29 research outputs found
Encouraging Healthy Lifestyle Choices Among At-Risk Youth: The RESOLVE Program
This study describes results for the second year of RESOLVE, a federally-funded (U.S. Administration for Children and Families, CBAE) program designed to teach healthy lifestyles, goal setting, refusal skills, and abstinence education to at-risk youth that was developed and implemented by the Jewish Child Care Association. These data examine changes in content knowledge, self-esteem, attitudes and intentions regarding pre-marital sexual behavior from pre- to post-test, as well as self-report data on actual sexual activity. Results for the 303 youth who completed the program indicate positive changes in content-knowledge, attitudes and intentions regarding sexual behavior. Qualitative results highlight the importance of health educators as role models and mentors for youth, enhancing the information provided by the formal curriculum
High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation
Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple cafe-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P<0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients
Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency
Purpose Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Methods Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. Results Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. Conclusions This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features
Risk governance in organizations
Dieses Buch dokumentiert 10 Jahre Risk-Governance-Forschung an der Universität Siegen. In 50 Beiträgen reflektieren Forscher und Praktiker Risk Governance vor dem Hintergrund ihrer eigenen Forschungen und/oder Erfahrungen und geben jeweils einen Entwicklungsimpuls für die Zukunft der Risk Governance. Das Buch zeigt die große Bandbreite und Tiefe des Forschungsgebietes auf und diskutiert Grundannahmen, Implementierungsfragen, die Rolle der Risk Governance als Transformationsmotor, ihre Wirkung in den verschiedenen betrieblichen Funktionen, Entwicklungsperspektiven und den Beitrag der Risk Governance zu einer nachhaltigen Ausrichtung von Unternehmen.This book documents 10 years of risk governance research at the University of Siegen. In 50 contributions, researchers and practitioners reflect on risk governance against the background of their own research and/or experience and provide a development impetus for the future of risk governance. The book shows the wide range and depth of the research field and discusses basic assumptions, implementation issues, the role of risk governance as transformation engine, its impact in the various operational functions, development perspectives, and the contribution of risk governance to a sustainable orientation of companies
Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.
Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems
Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly
Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms
Lexical Development.
The question of how children master impressive quantities of words at an early age has received scant attention from the language development literature. A small body of literature has demonstrated that children as young three can take advantage of linguistic context to learn new words, and at least one study suggests that even two-year olds can do so. The current study explored early lexical development by examining how linguistic sophistication (determined by the early stages of word learning described in the literature) affected children's ability to take advantage of different linguistic contexts. Children at four levels of productive language ability were exposed to nonsense labels for novel animals in a picture book. In a within-subject design, six conditions determined the linguistic context with which each label/animal pair was presented: (1) Simple (label only); (2) Fixed ("That's a "); (3) Article (article plus label); (4) Question ("Is that a "?); (5) Mixed (conditions 2-4); (6) Control (no label). Three post-tests each were administered on two different days (S1 and S2) testing: (1) production; (2) comprehension of stimuli highly similar to the book pictures; (3) comprehension of stimuli less similar to the pictures. Learning from input was demonstrated by all sophistication groups comprehending above chance overall. Data also showed a curvilinear relationship between comprehension and language sophistication. Comprehension performance was significantly lower in the Control Condition, tended to be higher in the Article Condition on High Similarity and Session 1 tests, and was higher in the Mixed Condition on Low Similarity tests. There was no overall difference between S1 and S2 comprehension, reflecting substantial retention. Production data suggested a facilitative role for the Mixed Condition. There was no statistically significant comprehension/production correspondence, but descriptive data suggested a complex relationship. An interactive developmental framework was proposed to account for the findings. Language group differences were explained in terms of the allocation of cognitive resources. The data were interpreted as suggesting that given input conditions affect the level at which information is stored in memory. Comprehension/production data suggested that further research is needed to elaborate the relationship between these skills. Directions for future research motivated by this exploratory study were discussed.Ph.D.Developmental psychologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/159822/1/8402367.pd
Lexical Development
PHDPsychologyUniversity of Michiganhttps://deepblue.lib.umich.edu/bitstream/2027.42/150909/1/psychdiss022.pd
Encouraging Healthy Lifestyle Choices Among At-Risk Youth: The RESOLVE Program
This study describes results for the second year of RESOLVE, a federally-funded (U.S. Administration for Children and Families, CBAE) program designed to teach healthy lifestyles, goal setting, refusal skills, and abstinence education to at-risk youth that was developed and implemented by the Jewish Child Care Association. These data examine changes in content knowledge, self-esteem, attitudes and intentions regarding pre-marital sexual behavior from pre- to post-test, as well as self-report data on actual sexual activity. Results for the 303 youth who completed the program indicate positive changes in content-knowledge, attitudes and intentions regarding sexual behavior. Qualitative results highlight the importance of health educators as role models and mentors for youth, enhancing the information provided by the formal curriculum