Prenatal exposure to pyrethroid pesticides and childhood behavior and executive functioning

Several previous studies of pyrethroid biomarkers and behavior have reported associations between concurrent pyrethroid levels and adverse behavioral problems in children. One geospatial study reported associations between prenatal exposure to pyrethroids and autism. However, the association between prenatal pyrethroid biomarkers and childhood behavior is unknown. The Mount Sinai Children's Environmental Health Center is a prospective birth cohort with urinary pyrethroid biomarkers during pregnancy and behavioral measurements at 4, 6, and 7–9 years of age. Primiparous women were enrolled between 1998 and 2002. 162 mother/child pairs with complete exposure and behavioral outcomes data were used to investigate associations between detectable levels of prenatal pyrethroid metabolites and scores on the Behavioral Assessment System for Children and the Behavior Rating Inventory of Executive Function. Overall, detection frequencies of pyrethroid metabolites were low (<30%). In longitudinal mixed models, detectable levels of 3-PBA during pregnancy were associated with worse Internalizing (β −4.50, 95% CI −8.05, −0.95), Depression (β −3.21, 95% CI −6.38, −0.05), Somatization (β −3.22, 95% CI −6.38, −0.06), Behavioral Regulation (β −3.59, 95% CI −6.97, −0.21), Emotional Control (β −3.35, 95% CI −6.58, −0.12), Shifting (β −3.42, 95% CI −6.73, −0.11), and Monitoring (β −4.08, 95% CI −7.07, −1.08) scales. Detectable levels of cis-DCCA were associated with worse Externalizing (β −4.74, 95% CI −9.37, −0.10), Conduct Problems (β −5.35, 95% CI −9.90, −0.81), Behavioral Regulation (β −6.42, 95% CI −11.39, −1.45), and Inhibitory Control (β −7.20, 95% CI −12.00, −2.39). Although detection frequencies of pyrethroid metabolites were low, we found suggestive evidence that prenatal exposure to 3-PBA and cis-DCCA may be associated with a variety of behavioral and executive functioning deficits

A conserved role for Snail as a potentiator of active transcription

The transcription factors of the Snail family are key regulators of epithelial-mesenchymal transitions, cell morphogenesis, and tumor metastasis. Since its discovery in Drosophila ~25 years ago, Snail has been extensively studied for its role as a transcriptional repressor. Here we demonstrate that Drosophila Snail can positively modulate transcriptional activation. By combining information on in vivo occupancy with expression profiling of hand-selected, staged snail mutant embryos, we identified 106 genes that are potentially directly regulated by Snail during mesoderm development. In addition to the expected Snail-repressed genes, almost 50% of Snail targets showed an unanticipated activation. The majority of "Snail-activated" genes have enhancer elements cobound by Twist and are expressed in the mesoderm at the stages of Snail occupancy. Snail can potentiate Twist-mediated enhancer activation in vitro and is essential for enhancer activity in vivo. Using a machine learning approach, we show that differentially enriched motifs are sufficient to predict Snail's regulatory response. In silico mutagenesis revealed a likely causative motif, which we demonstrate is essential for enhancer activation. Taken together, these data indicate that Snail can potentiate enhancer activation by collaborating with different activators, providing a new mechanism by which Snail regulates development

Changing youth? : continuities and ruptures in transitions into adulthood among Catalan young people

The globalisation process has an impact at the micro-level on life-course patterns: concretely, the trajectories of young people into adulthood are being sharply modified. At a European level, the extension, de-linearisation, reversibility and diversification of youth trajectories have been identified as major changes. However, the extent to which these changes affect young people within each country depends on their respective welfare regimes. This article analyses how the Mediterranean welfare regime shapes youth trajectories among Catalan young people and explores the hypothesis that these constraints will make those trajectories less sensitive to the general trends of change identified at a European level. The research is based on an analysis of the Catalan Youth Survey, an official statistic that contains retrospective data on Educational, Work, Housing and Family transitions. The results offer an integrated typology of youth transitions in Catalonia and show how the persistence of traditional patterns of transition are the logical result of the particular articulation of the welfare regime and cultural patterns among Catalan young people

Prenatal exposure to organophosphorus pesticides and childhood neurodevelopmental phenotypes

Prenatal exposure to organophosphorus pesticides (OPs) has been associated with different neurodevelopmental outcomes across different cohorts. A phenotypic approach may address some of these differences by incorporating information across scales and accounting for the complex correlational structure of neurodevelopmental outcomes. Additionally, Bayesian hierarchical modeling can account for confounding by collinear co-exposures. We use this framework to examine associations between prenatal exposure to OPs and behavior, executive functioning, and IQ assessed at age 6–9 years in a cohort of 404 mother/infant pairs recruited during pregnancy. We derived phenotypes of neurodevelopment with a factor analysis, and estimated associations between OP metabolites and these phenotypes in Bayesian hierarchical models for exposure mixtures. We report seven factors: 1) Impulsivity and Externalizing, 2) Executive Functioning, 3) Internalizing, 4) Perceptual Reasoning, 5) Adaptability, 6) Processing Speed, and 7) Verbal Intelligence. These, along with the Working Memory Index, were standardized and scaled so that positive values reflected positive attributes and negative values represented adverse outcomes. Standardized dimethylphosphate metabolites were negatively associated with Internalizing factor scores (β^ − 0.13, 95% CI − 0.26, 0.00) but positively associated with Executive Functioning factor scores (β^ 0.18, 95% CI 0.04, 0.31). Standardized diethylphosphate metabolites were negatively associated with the Working Memory Index (β^ − 0.17, 95% CI − 0.33, − 0.03). Associations with factor scores were generally stronger and more precise than associations with individual instrument-specific items. Factor analysis of outcomes may provide some advantages in etiological studies of childhood neurodevelopment by incorporating information across scales to reduce dimensionality and improve precision

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease