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In the budding yeast Saccharomyces cerevisiae, ribosomal RNA genes are encoded in a highly repetitive tandem array referred to as the ribosomal DNA (rDNA) locus. The yeast rDNA is the site of a diverse set of DNA-dependent processes, including transcription of ribosomal RNAs by RNA polymerases I and III, transcription of noncoding RNAs by RNA polymerase II, DNA replication initiation, replication fork blocking, and recombination-mediated regulation of rDNA repeat copy number. All of this takes place in the context of chromatin, but little is known about the roles played by ATP-dependent chromatin remodeling factors at the yeast rDNA. In this work, we report that the Isw2 and Ino80 chromatin remodeling factors are targeted to this highly repetitive locus. We characterize for the first time their function in modifying local chromatin structure, finding that loss of these factors decreases the fraction of actively transcribed 35S ribosomal RNA genes and the positioning of nucleosomes flanking the ribosomal origin of replication. In addition, we report that Isw2 and Ino80 promote efficient firing of the ribosomal origin of replication and facilitate the regulated increase of rDNA repeat copy number. This work significantly expands our understanding of the importance of ATP-dependent chromatin remodeling for rDNA biology.

Objectives To perform a case-control study of maternal occupational physical activity and risk for orofacial clefts in Texas during 1999-2009. Methods We used logistic regression to assess 14 measures of physical activity estimated from a job exposure matrix, using the maternal occupation reported on the birth certificate, among 887 children with cleft lip with or without cleft palate (CLP), 436 children with cleft palate only (CP), and 1932 controls. Results After adjusting for several potential confounders, seven measures of physical activity (as a categorical and/or continuous variable) were significantly associated with CLP, CP, or both. Positive associations were seen for keeping balance, kneeling, standing, and walking/running (odds ratio 95% confidence interval range 1.0-1.9 for fourth versus first quartile). A significant positive trend was also seen for bending/twisting. Negative associations were seen for repetitive motion and sitting. Conclusions Maternal occupational physical activity may be related to the etiology of orofacial clefts.

Interruption of blood supply to the heart is a leading cause of death and disability. However, the molecular events that occur during heart ischaemia, and how these changes prime consequent cell death upon reperfusion, are poorly understood. Protein SUMOylation is a post-translational modification that has been strongly implicated in the protection of cells against a variety of stressors, including ischaemia-reperfusion. In particular, the SUMO2/3-specific protease SENP3 has emerged as an important determinant of cell survival after ischaemic infarct. Here, we used the Langendorff perfusion model to examine changes in the levels and localisation of SUMOylated target proteins and SENP3 in whole heart. We observed a 50% loss of SENP3 from the cytosolic fraction of hearts after preconditioning, a 90% loss after ischaemia and an 80% loss after ischaemia-reperfusion. To examine these effects further, we performed ischaemia and ischaemia-reperfusion experiments in the cardiomyocyte H9C2 cell line. Similar to whole hearts, ischaemia induced a decrease in cytosolic SENP3. Furthermore, shRNA-mediated knockdown of SENP3 led to an increase in the rate of cell death upon reperfusion. Together, our results indicate that cardiac ischaemia dramatically alter levels of SENP3 and suggest that this may a mechanism to promote cell survival after ischaemia-reperfusion in heart.

Background Knowledge of the prevalence of work-related physical activities, sedentary behaviors, and emotional stressors among pregnant women is limited, and the extent to which these exposures vary by maternal characteristics remains unclear. Methods Data on mothers of 6,817 infants without major birth defects, with estimated delivery during 1997 through 2009 who worked during pregnancy were obtained from the National Birth Defects Prevention Study. Information on multiple domains of occupational exposures was gathered by linking mother's primary job to the Occupational Information Network Version 9.0. Results The most frequent estimated physical activity associated with jobs during pregnancy was standing. Of 6,337 mothers, 31.0% reported jobs associated with standing for ≥75% of their time. There was significant variability in estimated occupational exposures by maternal age, race/ethnicity, and educational level. Conclusions Our findings augment existing literature on occupational physical activities, sedentary behaviors, emotional stressors, and occupational health disparities during pregnancy. Am. J. Ind. Med. 59:137–149, 2016. © 2015 Wiley Periodicals, Inc.

In the budding yeast Saccharomyces cerevisiae, ribosomal RNA genes are encoded in a highly repetitive tandem array referred to as the ribosomal DNA (rDNA) locus. The yeast rDNA is the site of a diverse set of DNA-dependent processes, including transcription of ribosomal RNAs by RNA polymerases I and III, transcription of noncoding RNAs by RNA polymerase II, DNA replication initiation, replication fork blocking, and recombination-mediated regulation of rDNA repeat copy number. All of this takes place in the context of chromatin, but little is known about the roles played by ATP-dependent chromatin remodeling factors at the yeast rDNA. In this work, we report that the Isw2 and Ino80 chromatin remodeling factors are targeted to this highly repetitive locus. We characterize for the first time their function in modifying local chromatin structure, finding that loss of these factors decreases the fraction of actively transcribed 35S ribosomal RNA genes and the positioning of nucleosomes flanking the ribosomal origin of replication. In addition, we report that Isw2 and Ino80 promote efficient firing of the ribosomal origin of replication and facilitate the regulated increase of rDNA repeat copy number. This work significantly expands our understanding of the importance of ATP-dependent chromatin remodeling for rDNA biology.

In the budding yeastSaccharomyces cerevisiae, ribosomal RNA genes are encoded in a highly repetitive tandem array referred to as the ribosomal DNA (rDNA) locus. The yeast rDNA is the site of a diverse set of DNA-dependent processes, including transcription of ribosomal RNAs by RNA Polymerases I and III, transcription of non-coding RNAs by RNA Polymerase II, DNA replication initiation, replication fork blocking, and recombination-mediated regulation of rDNA repeat copy number. All of this takes place in the context of chromatin, but relatively little is known about the roles played by ATP-dependent chromatin remodeling factors at the yeast rDNA. In this work, we report that the Isw2 and Ino80 chromatin remodeling factors are targeted to this highly repetitive locus. We characterize for the first time their function in modifying local chromatin structure, finding that loss of these factors affects the occupancy of nucleosomes in the 35S ribosomal RNA gene and the positioning of nucleosomes flanking the ribosomal origin of replication. In addition, we report that Isw2 and Ino80 promote efficient firing of the ribosomal origin of replication and facilitate the regulated increase of rDNA repeat copy number. This work significantly expands our understanding of the importance of ATP-dependent chromatin remodeling for rDNA biology.Author SummaryTo satisfy high cellular demand for ribosomes, genomes contain many copies of the genes encoding the RNA components of ribosomes. In the budding yeastSaccharomyces cerevisiae, these ribosomal RNA genes are located in the “ribosomal DNA locus”, a highly repetitive array that contains approximately 150 copies of the same unit, in contrast to the single copies that suffice for most genes. This repetitive quality creates unique regulatory needs. Chromatin structure, the packaging and organization of DNA, is a critical determinant of DNA-dependent processes throughout the genome. ATP-dependent chromatin remodeling factors are important regulators of chromatin structure, and yet relatively little is known about how members of this class of protein affect DNA organization or behavior at the rDNA. In this work, we show that the Isw2 and Ino80 chromatin remodeling factors regulate two features of chromatin structure at the rDNA, the occupancy and the positioning of nucleosomes. In addition, we find that these factors regulate two critical processes that function uniquely at this locus: DNA replication originating from within the rDNA array, and the regulated increase of rDNA repeat copy number.

Background There is evidence that exposure to chlorinated solvents may be associated with childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET) risk. Animal models suggest genes related to detoxification and DNA repair are important in the carcinogenicity of these pollutants; however, there have been no human studies assessing the modifying effects of these genotypes on the association between chlorinated solvents and childhood M/PNET risk. Procedure We conducted a case-only study to evaluate census tract-level exposure to chlorinated solvents and the risk of childhood M/PNET in the context of detoxification and DNA repair genotypes. Cases (n = 98) were obtained from Texas Children's Hospital and MD Anderson Cancer Center. Key genotypes (n = 22) were selected from the Illumina Human 1M Quad SNP Chip. Exposure to chlorinated solvents (methylene chloride, perchloroethylene, trichloroethylene, and vinyl chloride) was estimated from the US EPA's 1999 Assessment System for Population Exposure Nationwide (ASPEN). Logistic regression was used to estimate the case-only odds ratios and 95% confidence intervals (CIs). Results There were 11 significant gene–environment interactions associated with childhood M/PNET risk. However, after correcting for multiple comparisons, only the interaction between high trichloroethylene levels and OGG1 rs293795 significantly increased the risk of childhood M/PNET risk (OR = 9.24, 95% CI: 2.24, 38.24, Q = 0.04). Conclusions This study provides an initial assessment of the interaction between ambient levels of chlorinated solvents and potentially relevant genotypes on childhood M/PNET risk. Our results are exploratory and must be validated in animal models, as well as additional human studies. Pediatr Blood Cancer 2012;59:605–610. © 2012 Wiley Periodicals, Inc.

The yeast INO80 chromatin remodeling complex plays essential roles in regulating DNA damage repair, replication, and promoter architecture. INO80's role in these processes is likely related to its ability to slide nucleosomes, but the underlying mechanism is poorly understood. Here we use ensemble and single-molecule enzymology to study INO80-catalyzed nucleosome sliding. We find that the rate of nucleosome sliding by INO80 increases ∼100-fold when the flanking DNA length is increased from 40 to 60bp. Furthermore, once sliding is initiated, INO80 moves the nucleosome rapidly at least 20bp without pausing to re-assess flanking DNA length, and it can change the direction of nucleosome sliding without dissociation. Finally, we show that the Nhp10 module of INO80 plays an auto-inhibitory role, tuning INO80's switch-like response to flanking DNA. Our results indicate that INO80 is a highly processive remodeling motor that is tightly regulated by both substrate cues and non-catalytic subunits.

When cells undergo replication stress, proper checkpoint activation and deactivation are critical for genomic stability and cell survival and therefore must be highly regulated. Although mechanisms of checkpoint activation are well studied, mechanisms of checkpoint deactivation are far less understood. Previously, we reported that chromatin remodeling factors Isw2 and Ino80 attenuate the S-phase checkpoint activity in Saccharomyces cerevisiae, especially during recovery from hydroxyurea. In this study, we found that Isw2 and Ino80 have a more pronounced role in attenuating checkpoint activity during late S phase in the presence of methyl methanesulfonate (MMS). We therefore screened for checkpoint factors required for Isw2 and Ino80 checkpoint attenuation in the presence of MMS. Here we demonstrate that Isw2 and Ino80 antagonize checkpoint activators and attenuate checkpoint activity in S phase in MMS either through a currently unknown pathway or through RPA. Unexpectedly, we found that Isw2 and Ino80 increase chromatin accessibility around replicating regions in the presence of MMS through a novel mechanism. Furthermore, through growth assays, we provide additional evidence that Isw2 and Ino80 partially counteract checkpoint activators specifically in the presence of MMS. Based on these results, we propose that Isw2 and Ino80 attenuate S-phase checkpoint activity through a novel mechanism.

Maternal hypertension is common during pregnancy, and multiple studies have reported on an association between maternal hypertension and congenital heart defects (CHDs) in offspring; however, there is variability in the quality of these studies. A systematic review and meta-analysis was conducted on the associations between untreated and treated maternal hypertension and the risk of CHDs, evaluating CHDs overall as well as specific CHD subtypes. A systematic search of peer-reviewed articles published before August 2013 identified 16 studies evaluating the associations between untreated and treated maternal hypertension and CHDs. Summary relative risk (RR) estimates were calculated using fixed-effects models and random-effects models. Significant associations were observed between maternal hypertension and overall CHDs, for both treated [RR 2.0; 95 % confidence interval (CI) 1.5, 2.7] and untreated (RR 1.4; 95 % CI 1.2, 1.7) hypertension, as well as for overall hypertension regardless of treatment status (RR 1.8; 95 % CI 1.5, 2.2). The magnitude of effect was similar for the majority of CHD sub-types evaluated. The effects were also similar among women with hypertension who used one of multiple specific hypertension medications. There was no evidence of publication bias, and our results were robust to several factors considered in sensitivity analyses (e.g., source of exposure data, adjustment for potential confounders, and study design). Maternal hypertension was associated with CHDs. By understanding the specific mechanisms involved, appropriate strategies may be developed to reduce this risk, in order to prevent CHDs.

This chapter examines the patterns of violence associated with the tenure process for the African American professor in traditionally white higher education institutions. In this article, violence is examined in the context of its psychological and demeaning effects. The following dimensions are reviewed: recruitment of African American faculty; the review process for tenure; the politics of tenure; socialization and orientation of faculty; junior faculty as victims and tenure denial. Intervention strategies for addressing the problems of violence are recommended.

The causes of choanal atresia or stenosis (CA) are largely unknown. Infant thyroxine (T(4) ) levels collected during newborn screening may be proxy measures for a risk factor present during the critical period of development. Therefore, we conducted a case-control study to examine the association between newborn T(4) levels and CA.Data for cases with CA and controls were obtained from the Texas Birth Defects Registry for the period of 2004 to 2007. Information on infant T(4) levels at birth was obtained from the Texas Newborn Screening Program. Controls (n = 3570) were drawn from unaffected births in Texas for the same period and frequency matched to cases (n = 69) on year of birth, then linked to the newborn screening database. Logistic regression was used to evaluate the association between continuous and categorical infant T(4) levels and nonsyndromic CA.After adjustment for gestational age and year of birth, infant T(4) levels were inversely associated with CA (adjusted odds ratio [AOR], 0.85; 95% confidence interval [CI], 0.80-0.90). We observed a linear trend (p0.001) across quartiles of T(4) ; compared to infants with low levels, AORs for CA were 0.50 (95% CI, 0.28-0.91), 0.39 (95% CI, 0.20-0.75), and 0.15 (95% CI, 0.06-0.40) for infants with medium-to-low, medium, and high levels, respectively.Our findings suggest a role of low thyroid hormone levels in the development of CA, or that low newborn T(4) levels are potential proxy measures of a risk factor present during the critical period. Birth Defects Research (Part A), 2012.

There is evidence that exposure to chlorinated solvents may be associated with childhood medulloblastoma and primitive neuroectodermal tumor (M/PNET) risk. Animal models suggest genes related to detoxification and DNA repair are important in the carcinogenicity of these pollutants; however, there have been no human studies assessing the modifying effects of these genotypes on the association between chlorinated solvents and childhood M/PNET risk.We conducted a case-only study to evaluate census tract-level exposure to chlorinated solvents and the risk of childhood M/PNET in the context of detoxification and DNA repair genotypes. Cases (n = 98) were obtained from Texas Children's Hospital and MD Anderson Cancer Center. Key genotypes (n = 22) were selected from the Illumina Human 1M Quad SNP Chip. Exposure to chlorinated solvents (methylene chloride, perchloroethylene, trichloroethylene, and vinyl chloride) was estimated from the US EPA's 1999 Assessment System for Population Exposure Nationwide (ASPEN). Logistic regression was used to estimate the case-only odds ratios and 95% confidence intervals (CIs).There were 11 significant gene-environment interactions associated with childhood M/PNET risk. However, after correcting for multiple comparisons, only the interaction between high trichloroethylene levels and OGG1 rs293795 significantly increased the risk of childhood M/PNET risk (OR = 9.24, 95% CI: 2.24, 38.24, Q = 0.04).This study provides an initial assessment of the interaction between ambient levels of chlorinated solvents and potentially relevant genotypes on childhood M/PNET risk. Our results are exploratory and must be validated in animal models, as well as additional human studies.

Chd proteins are ATP–dependent chromatin remodeling enzymes implicated in biological functions from transcriptional elongation to control of pluripotency. Previous studies of the Chd1 subclass of these proteins have implicated them in diverse roles in gene expression including functions during initiation, elongation, and termination. Furthermore, some evidence has suggested a role for Chd1 in replication-independent histone exchange or assembly. Here, we examine roles of Chd1 in replication-independent dynamics of histone H3 in both Drosophila and yeast. We find evidence of a role for Chd1 in H3 dynamics in both organisms. Using genome-wide ChIP-on-chip analysis, we find that Chd1 influences histone turnover at the 5′ and 3′ ends of genes, accelerating H3 replacement at the 5′ ends of genes while protecting the 3′ ends of genes from excessive H3 turnover. Although consistent with a direct role for Chd1 in exchange, these results may indicate that Chd1 stabilizes nucleosomes perturbed by transcription. Curiously, we observe a strong effect of gene length on Chd1's effects on H3 turnover. Finally, we show that Chd1 also affects histone modification patterns over genes, likely as a consequence of its effects on histone replacement. Taken together, our results emphasize a role for Chd1 in histone replacement in both budding yeast and Drosophila melanogaster, and surprisingly they show that the major effects of Chd1 on turnover occur at the 3′ ends of genes., Author Summary Nucleosomes prevent transcription by interfering with transcription factor binding at the beginning of genes and blocking elongating RNA polymerase II across the bodies of genes. To overcome this repression, regulatory proteins move, remove, or structurally alter nucleosomes, allowing the transcription machinery access to gene sequences. Over the body of a gene, it is important that nucleosome structure be restored after a polymerase has passed by; failure to do so may lead to activation of transcription from internal gene sequences. Interestingly, although nucleosomes constantly move on and off of promoters, they are relatively stable over the bodies of genes. Thus, the same nucleosomes that are removed to allow a polymerase to pass by must be reassembled in its wake. Here, we examine the role of an ATP–dependent chromatin remodeling protein, Chd1, in regulating nucleosome dynamics. We find that Chd1 is important for exchange of the histone H3 in both yeast and Drosophila and that, surprisingly, while it promotes exchange of histones at the beginning of genes, it prevents exchange at the ends of genes. Finally, we show that Chd1 helps determine the characteristic pattern of chemical modifications of histone H3 found over actively transcribed gene sequences.

BACKGROUND:There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring. METHODS:Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring. RESULTS:The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58–1.67), septal defects (AOR, 1.28; 95% CI, 0.86–1.90), or with any isolated CHD subtype. CONCLUSIONS:Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism. Birth Defects Research (Part A), 2012. © 2012 Wiley Periodicals, Inc.

Disinfection is a critical part of the response to transboundary animal disease virus (TADV) outbreaks by inactivating viruses on fomites to help control infection. To model the inactivation of TADV on fomites, we tested selected chemicals to inactivate Foot and Mouth Disease virus (FMDV), African Swine Fever virus (ASFV), and Classical Swine Fever virus (CSFV) dried on steel and plastic surfaces. For each of these viruses, we observed a 2 to 3 log reduction of infectivity due to drying alone. We applied a modified surface disinfection method to determine the efficacy of selected disinfectants to inactivate surface-dried high-titer stocks of these three structurally different TADV. ASFV and FMDV were susceptible to sodium hypochlorite (500 and 1000 ppm, respectively) and citric acid (1%) resulting in complete disinfection. Sodium carbonate (4%), while able to reduce FMDV infectivity by greater than 4-log units, only reduced ASFV by 3 logs. Citric acid (2%) did not totally inactivate dried CSFV, suggesting it may not be completely effective for disinfection in the field. Based on these data we recommend disinfectants be formulated with a minimum of 1000 ppm sodium hypochlorite for ASFV and CSFV disinfection, and a minimum of 1% citric acid for FMDV disinfection.

Summary Past reviews suggest that men and women not only make socially desirable attributions toward attractive and unattractive people, but that such attributions are correlated with positive social behavior toward attractive persons. To assess these suggestions 40 male and female Ss engaged in a social persuasion task and provided attributions toward an attractive or unattractive female confederate. While the female confederate received more socially desirable attributions in the attractive versus unattractive condition, no differences were observed in social persuasion behavior. Such findings question the assumption that social attributions are associated with differential social experiences based on a physical attractiveness stereotype.

This article focuses on prevention and reduction of drug use among Black adolescents. The family is considered to be a major source in preparing children to handle adolescent stresses such as drug involvement pressures. Primary prevention of drug use begins in early childhood. The family is an underutilized and minimally acknowledged resource in drug abuse prevention efforts. The discussion centers on a review of research findings intimately related to adolescent drug use and Black family issues. An argument is made for a national family policy in support of all American famiiies. Young famiIies are a prime area for the investment or resources. Now and in the future, the American family represents the best primary prevention program available.

This article focuses on the implementation and outcome of a grief group study conducted with substance abusers. Group participants were chosen through a stratified random sampling from a residential drug and alcohol treatment facility. Control and experimental groups were used to test the efficacy of grief group therapy. Study results indicated that treatment group participants were significantly less depressed and better able to resolve painful feelings about their losses. The grief group approach is generic and can be modified to meet the needs of varied target groups. The distinctive approach and the empirical results both were completed by a clinician without disrupting the facility, patients or clinician's daily practices.