Gestational SARS-CoV-2 infection is associated with placental expression of immune and trophoblast genes.

Introduction: Maternal SARS-CoV-2 infection during pregnancy is associated with adverse pregnancy outcomes and can have effects on the placenta, even in the absence of severe disease or vertical transmission to the fetus. This study aimed to evaluate histopathologic and molecular effects in the placenta after SARS-CoV-2 infection during pregnancy.

Methods: We performed a study of 45 pregnant participants from the Generation C prospective cohort study at the Mount Sinai Health System in New York City.

Histology and Transcriptome Profiles of the Mammary Gland across Critical Windows of Development in Sprague Dawley Rats.

Breast development occurs through well-defined stages representing 'windows of susceptibility' to adverse environmental exposures that potentially modify breast cancer risk. Systematic characterization of morphology and transcriptome during normal breast development lays the foundation of our understanding of cancer etiology. We examined mammary glands in female Sprague Dawley rats across six developmental stages - pre-pubertal, peri-pubertal, pubertal, lactation, adult parous and adult nulliparous.

Novel Predictors of Breast Cancer Survival Derived from miRNA Activity Analysis.

Breast cancer is among the leading causes of cancer-related death; discovery of novel prognostic markers is needed to improve outcomes. Combining systems biology and epidemiology, we investigated miRNA-associated genes and breast cancer survival in a well-characterized population-based study. A recently developed algorithm, , was used to identify key miRNA "activities" corresponding to target gene degradation, which were predictive of breast cancer mortality in published databases.

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.

Changes in mammary histology and transcriptome profiles by low-dose exposure to environmental phenols at critical windows of development.

Exposure to environmental chemicals has been linked to altered mammary development and cancer risk at high doses using animal models. Effects at low doses comparable to human exposure remain poorly understood, especially during critical developmental windows. We investigated the effects of two environmental phenols commonly used in personal care products - methyl paraben (MPB) and triclosan (TCS) - on the histology and transcriptome of normal mammary glands at low doses mimicking human exposure during critical windows of development.

Enlarged leukocyte referent libraries can explain additional variance in blood-based epigenome-wide association studies.

Aim: We examined whether variation in blood-based epigenome-wide association studies could be more completely explained by augmenting existing reference DNA methylation libraries.

Materials & Methods: We compared existing and enhanced libraries in predicting variability in three publicly available 450K methylation datasets that collected whole-blood samples. Models were fit separately to each CpG site and used to estimate the additional variability when adjustments for cell composition were made with each library.

Prenatal Exposure to Organophosphorous Pesticides and Fetal Growth: Pooled Results from Four Longitudinal Birth Cohort Studies.

Background: Organophosphorous (OP) pesticides are associated with reduced fetal growth in animals, but human studies are inconsistent.

Objectives: We pooled data from four cohorts to examine associations of prenatal OP exposure with birth weight (n = 1,169), length (n = 1,152), and head circumference (n = 1,143).

Methods: Data were from the CHAMACOS, HOME, Columbia, and Mount Sinai birth cohorts.

Prenatal Organophosphorus Pesticide Exposure and Child Neurodevelopment at 24 Months: An Analysis of Four Birth Cohorts.

Background: Organophosphorus pesticides (OPs) are used in agriculture worldwide. Residential use was common in the United States before 2001.

Objectives: We conducted a pooled analysis of four birth cohorts (children's centers; n = 936) to evaluate associations of prenatal exposure to OPs with child development at 24 months.

Human Dendritic Cell Response Signatures Distinguish 1918, Pandemic, and Seasonal H1N1 Influenza Viruses.

Unlabelled: Influenza viruses continue to present global threats to human health. Antigenic drift and shift, genetic reassortment, and cross-species transmission generate new strains with differences in epidemiology and clinical severity. We compared the temporal transcriptional responses of human dendritic cells (DC) to infection with two pandemic (A/Brevig Mission/1/1918, A/California/4/2009) and two seasonal (A/New Caledonia/20/1999, A/Texas/36/1991) H1N1 influenza viruses.

Mouse dendritic cell (DC) influenza virus infectivity is much lower than that for human DCs and is hemagglutinin subtype dependent.

We show that influenza A H1N1 virus infection leads to very low infectivity in mouse dendritic cells (DCs) in vitro compared with that in human DCs. This holds when H3 or H5 replaces H1 in recombinant viruses. Viruslike particles confirm the difference between mouse and human, suggesting that reduced virus entry contributes to lower mouse DC infectivity.

DNA methylation in peripheral blood measured by LUMA is associated with breast cancer in a population-based study.

Our purpose was to identify epigenetic markers of breast cancer risk, which can be reliably measured in peripheral blood and are amenable for large population screening. We used 2 independent assays, luminometric methylation assay (LUMA) and long interspersed elements-1 (LINE-1) to measure "global methylation content" in peripheral blood DNA from a well-characterized population-based case-control study. We examined associations between methylation levels and breast cancer risk among 1055 cases and 1101 controls and potential influences of 1-carbon metabolism on global methylation.

The influence of one-carbon metabolism on gene promoter methylation in a population-based breast cancer study.

Abnormal methylation in gene promoters is a hallmark of the cancer genome; however, factors that may influence promoter methylation have not been well elucidated. As the one-carbon metabolism pathway provides the universal methyl donor for methylation reactions, perturbation of this pathway might influence DNA methylation and, ultimately, affect gene functions. Utilizing approximately 800 breast cancer tumor tissues from a large population-based study, we investigated the relationships between dietary and genetic factors involved in the one-carbon metabolism pathway and promoter methylation of a panel of 13 breast cancer-related genes.

Differential methylation of imprinted genes in growth-restricted placentas.

A complex network of epigenetic factors participates in regulating the monoallelic expression of a small subset of genes (~1%) in the human genome. This phenomenon goes under the definition of genomic imprinting, a parent-of-origin effect that, when altered during early embryogenesis, may influence fetal development into adulthood. Pertubations in genomic imprinting have been associated with placental and fetal growth restrictions.

Prenatal exposure to organophosphates, paraoxonase 1, and cognitive development in childhood.

Background: Prenatal exposure to organophosphate pesticides has been shown to negatively affect child neurobehavioral development. Paraoxonase 1 (PON1) is a key enzyme in the metabolism of organophosphates.

Objective: We examined the relationship between biomarkers of organophosphate exposure, PON1, and cognitive development at ages 12 and 24 months and 6-9 years.

Role of cell-to-cell variability in activating a positive feedback antiviral response in human dendritic cells.

In the first few hours following Newcastle disease viral infection of human monocyte-derived dendritic cells, the induction of IFNB1 is extremely low and the secreted type I interferon response is below the limits of ELISA assay. However, many interferon-induced genes are activated at this time, for example DDX58 (RIGI), which in response to viral RNA induces IFNB1. We investigated whether the early induction of IFNBI in only a small percentage of infected cells leads to low level IFN secretion that then induces IFN-responsive genes in all cells.

Comparing genetic ancestry and self-reported race/ethnicity in a multiethnic population in New York City.

Self-reported race/ethnicity is frequently used in epidemiological studies to assess an individual's background origin. However, in admixed populations such as Hispanic, self-reported race/ethnicity may not accurately represent them genetically because they are admixed with European, African and Native American ancestry. We estimated the proportions of genetic admixture in an ethnically diverse population of 396 mothers and 188 of their children with 35 ancestry informative markers (AIMs) using the STRUCTURE version 2.

Linking emulsion PCR haplotype analysis.

The experimental measurement of haplotype requires the determination of two or more genotypes on the same DNA molecule. Because such measurements are much more complicated than measurements of genotypes, haplotypes are typically inferred using population data for linkage disequilibrium between the markers of interest. We have developed a method for molecular haplotyping, linking emulsion PCR (LE-PCR), and have demonstrated that the method is sufficiently robust to determine haplotypes for multiple markers in a population setting.

A common polymorphism in the caspase recruitment domain of RIG-I modifies the innate immune response of human dendritic cells.

Infection of human dendritic cells (DCs) by negative-strand RNA viruses, such as Newcastle disease virus, leads to the induction of the IFNbeta gene, IFNB1, through the activation of the RNA helicase RIG-I, which is encoded by DDX58. Expression levels of IFNB1 and DDX58 in infected DCs showed positive correlations at the population and the single-cell levels. DDX58 has a common and potentially functional single nucleotide polymorphism, rs10813831 (A/G), encoding an Arg7Cys amino acid change in the RIG-I protein caspase recruitment domain (CARD).

Genomic loss of imprinting in first-trimester human placenta.

Objective: The purpose of this study was to investigate imprinting patterns in first-trimester human placentas.

Study Design: Using samples of 17 first-trimester and 14 term placentas from uncomplicated pregnancies, we assessed loss of imprinting (LOI) at the RNA level in a panel of 14 genes that are known to be imprinted in the placenta with the use of a quantitative allele-specific reverse transcriptase polymerase chain reaction analysis of those genes that contained readout single nucleotide polymorphisms in their transcripts.

Results: There is significant LOI (ie, biallelic expression) in all 14 genes in first-trimester placentas.

Coregulation mapping based on individual phenotypic variation in response to virus infection.

Background: Gene coregulation across a population is an important aspect of the considerable variability of the human immune response to virus infection. Methodology to investigate it must rely on a number of ingredients ranging from gene clustering to transcription factor enrichment analysis.

Results: We have developed a methodology to investigate the gene to gene correlations for the expression of 34 genes linked to the immune response of Newcastle Disease Virus (NDV) infected conventional dendritic cells (DCs) from 145 human donors.

Antiviral response dictated by choreographed cascade of transcription factors.

The dendritic cell (DC) is a master regulator of immune responses. Pathogenic viruses subvert normal immune function in DCs through the expression of immune antagonists. Understanding how these antagonists interact with the host immune system requires knowledge of the underlying genetic regulatory network that operates during an uninhibited antiviral response.

Gene promoter methylation is associated with increased mortality among women with breast cancer.

To better understand breast cancer etiology and progression, we explored the association between promoter methylation status of three breast cancer-related genes (BRCA1, APC, and p16) and survival in a large cohort of women with breast cancer. About 800 archived tumor tissues were collected from women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997. The vital status of the participants was followed through the end of year 2005 with a mean follow-up time of 8.

Power-laws in interferon-B mRNA distribution in virus-infected dendritic cells.

Interferon-beta (IFNB1) mRNA shows very large cell-to-cell variability in primary human dendritic cells infected by Newcastle disease virus, with copy numbers varying from a few to several thousands. Analysis of data from the direct measurement of the expression of this gene in its natural chromatin environment in primary human cells shows that the distribution of mRNA across cells follows a power law with an exponent close to -1, and thus encompasses a range of variation much more extensive than a Gaussian. We also investigate the single cell levels of IFNB1 mRNA induced by infection with Texas influenza A mutant viruses, which vary in their capacity to inhibit the signaling pathways responsible for activation of this gene.

Demonstration of all-or-none loss of imprinting in mRNA expression in single cells.

Loss of imprinting (LOI) is the reactivation of the silenced allele of an imprinted gene, leading to perturbation of monoallelic expression. We tested the hypothesis that LOI of PLAGL1, a representative maternally imprinted gene, occurs through an all-or-none process leading to a mixture of fully imprinted and nonimprinted cells. Herein using a quantitative RT-PCR-based experimental approach, we measured LOI at the single cell level in human trophoblasts and demonstrated a broad distribution of LOI among cells exhibiting LOI, with the mean centered at approximately 100% LOI.