Neural crest expression of Cre recombinase directed by the proximal Pax3 promoter in transgenic mice.
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Animals↗
Biomedical subjects
J A Epstein
Publications and source records attributed to J A Epstein.
A model of smoking among inner-city adolescents: the role of personal competence and perceived social benefits of smoking.
BACKGROUND: Based on current trends, smoking will remain a major public health problem in the 21st century. Effective smoking prevention approaches offer the best hope for decreasing the rise in adolescent smoking rates. Competence enhancement approaches to smoking prevention are among the most successful. Yet, there is not a full understanding of how effective prevention approaches work. This study tests whether a deficiency in competence (poor decision-making skills and low personal efficacy) is linked to acquiring beliefs in the perceived benefits of smoking and whether these perceived benefits are then related to subsequent smoking. METHODS: A sample of 1459 students attending 22 middle and junior high schools in New York City participated. Students completed surveys at baseline, 1-year follow-up and 2-year follow-up during a regular class period. They self-reported smoking, decision-making skills, personal efficacy and beliefs in the perceived benefits of smoking. RESULTS: The tested structural equation model had a good fit and was parsimonious and consistent with the theory underlying the competence approach to smoking prevention. CONCLUSIONS: This research highlights the importance of addressing decision-making skills, personal efficacy, and beliefs in the social benefits of smoking within adolescent smoking prevention programs.
Adolescent↗
Cloning and expression analysis of murine lupin, a member of a novel gene family that is conserved through evolution and associated with Lupus inclusions.
We describe here the first full-length sequence of a member of a novel gene family encoding a protein in the mouse that we call Lupin. Lupin is homologous to a human protein previously called p36, which was purified from alpha-interferon-treated cells that formed lupus inclusions. Lupus inclusions are dense intracellular deposits found in endothelial cells and lymphocytes of patients with systemic lupus erythematosis and AIDS. Proteins closely related to Lupin exist in evolutionarily divergent species including Caenorhabditis elegans, Drosophila and zebrafish. At least one other lupin-related gene is expressed in the mouse and in man. Lupin is expressed in mouse embryos and adults, notably in liver, spleen, central nervous system, multiple epithelia and all types of muscle. In skeletal muscle, expression analysis suggests that Lupin associates with the contractile apparatus.
5'-Nucleotidase↗
Competence skills help deter smoking among inner city adolescents.
OBJECTIVE: To test whether higher levels of general competence are linked to more frequent use of refusal assertiveness that is in turn related to less subsequent smoking among inner city adolescents. METHODS: Longitudinal study conducted during three year middle school or junior high school period. A sample of 1459 students attending 22 middle (ages 11-14 years) and junior high (ages 12-15 years) schools in New York City participated. Students completed surveys at baseline, one year follow up, and two year follow up. The students self reported smoking, decision making skills, personal efficacy, and refusal assertiveness. Teams of three to five data collectors administered the questionnaire following a standardised protocol. These data were collected in school during a regular 40 minute class period. RESULTS: Based on the tested structural equation model, decision making and personal efficacy (that is, general competence) predicted higher refusal assertiveness and this greater assertiveness predicted less smoking at the two year follow up. The tested model had a good fit and was parsimonious and consistent with theory. CONCLUSIONS: Adolescent smoking prevention programmes often teach refusal skills in order to help youth resist peer pressure to smoke. The present findings suggest that teaching general competence skills as well may help to reduce smoking because youth with better personal efficacy and decision making skills are better able to implement smoking refusal strategies.
Adolescent↗
Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret.
Hirschsprung disease and Waardenburg syndrome are human genetic diseases characterized by distinct neural crest defects. Patients with Hirschsprung disease suffer from gastrointestinal motility disorders, whereas Waardenburg syndrome consists of defective melanocyte function, deafness, and craniofacial abnormalities. Mutations responsible for Hirschsprung disease and Waardenburg syndrome have been identified, and some patients have been described with characteristics of both disorders. Here, we demonstrate that PAX3, which is often mutated in Waardenburg syndrome, is required for normal enteric ganglia formation. Pax3 can bind to and activate expression of the c-RET gene, which is often mutated in Hirschsprung disease. Pax3 functions with Sox10 to activate transcription of c-RET, and SOX10 mutations result in Waardenburg-Hirschsprung syndrome. Thus, Pax3, Sox10, and c-Ret are components of a neural crest development pathway, and interruption of this pathway at various stages results in neural crest-related human genetic syndromes.
Animals↗
Transcriptional regulation of cardiac development: implications for congenital heart disease and DiGeorge syndrome.
In recent years, impressive advances have occurred in our understanding of transcriptional regulation of cardiac development. These insights have begun to elucidate the mystery of congenital heart disease at the molecular level. In addition, the molecular pathways emerging from the study of cardiac development are being applied to the understanding of adult cardiac disease. Preliminary results support the contention that a thorough understanding of molecular programs governing cardiac morphogenesis will provide important insights into the pathogenesis of human cardiac diseases. This review will focus on examples of transcription factors that play critical roles at various phases of cardiac development and their relevance to cardiac disease. This is an exciting and burgeoning area of investigation. It is not possible to be all-inclusive, and the reader will note important efforts in the areas of cardiomyocyte determination, left-right asymmetry, cardiac muscular dystrophies, electrophysiology and vascular disease are not covered. For a more complete discussion, the reader is referred to recent reviews including the excellent compilation of observations assembled by Harvey and Rosenthal (1).
Abnormalities, Multiple↗
Migration of cardiac neural crest cells in Splotch embryos.
Pax3 encodes a transcription factor expressed during mid-gestation in the region of the dorsal neural tube that gives rise to migrating neural crest populations. In the absence of Pax3, both humans and mice develop with neural crest defects. Homozygous Splotch embryos that lack Pax3 die by embryonic day 13.5 with cardiac defects that resemble those induced by neural crest ablation in chick models. This has led to the hypothesis that Pax3 is required for cardiac neural crest migration. However, cardiac derivatives of Pax3-expressing precursor cells have not been previously defined, and Pax3-expressing cells within the heart have not been well demonstrated. Hence, the precise role of Pax3 during cardiac development remains unclear. Here, we use a Cre-lox method to fate map Pax3-expressing neural crest precursors to the cardiac outflow tract. We show that although Pax3 itself is extinguished prior to neural crest populating the heart, derivatives of these precursors contribute to the aorticopulmonary septum. We further show that neural crest cells are found in the outflow tract of Splotch embryos, albeit in reduced numbers. This indicates that contrary to prior reports, Pax3 is not required for cardiac neural crest migration. Using a neural tube explant culture assay, we demonstrate that neural crest cells from Splotch embryos show normal rates of proliferation but altered migratory characteristics. These studies suggest that Pax3 is required for fine tuning the migratory behavior of the cardiac neural crest cells while it is not essential for neural crest migration.
Animals↗
Pax3 and vertebrate development.
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Animals↗
Gene expression analysis by in situ hybridization. Radioactive probes.
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Animals↗
Role of general and specific competence skills in protecting inner-city adolescents from alcohol use.
OBJECTIVE: The purpose of this longitudinal investigation was to test whether higher levels of general competence are linked to greater refusal assertiveness that is, in turn, related to less subsequent alcohol use among inner-city adolescents. METHOD: A large sample of students attending 22 middle and junior high schools in New York City participated. Students completed surveys at baseline, at 1-year follow-up and at 2-year follow-up (N = 1,459; 54% female). The students self-reported alcohol use. decision-making skills, self-efficacy and refusal assertiveness. Teams of three to five data collectors administered the questionnaire following a standardized protocol. The data were collected in school during a regular 40-minute class period. RESULTS: According to the tested structural equation model, Decision Making (beta = .07, p < .05) and Self-Efficacy (beta = .24, p < .001) predicted higher Refusal Assertiveness and this greater assertiveness predicted less drinking at the 2-year follow-up (beta = -.21, p < .001). Earlier drinking predicted 2-year follow-up drinking (beta = .40, p < .001). Goodness-of-fit indices were excellent (chi2 = 1107.9, 238 df, N = 1,438, p < .001; NFI = .93, NNFI = .94, CFI = .95). CONCLUSIONS: The tested model had a good fit and was parsimonious and consistent with theory. This research highlights the importance of addressing decision-making skills, self-efficacy and refusal assertiveness within adolescent alcohol prevention programs.
Adolescent↗
Psychosocial and behavioral factors in early adolescence as predictors of heavy drinking among high school seniors.
OBJECTIVE: Most adolescents experiment with alcohol, and the use of alcohol typically escalates during the teenage years. The present study examined how several risk and protective factors measured during early adolescence were associated with heavy drinking in a sample of high school seniors. METHOD: As part of a school-based survey, seventh-grade students (N = 1,132) reported degrees of experimentation with alcohol and cigarettes. Several psychosocial factors deemed to be important in the etiology of drinking were also assessed. Students were followed-up in the twelfth grade, when 16% were categorized as heavy drinkers based on drinking and drunkenness frequency and quantity typically consumed. RESULTS: Logistic regression analyses revealed that heavy drinking was predicted by having had experimented with alcohol or cigarettes, having had a majority of one's friends drink and having had poor behavioral self-control in early adolescence. In addition, several effects were limited to either boys or girls. For example, positive alcohol expectancies predicted greater later heavy drinking in boys, while friends' smoking predicted later heavy drinking in girls. CONCLUSIONS: The findings suggest that early intervention programs aimed at preventing alcohol use by addressing the social and psychological determinants of alcohol use may have important preventive effects in terms of later heavy drinking.
Adolescent↗
Methods to decrease attrition in longitudinal studies with adolescents.
A summary of methods to decrease attrition in longitudinal school-based studies conducted with adolescents beginning junior high schools or middle schools is presented. These include collection of contact information about students, additional days to collect data from absentee students, data collection in new high schools once students graduate from junior high schools or middle schools, sending questionnaires by mail, and conducting telephone or home interviews.
Absenteeism↗
Radiation hybrid mapping of the zebrafish genome.
The zebrafish is an excellent genetic system for the study of vertebrate development and disease. In an effort to provide a rapid and robust tool for zebrafish gene mapping, a panel of radiation hybrids (RH) was produced by fusion of irradiated zebrafish AB9 cells with mouse B78 cells. The overall retention of zebrafish sequences in the 93 RH cell lines that constitute the LN54 panel is 22%. Characterization of the LN54 panel with 849 simple sequence length polymorphism markers, 84 cloned genes and 122 expressed sequence tags allowed the production of an RH map whose total size was 11,501 centiRays. From this value, we estimated the average breakpoint frequency of the LN54 RH panel to correspond to 1 centiRay = 148 kilobase. Placement of a group of 235 unbiased markers on the RH map suggests that the map generated for the LN54 panel, at present, covers 88% of the zebrafish genome. Comparison of marker positions in RH and meiotic maps indicated a 96% concordance. Mapping expressed sequence tags and cloned genes by using the LN54 panel should prove to be a valuable method for the identification of candidate genes for specific mutations in zebrafish.
Animals↗
Novel human and mouse homologs of Saccharomyces cerevisiae DNA polymerase eta.
The Saccharomyces cerevisiae RAD30 gene encodes a novel eukaryotic DNA polymerase, pol eta that is able to replicate across cis-syn cyclobutane pyrimidine dimers both accurately and efficiently. Very recently, a human homolog of RAD30 was identified, mutations in which result in the sunlight-sensitive, cancer-prone, Xeroderma pigmentosum variant group phenotype. We report here the cloning and localization of a second human homolog of RAD30. Interestingly, RAD30B is localized on chromosome 18q21.1 in a region that is often implicated in the etiology of many human cancers. The mouse homolog (Rad30b) is located on chromosome 18E2. The human RAD30B and mouse Rad30b mRNA transcripts, like many repair proteins, are highly expressed in the testis. In situ hybridization analysis indicates that expression of mouse Rad30b occurs predominantly in postmeiotic round spermatids. Database searches revealed genomic and EST sequences from other eukaryotes such as Aspergillus nidulans, Schizosaccharomyces pombe, Brugia malayi, Caenorhabditis elegans, Trypanosoma cruzi, Arabidopsis thaliana, and Drosophila melanogaster that also encode putative homologs of RAD30, thereby suggesting that Rad30-dependent translesion DNA synthesis is conserved within the eukaryotic kingdom.
Amino Acid Sequence↗
Neurofibromin deficiency in mice causes exencephaly and is a modifier for Splotch neural tube defects.
Neural tube defects are common and serious human congenital anomalies. These malformations have a multifactorial etiology and can be reproduced in mouse models by mutations of numerous individual genes and by perturbation of multiple environmental factors. The identification of specific genetic interactions affecting neural tube closure will facilitate our understanding of molecular pathways regulating normal neural development and will enhance our ability to predict and modify the incidence of spina bifida and other neural tube defects. Here, we report a genetic interaction between Nf1, encoding the intracellular signal transduction protein neurofibromin, and Pax3, a transcription factor gene mutated in the Splotch mouse. Both Pax3 and Nf1 are important for the development of neural crest-derived structures and the central nervous system. Splotch is an established model of folate-sensitive neural tube defects, and homozygous mutant embryos develop spina bifida and sometimes exencephaly. Neural development is grossly normal in heterozygotes and neural tube defects are not seen. In contrast, we found a low incidence of neural tube defects in heterozygous Splotch mice that also harbored a mutation in one Nf1 allele. All compound homozygotes had severe neural tube defects and died earlier in embryogenesis than either Nf1(-/-) or Sp(-/-) embryos. We also report occasional exencephaly in Nf1(-/-) mice and identify more subtle CNS abnormalities in normal-appearing Nf1(-/-) embryos. Though other genetic loci and environmental factors affect the incidence of neural tube defects in Splotch mice, these results establish Nf1 as the first known gene to act as a modifier of neural tube defects in Splotch.
Animals↗
Crystal structure of the human Pax6 paired domain-DNA complex reveals specific roles for the linker region and carboxy-terminal subdomain in DNA binding.
Pax6, a transcription factor containing the bipartite paired DNA-binding domain, has critical roles in development of the eye, nose, pancreas, and central nervous system. The 2.5 A structure of the human Pax6 paired domain with its optimal 26-bp site reveals extensive DNA contacts from the amino-terminal subdomain, the linker region, and the carboxy-terminal subdomain. The Pax6 structure not only confirms the docking arrangement of the amino-terminal subdomain as seen in cocrystals of the Drosophila Prd Pax protein, but also reveals some interesting differences in this region and helps explain the sequence specificity of paired domain-DNA recognition. In addition, this structure gives the first detailed information about how the paired linker region and carboxy-terminal subdomain contact DNA. The extended linker makes minor groove contacts over an 8-bp region, and the carboxy-terminal helix-turn-helix unit makes base contacts in the major groove. The structure and docking arrangement of the carboxy-terminal subdomain of Pax6 is remarkably similar to that of the amino-terminal subdomain, and there is an approximate twofold symmetry axis relating the polypeptide backbones of these two helix-turn-helix units. Our structure of the Pax6 paired domain-DNA complex provides a framework for understanding paired domain-DNA interactions, for analyzing mutations that map in the linker and carboxy-terminal regions of the paired domain, and for modeling protein-protein interactions of the Pax family proteins.
Amino Acid Sequence↗
Etiology of alcohol use among Hispanic adolescents: sex-specific effects of social influences to drink and problem behaviors.
BACKGROUND: Hispanic adolescents seem to be at greater risk for alcohol use; a greater understanding of the factors that predict alcohol use among Hispanic youth is needed. Social influences to drink and other problem behaviors often predict adolescent alcohol use. However, most past research has concentrated on samples of predominantly white adolescents residing in suburban areas. OBJECTIVES: To determine which demographic factors, social influences, and problem behaviors are associated with alcohol use among Hispanic adolescents and to eludicate the difference in the origins of alcohol use depending on sex. DESIGN: Cross-sectional study. SETTING: Middle schools in New York City. PARTICIPANTS: This study focuses on 1410 adolescents in grade 7 from inner-city schools who identified themselves as Hispanic at the baseline assessment of an investigation of alcohol and other drug use. MAIN OUTCOME MEASURES: Alcohol initiation, alcohol consumption, and future drinking. RESULTS: The findings showed that social influences to drink and reported problem behaviors were associated with alcohol use across and within sex groups. In particular, friends' drinking was related to alcohol initiation, consumption, and plans to drink in the future across sexes and within both sex groups. Other predictors (mother's drinking, siblings' drinking, ease of obtaining alcohol, deviance, cigarette smoking, and marijuana use) exhibited sex-specific effects. CONCLUSION: These findings lend support to teaching social resistance skills to improve Hispanic adolescents' ability to resist social influences to drink and use other drugs.
Adolescent↗
Marijuana use among minority youths living in public housing developments.
Youths residing in public housing developments appear to be at markedly heightened risk for drug use because of their constant exposure to violence, poverty, and drug-related activity. The purpose of this study was to develop and test a model of marijuana etiology with adolescents (N = 624) residing in public housing. African-American and Hispanic seventh graders completed questionnaires about their marijuana use, social influences to smoke marijuana, and sociodemographic and psychosocial characteristics. Results indicated that social influences, such as friends' marijuana use and perceived ease of availability of marijuana, significantly predicted both occasional and future use of marijuana. Individual characteristics such as antimarijuana attitudes and drug refusal skills also predicted marijuana use. The findings imply that effective prevention approaches that target urban youths residing in public housing developments should provide them with an awareness of social influences to use marijuana, correct misperceptions about the prevalence of marijuana smoking, and train adolescents in relevant psychosocial skills.
Adolescent↗