly similar \(INS^+\) cells, confirming robustness of directed differentiation protocols. Furthermore, nonfunctional hPSC-derived \(INS^+\) cells resemble human fetal \(\beta\) cells, which are distinct from adult \(\beta\) cells. We therefore suggest that in vitro directed differentiation mimics normal human development and reveal differences in gene expression that may account for the functional differences between hPSC-derived \(INS^+\) cells and true \(\beta\) cells.

The vertebrate small intestine is responsible for nutrient absorption during digestion. To this end, the surface area of the gut tube is maximally expanded, both through a series of loops extending its length and via the development of a complex luminal topography. Here, I first examine the mechanism behind the formation of intestinal loops. I demonstrate that looping morphogenesis is driven by mechanical forces that arise from differential growth between the gut tube and the anchoring dorsal mesenteric sheet. A computational model based on measured parameters not only quantitatively predicts the looping pattern in chick, verifying that these physical forces are sufficient to explain the process, but also accounts for the variation in the gut looping patterns seen in other species. Second, I explore the formation of intestinal villi in chick. I find that intestinal villi form in a stepwise process as a result of physical forces generated as proliferating endodermal and mesenchymal tissues are constrained by sequentially differentiating layers of smooth muscle. A computational model incorporating measured differential growth and the geometric and physical properties of the developing chick gut recapitulates the morphological patterns seen during chick villi formation. I also demonstrate that the same basic biophysical processes underlie the formation of intestinal folds in frog and villi in mice. Finally, I focus on the process by which intestinal stem cells are ultimately localized to the base of each villus. The endoderm expresses the morphogen, Sonic hedgehog (Shh). As the luminal surface of the gut is deformed during villus formation there are resulting local maxima of Shh signaling in the mesenchyme. This results, at high threshold, in the induction of a new signaling center under the villus tip termed the villus cluster. This, in turn, feeds back to restrict proliferating progenitors in the endoderm, the presumptive precursors of the stem cells, to the base of each villus. Together, these studies provide new insight into the formation of the small intestine as a functional organ and highlight the interplay between physical forces, tissue-level growth, and signaling during development.

No description available.

One hundred twenty-two mothers, 89 children with chronic illnesses, and 56 of their brothers and sisters participated in a study designed to elucidate the processes by which one child's chronic illness affects two children in the same family. The investigation was guided by assumptions of a phenomenological approach, behavioral geneticists' findings on nonshared environment and by Lazarus' and Folkman's (1984) transactional perspective on stress and coping. This study had four purposes. The first was to describe and compare three different levels of influence on children's developmental context: individual child characteristics, dyadic influences, and family level influences. The individual characteristic was each child's illness appraisals, while dyadic and family level influences were represented by sibling relationship quality and maternal differential treatment, respectively. The second goal was to examine the direct associations among these influences and social emotional adjustment. The third aim was to examine the effect of illness burden and maternal differential treatment on each child's perceptions of sibling relationship quality. The final goal was to examine the influence of these two variables and sibling relationship quality on each child's social-emotional adjustment. Families were recruited through a clinic in Southern Arizona by mail and were sent questionnaires to complete if they expressed interest. For the present study, mothers provided demographic information, and information on objective illness burdens and each child's behavioral adjustment. Children provided illness appraisals and information about their sibling relationships and social emotional adjustment. Children's illness appraisals, perceptions of sibling relationship quality, maternal differential treatment, and social emotional adjustment were remarkably similar to each other. Maternal differential treatment, illness appraisals, and objective illness burdens accounted for significant portions of the variance in siblings' perceptions of sibling relationship quality, but not in the perceptions of children with illnesses. A significant regression equation for social emotional adjustment was obtained for siblings. A significant beta weight indicated that conflict was associated with more negative outcomes.

The present dissertation investigated children's ability to understand denominal verbs and deverbal nouns that share the same forms as their parent words (e.g. brushv/brushn). Specifically, we sought to answer two general questions: 1) When do young children acquire class extension rules for denominal verbs and deverbal nouns? 2) How do children acquire these rules? We addressed these questions using a series of studies in which we tested children's ability to understand and produce flexible noun-verb pairs. The results from the study reported in Chapter 2 demonstrated that while both 2.5- and 3-year-old French-speaking children were able to understand novel nouns and verbs, only the 3-year-old children were able to understand novel denominal verbs and deverbal nouns derived from these parent words. This suggests that children acquire class extension rules for denominal verbs and deverbal nouns by 3 years of age. The results from the two studies reported in Chapter 3 demonstrated that children's ability to produce and understand flexible noun-verb pairs is related to the amount of flexible use in their input. Furthermore, children tend to use more object-denoting words flexibly than non-object and action denoting words. This suggests that children use the semantic and distributional cues associated with the flexible use of object-denoting words in their input to learn the flexible use of object-denoting words, and subsequently form class extension rules. The study reported in Chapter 4 confirmed this finding by demonstrating that 2.5-year-old children can only understand the flexible use of novel object-denoting noun-verb pairs in an experimental task if they are provided with semantic information coupled with noun and verb distributional cues in the input of the teaching trial. If they are provided with semantic information coupled with noun only distributional cues, they cannot do so. Furthermore, after having observed the flexible use of two object-denoting words, at least some of the 2.5-year-olds tested were able to understand a novel denominal-verb based on their understanding of the parent noun. Altogether, the results from the present dissertation are the first to provide direct evidence that young children acquire class extension rules by 3 years of age, by using the semantic and distributional cues that accompany the flexible use of object-denoting words in their input. / La présente thèse enquête sur la capacité des enfants à comprendre les verbes dénominaux et les noms déverbaux qui possèdent la même forme que leurs mots parents (e.g., il brossev / une brossen). Plus précisément, nous avons cherché à répondre à deux questions: 1) Quand les jeunes enfants acquièrent-ils des règles d'extension pour les verbes dénominaux et les noms déverbaux? 2) Comment les enfants acquièrent-ils ces règles? Nous avons abordé ces questions en utilisant une série d'études dans lesquelles nous avons testé la capacité des enfants à comprendre et à produire des paires de noms-verbes flexibles. Dans le Chapitre 2, les résultats de l'étude démontrent que même si les enfants francophones de 2 ans 1/2 et 3 ans sont capables de comprendre de nouveaux noms et verbes, seuls les enfants de 3 ans sont capables de comprendre de nouveaux verbes dénominaux et noms déverbaux dérivés de ces mots parents. Ceci suggère que les enfants acquièrent des règles d'extension pour les verbes dénominaux et les noms déverbaux autour de 3 ans. Dans le Chapitre 3, les résultats des deux études démontrent que la capacité des enfants à produire et à comprendre des paires de noms-verbes flexibles est liée à l'utilisation de ces mots par leurs mères. En outre, les enfants ont tendance à utiliser plus de mots désignant des objets d'une manière flexible que les non-objets et les mots dénotant une action. Ceci suggère que les enfants utilisent l'information sémantique et contextuelle associée avec l'utilisation flexible des mots dénotant des objets pour apprendre l'utilisation flexible de ces mots, et par la suite former des règles d'extension. Dans le Chapitre 4, l'étude rapportée confirme cette conclusion. Les enfants de 2 ans 1/2 ans peuvent comprendre l'utilisation flexible de nouvelles paires de noms-verbes dénotant des objets que si des informations sémantiques couplées avec des contextes nominaux et verbaux leur ont été procurées. Avec des informations sémantiques couplées avec un contexte nominal seulement, ils ne peuvent pas le faire. En outre, après avoir observé l'utilisation flexible de deux mots désignant des objets, au moins une partie des enfants de 2 ans 1/2 testés étaient capables de comprendre un nouveau verbe dénominal à partir de leur compréhension du nom parent. En conclusion, les résultats de la présente thèse sont les premiers à fournir une preuve directe que les jeunes enfants acquièrent des règles d'extension des 3 ans, à l'aide des indices sémantiques et contextuels qui accompagnent l'utilisation flexible des mots dénotant objets.

This investigation reports on the linguistic and communicative abilities of a deaf child whose initial exposure to conventional linguistic input occurred at the age of 10. At the time of data collection, the participant had been exposed to American Sign Language (ASL) for three years. Information concerning the participant's background, language and communication abilities was collected through caregiver interviews. Language samples were gathered through storybook and video retelling tasks and spontaneous conversations. Samples were videotaped, and later transcribed by a native deaf signer of ASL. Analyses of the participant's lexical, morphological, syntactic, and pragmatic skills were performed. Results showed deficits across linguistic subsystems. Comparisons to native language learners of ASL and late first-language learners of spoken and signed languages revealed both typical and unique characteristics of late language acquisition. The results contradict past theoretical claims concerning the selective impact of language deprivation on the faculty of grammar. Clinical implications and directions for future research are discussed.

Infants understand others' goals and use them to predict others' actions. Do 9.5-month-olds understand that others can act on the basis of goals not tied to specific objects? Particularly, do infants understand that a person's goal could be to select either the bigger (smaller) of two objects, a goal based on object relations? Across 4 familiarization trials, each with a different pair of objects differing only in size, an Experimenter selected either the bigger (Big object condition) or smaller (Small object condition) of two objects. In test trials with new objects, in the Big object condition, infants looked longer when the Experimenter selected the smaller than the bigger object, but in the Small object condition they looked about equally at the two test events (Experiment 1). Conditions under which the goal of smaller could be understood were further explored. Infants provided with additional information about the Experimenter's goal still looked equally at the two test events (Experiment 2), while those encouraged to compare object size both within and between pairs, looked longer when the Experimenter selected the bigger object than the smaller object (Experiment 3). 9.5-month-olds seem to understand that a person's goal can be to select either the bigger or smaller of two objects. The goal of smaller seems to be more difficult, perhaps due to infants' own preference for larger quantities or because their understanding of the size concept of small. The results suggested that infants' understanding of size relational goals involves the comprehension of the relational category of the object (big or small) and the ability to use that information to make sense of others' actions. / Les jeunes enfants comprennent les buts des autres et prédisent leurs actions en se basant sur cette compréhension. Les enfants de 9,5 mois comprennent-ils que les autres peuvent agir en fonction d'un but relationnel (des buts qui ne sont pas liés à un objet spécifique)? En particulier, est-ce que les enfants comprennent que l'expérimentateur veut toujours prendre l'objet le plus grand (ou le plus petit), un but basé sur des relations entre objets? Pendant 4 événements de familiarisation, chacun avec une paire d'objets identiques mais de différentes tailles, l'Expérimentateur choisi soit le plus grand (Condition du grand objet) ou le plus petit (Condition du petit objet) des deux objets. Dans les événements tests avec de nouveaux objets, dans la Condition du grand objet, les enfants regardent plus longtemps lorsque l'Expérimentateur choisi le plus petit des deux objets. Par contre, dans la Condition du petit objet, les enfants ont regardé à peu près également dans les deux tests (Expérience 1). Deux autres expériences avec le but du petit objet ont été explorées. Les enfants ayant obtenu des informations supplémentaires sur le but de l'Expérimentateur regardaient toujours également aux deux événements tests (Expérience 2). Contrairement, ceux invités à comparer la taille des objets de chaque paire et entre les paires, ont regardé plus longtemps lorsque l'Expérimentateur choisi le plus grand objet des deux objets (Expérience 3). Les enfants de 9,5 mois semblent comprendre que le but d'une personne peut être de choisir les plus grands ou plus petits objets. Comprendre que l'Expérimentateur a le but de choisir un petit objet semble être plus difficile, peut-être à cause de la préférence pour les grandes quantités chez les enfants eux-mêmes, ou pour leur compréhension du concept de petit. Les résultats suggèrent que la compréhension des buts relationnels implique la compréhension de la catégorie relationnelle de l'objet (grand ou petit) et la possibilité d'utiliser cette information pour comprendre les actions des autres.

Little is known empirically about parental perceptions of their young child's understanding of death, or how this perception relates to how parents talk about death with their children (Siegel, Mesagno, & Christ, 1990). The aim of the current study was to explore parental perceptions of their child's (N = 57; n males = 29, 3-8 years) understanding of death, how they talk about death with their children, and what their children actually understand about death. Firstly, parent-child dyads watched and discussed a Sesame Street video where Big Bird learns about the death of his friend Mr. Hooper. Parent-child conversations were then coded using an adaptation of a death concept coding manual (Neimeyer, Fontana, & Gold, 1984). Children's death understanding was measured using the Smilansky Death Concept Questionnaire (1987), and child fear was measured using the the Koala Fear Survey Scale for Children (FSSC-R; Ollendick, 1983). The current results indicate that parents do address a range of death-related concepts when conversing with their young children about death. It is also indicated that a child's level of fear may influence the types of death-related concepts discussed. Finally, results suggest that there is a significant positive relationship between parent perception and child understanding of death (p = .029). The current research has implications for the training of professionals who work with children and parents who are often faced with questions about death. / On connait peu de manière empirique sur la façon dont les parents perçoivent la compréhension de leurs jeunes enfants au sujet de la mort ou comment cette perception est reliée à la façon dont les parents parlent de la mort avec leurs enfants (Siegel, Mesagno, & Christ, 1990). Le but de la présente étude est d'explorer les perceptions des parents face à la compréhension des jeunes enfants (n = 57; n mâles = 29, 3-8 ans) vis-à-vis la mort, comment ils adressent le sujet de la mort avec leurs enfants, et ce que leurs enfants comprennent à ce sujet. Tout d'abord, les couples parents-enfants ont vus et ont discutés du vidéo « Sesame Street » où « Big Bird » apprend que son ami M. Hooper est décédé. Par la suite, les conversations parents-enfants ont été codées en utilisant une adaptation d'un manuel de codage du concept de la mort (Neimeyer, Fontana, & Gold, 1984). La compréhension de la mort des enfants a été mesurée en utilisant le Smilansky Death Concept Questionnaire (1987), et la peur des enfants a été mesurée en utilisant le questionnaire Koala Fear Survey Scale for Children (FSSC-R; Ollendick, 1983). Les résultats actuels indiquent que les parents prennent la parole à une gamme de concepts liés à la mort lors d'une conversation avec leurs jeunes enfants au sujet de la mort. Il est également indiqué que le niveau de peur d'un enfant peut influencer les types de concepts liés à la mort qui sont abordés. Enfin, les résultats suggèrent qu'il existe une relation significative et positive entre la perception des parents et la compréhension de la mort des enfants (p = .029). La recherche actuelle a des implications pour la formation des professionnels qui travaillent avec les enfants, et leurs parents qui sont souvent approchés de questions sur la mort.

The ability to reorient attention rapidly in both the auditory and visual modalities was first assessed developmentally and then assessed in children diagnosed as having Attention Deficit Disorder with Hyperactivity (314.01, DSM III). In the first experiment, eight-year old, eleven-year old, and college age subjects listened to dichotically presented lists for prespecified targets. On half of the trials, subjects were signaled to reorient their attention from one ear to the other during the list; on the other half, they remained on the same ear throughout the list. When performance was compared in the switch and no switch conditions, a progressive improvement with age was found in the ability to "switch gears." The ability to reorient attention visually in the same age range was measured in a second experiment. In this experiment, subjects first oriented their attention to the center of a cathode ray tube. Subjects were then cued that a target would shortly appear either to the left or to the right of this central location. Following a variable interval, the target appeared at the cued location. A steady improvement with age was found in the speed of reorientation from the central point to the target area. In a third experiment, auditory reorientation of attention was measured in hyperactive and nonhyperactive children matched for age, sex, and IQ. Using the same task used in the first experiment, it was found that although nonhyperactive children were temporarily disrupted by the switch, they eventually reoriented to the correct ear. In contrast, once the hyperactive children were disrupted by the switch, they never seemed to recover, at least not within the time frame of this experiment. This pattern resembled that of the youngest group in the first experiment, thus lending support to the hypothesis that hyperactive children are developmentally immature. A final experiment measured differences in visual reorientation in hyperactive and nonhyperactive children. Using the paradigm used in the second experiment, no differences were found between the two groups. It was suggested that the attentional abilities of hyperactive children may be highly dependent upon task characteristics.

The goal of the current study is to examine whether fatigue level of children diagnosed with Cri du Chat syndrome or moderate to severe learning disabilities, is associated with their expression of autistic symptoms. Sixty-nine children with Cri du Chat syndrome and 47 children with moderate to severe learning disabilities were assessed using the ISQ-A for fatigue level and the CARS for autism level rating. In line with our hypothesis, results of hierarchical multiple regression analyses indicated that children who exhibited high levels of fatigue were more likely than children who exhibited low levels of fatigue to express high levels of autistic symptoms. Contrary to our hypothesis, children with moderate to severe learning disabilities who exhibited high levels of fatigue conferred the greatest vulnerability to the expression of autistic symptoms. / L'objectif de la présente étude est de déterminer s'il y a un lien entre le niveau de fatigue et l'expression de symptômes associées à l'autisme chez les enfants ayant été diagnostiqués avec le syndrome du Cri du Chat ou des difficultés d'apprentissage modérées ou sévères. Soixante-et-neuf enfants ayant le syndrome Cri du Chat et quarante-sept enfants souffrant de difficultés d'apprentissage modérées ou sévères ont fait l'objet d'examen en utilisant le ISQ-A pour déterminer les niveaux de fatigue et le CARS pour l'évaluation du niveau d'autisme. En accord avec notre hypothèse, les résultats des analyses de régression multiple indiquent que les enfants exhibant des niveaux plus élevés de fatigue étaient plus sujets que les enfants exhibant des niveaux plus bas de fatigue à montrer des niveaux élevés de symptômes d'autisme. Contrairement à notre hypothèse, ce sont les enfants ayant des difficultés d'apprentissage modérées ou sévères et exhibant des niveaux élevés de fatigue qui étaient les plus sujets à l'expression de symptômes d'autisme.