Autism genes converge on asynchronous development of shared neuron classes.

Genetic risk for autism spectrum disorder (ASD) is associated with hundreds of genes spanning a wide range of biological functions1-6. The alterations in the human brain resulting from mutations in these genes remain unclear. Furthermore, their phenotypic manifestation varies across individuals7,8. Here we used organoid models of the human cerebral cortex to identify cell-type-specific developmental abnormalities that result from haploinsufficiency in three ASD risk genes-SUV420H1 (also known as KMT5B), ARID1B and CHD8-in multiple cell lines from different donors, using single-cell RNA-sequencing (scRNA-seq) analysis of more than 745,000 cells and proteomic analysis of individual organoids, to identify phenotypic convergence. Each of the three mutations confers asynchronous development of two main cortical neuronal lineages-γ-aminobutyric-acid-releasing (GABAergic) neurons and deep-layer excitatory projection neurons-but acts through largely distinct molecular pathways. Although these phenotypes are consistent across cell lines, their expressivity is influenced by the individual genomic context, in a manner that is dependent on both the risk gene and the developmental defect. Calcium imaging in intact organoids shows that these early-stage developmental changes are followed by abnormal circuit activity. This research uncovers cell-type-specific neurodevelopmental abnormalities that are shared across ASD risk genes and are finely modulated by human genomic context, finding convergence in the neurobiological basis of how different risk genes contribute to ASD pathology.

Application of a Web-based Tool for Quantitative Bias Analysis: The Example of Misclassification Due to Self-reported Body Mass Index.

BACKGROUND: We describe the use of Apisensr, a web-based application that can be used to implement quantitative bias analysis for misclassification, selection bias, and unmeasured confounding. We apply Apisensr using an example of exposure misclassification bias due to use of self-reported body mass index (BMI) to define obesity status in an analysis of the relationship between obesity and diabetes. METHODS: We used publicly available data from the National Health and Nutrition Examination Survey. The analysis consisted of: (1) estimating bias parameter values (sensitivity, specificity, negative predictive value, and positive predictive value) for self-reported obesity by sex, age, and race-ethnicity compared to obesity defined by measured BMI, and (2) using Apisensr to adjust for exposure misclassification. RESULTS: The discrepancy between self-reported and measured obesity varied by demographic group (sensitivity range: 75%-89%; specificity range: 91%-99%). Using Apisensr for quantitative bias analysis, there was a clear pattern in the results: the relationship between obesity and diabetes was underestimated using self-report in all age, sex, and race-ethnicity categories compared to measured obesity. For example, in non-Hispanic White men aged 40-59 years, prevalence odds ratios for diabetes were 3.06 (95% confidence inerval = 1.78, 5.30) using self-reported BMI and 4.11 (95% confidence interval = 2.56, 6.75) after bias analysis adjusting for misclassification. CONCLUSION: Apisensr is an easy-to-use, web-based Shiny app designed to facilitate quantitative bias analysis. Our results also provide estimates of bias parameter values that can be used by other researchers interested in examining obesity defined by self-reported BMI.

Opposing functions of the plant TOPLESS gene family during SNC1-mediated autoimmunity.

Regulation of the plant immune system is important for controlling the specificity and amplitude of responses to pathogens and in preventing growth-inhibiting autoimmunity that leads to reductions in plant fitness. In previous work, we reported that SRFR1, a negative regulator of effector-triggered immunity, interacts with SNC1 and EDS1. When SRFR1 is non-functional in the Arabidopsis accession Col-0, SNC1 levels increase, causing a cascade of events that lead to autoimmunity phenotypes. Previous work showed that some members of the transcriptional co-repressor family TOPLESS interact with SNC1 to repress negative regulators of immunity. Therefore, to explore potential connections between SRFR1 and TOPLESS family members, we took a genetic approach that examined the effect of each TOPLESS member in the srfr1 mutant background. The data indicated that an additive genetic interaction exists between SRFR1 and two members of the TOPLESS family, TPR2 and TPR3, as demonstrated by increased stunting and elevated PR2 expression in srfr1 tpr2 and srfr1 tpr2 tpr3 mutants. Furthermore, the tpr2 mutation intensifies autoimmunity in the auto-active snc1-1 mutant, indicating a novel role of these TOPLESS family members in negatively regulating SNC1-dependent phenotypes. This negative regulation can also be reversed by overexpressing TPR2 in the srfr1 tpr2 background. Similar to TPR1 that positively regulates snc1-1 phenotypes by interacting with SNC1, we show here that TPR2 directly binds the N-terminal domain of SNC1. In addition, TPR2 interacts with TPR1 in vivo, suggesting that the opposite functions of TPR2 and TPR1 are based on titration of SNC1-TPR1 complexes by TPR2 or altered functions of a SNC1-TPR1-TPR2 complex. Thus, this work uncovers diverse functions of individual members of the TOPLESS family in Arabidopsis and provides evidence for the additive effect of transcriptional and post-transcriptional regulation of SNC1.

Association between breakfast skipping and blood levels of lead and cadmium in children and adolescents aged 6-17 years: Results from the National Health and Nutrition Examination Survey 2013-2018.

INTRODUCTION: Previous research suggests that fasting increases lead absorption in the gastrointestinal tract, and that regularly eating meals may reduce blood lead. However, there is insufficient evidence linking breakfast status and blood-metal levels in children. We assessed the cross-sectional association between breakfast consumption status and children and adolescent's blood levels of lead and cadmium. We also explored blood hemoglobin, serum ferritin, and age group as potential effect modifiers of these associations. METHODS: This analysis included children and adolescents aged 6-17 years who participated in the National Health and Nutrition Examination Survey (NHANES) cycles 2013-2018 with complete data on breakfast consumption status (consumers vs. skippers), blood metals, and covariates (N=3722). Blood metal variables were log-transformed. Crude and covariate-adjusted, survey-weighted linear regression models were conducted for each blood metal outcome. Potential effect modification was explored using stratification. RESULTS: Overall fewer participants reported skipping breakfast (n=719) than eating breakfast (n=3003). Mean (SE) concentrations of blood lead and cadmium (µg/L) were 0.63 (0.01) µg/dL and 0.13 (0.00) µg/L, respectively. Children and adolescents who skipped breakfast were more likely to be female (51.2%), older (mean 12.2 years, SE = 0.1), have a higher body mass index (mean 22.8 kg/m2, SE = 0.2), and a lower income-poverty ratio (mean 1.7, SE = 0.1) than breakfast consumers. No associations between breakfast consumption and any of the blood metals were found. When stratified by age (≤ 10, 11-13, and 14-17 years), children aged 11-13 years who consumed breakfast had lower log-transformed blood lead levels [ß = -0.14 µg/L; 95% CI: (-0.25, -0.03)] compared to children of the same age who skipped breakfast. CONCLUSION: Children 11-13 years-old who were breakfast consumers had lower blood lead levels compared to children of the same age who skipped breakfast. Our results support that encouraging breakfast consumption among school-age children may contribute to lower blood lead levels.

The East Indies reptile tick Amblyomma helvolum Koch, 1844 (Acari: Ixodidae), taxonomy, biology and new host records, including the first record of human infestation.

Amblyomma helvolum is a widespread, generalist ectoparasite of reptiles in the oriental region, and has the potential to become highly invasive should it be inadvertently introduced outside its native range through the exotic pet trade. All life stages of A. helvolum are re-characterised morphologically and the first examples of nanism (dwarfism) and gynandromorphy (male and female tissue in one animal) for the species are described. Eighteen new hosts records are presented for A. helvolum, including the first case of human infestation. The taxonomy, distribution, ecology, phenology, disease associations, and invasion biology of the species are also discussed.