Epilepsy-Associated SCN2A-L1342P Mutation Drives Network Hyperexcitability and Widespread Transcriptomic Changes in Human Cortical Organoids.

Objective: pathogenic mutations, such as the recurrent heterozygous Nav1.2-L1342P, are monogenic causes of epilepsy. In this human-induced pluripotent stem cell model system, we aim to investigate the molecular and cellular mechanisms underlying the SCN2A-L1342P-associated pathology.

Repurposing the anatomy lab: A developmental model for physician formation and human flourishing.

The anatomy lab has traditionally been a cornerstone of medical education, combining technical skill acquisition with professional identity formation. However, a predominant focus on academic performance, coupled with the intensity of this experience, has raised concerns about learner burnout and diminished humanistic development of students. To address these challenges, we adapted Michael Quinn Patton's Developmental Evaluation-a systems-based approach to social innovation-as the Developmental Change Model for Flourishing in Medical Education (DCM-FME).

Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying mutation: Microglial diversity and response in assembloids.

Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABA receptor gene within striatal organoids.

Gene therapies alleviate absence epilepsy associated with deficiency in DBA/2J mice.

Mutations in the voltage-gated sodium channel gene , which encodes the Na1.2 channel, cause severe epileptic seizures. Patients with loss-of-function (LoF) mutations, such as protein-truncating mutations, often experience later-onset and drug-resistant epilepsy, highlighting an urgent unmet clinical need for new therapies.

Autism-associated deficiency disrupts cortico-striatal circuitry in human brain assembloids.

Profound autism spectrum disorder (ASD) is frequently attributable to single-gene mutations, with (voltage-gated sodium channel Na1.2) protein-truncating variants (PTVs) being one of the most penetrant. Although cortico-striatal circuitry is implicated as a key node in ASD, the impact of deficiency on human neural circuits is unknown.

Environmental and dietary factors associated with urinary OH-PAHs in mid-pregnancy in a large multi-site study.

Background: PAH exposure is associated with adverse health outcomes, but exposure sources in pregnancy are not well-understood.

Objectives: We examined associations between urinary OH-PAHs during pregnancy and environmental tobacco smoke (ETS) and short-term ambient air pollution exposure. Participants included 1603 pregnant non-smokers in three cohorts from 7 sites across the USA.

A Prospective Analysis of Per- and Polyfluoroalkyl Substances from Early Pregnancy to Delivery in the Atlanta African American Maternal-Child Cohort.

Background: Longitudinal trends in per- and polyfluoroalkyl substances (PFAS) serum concentrations across pregnancy have not been thoroughly examined, despite evidence linking prenatal PFAS exposures with adverse birth outcomes.

Objectives: We sought to characterize longitudinal PFAS concentrations across pregnancy and to examine the maternal-fetal transfer ratio among participants in a study of risk and protective factors for adverse birth outcomes among African Americans.

Methods: In the Atlanta African American Maternal-Child cohort (2014-2020), we quantified serum concentrations of four PFAS in 376 participants and an additional eight PFAS in a subset of 301 participants during early (8-14 weeks gestation) and late pregnancy (24-30 weeks gestation).

Organophosphate ester flame retardant chemicals and maternal depression during pregnancy.

Background: Depression substantially contributes to pregnancy-related morbidity, and pregnancy is increasingly recognized as a vulnerable window for exposure effects on maternal mental health. Exposures to organophosphate esters (OPEs) are ubiquitous and may have neurotoxic effects; however, their impacts on prenatal depression remain unknown. We evaluated associations of third trimester OPE metabolites on maternal depressive symptoms during pregnancy.

Urinary polycyclic aromatic hydrocarbon (PAH) metabolite concentrations in three pregnancy cohorts from 7 U.S. study sites.

Objective: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse birth and developmental outcomes in children. We aimed to describe prenatal PAH exposures in a large, multisite U.S.

Prenatal exposures to organophosphate ester metabolites and early motor development in the MADRES cohort.

Organophosphate esters (OPEs) are increasingly considered neurotoxicants which may impact gross and fine motor development. We evaluated associations between prenatal OPE exposures and infant motor development. Third trimester urinary concentrations of nine OPE metabolites were measured in 329 mother-infant dyads participating in the Maternal And Developmental Risks from Environmental and Social Stressors (MADRES) cohort.

The Interplay Between Cholesterol and Amyloid-β on HT22 Cell Viability, Morphology, and Receptor Tyrosine Kinase Signaling.

Background: There is a lack of understanding in the molecular and cellular mechanisms of Alzheimer's disease that has hindered progress on therapeutic development. The focus has been on targeting toxic amyloid-β (Aβ) pathology, but these therapeutics have generally failed in clinical trials. Aβ is an aggregation-prone protein that has been shown to disrupt cell membrane structure in molecular biophysics studies and interfere with membrane receptor signaling in cell and animal studies.

PFAS concentrations in early and mid-pregnancy and risk of gestational diabetes mellitus in a nested case-control study within the ethnically and racially diverse PETALS cohort.

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals and are commonly found in everyday items. PFAS have been linked to disrupting glucose homeostasis, however, whether they are associated with gestational diabetes mellitus (GDM) risk remains inconclusive. We examined prospective associations of PFAS concentrations measured twice in pregnancy with GDM risk.

Synthesis of a photocleavable bola-phosphatidylcholine.

Phosphatidylinositol transfer proteins (PITPs) are ubiquitous in eukaryotes and are involved in the regulation of phospholipid metabolism, membrane trafficking, and signal transduction. Sec14 is a yeast PITP that has been shown to transfer phosphatidylinositol (PI) or phosphatidylcholine (PC) from the endoplasmic reticulum to the Golgi. It is now believed that Sec14 may play a greater role than just shuttling PI and PC throughout the cell.

Perfluoroalkyl substances (PFAS) and lead (Pb) as "cardiovascular disruptors" in 9-11-year-old children living in Syracuse, New York, United States.

Objective: Per- and polyfluoro-alkyl substances (PFAS) and lead (Pb) are ubiquitous environmental toxicants with apparent impact on cardiovascular disease (CVD) risk. As one possible mechanism for this increased risk, we have previously demonstrated an association between Pb exposure and heightened cardiovascular reactivity to acute psychological stress, a CVD risk factor. The present study expands this approach and considers both PFAS and Pb exposures (and the possible interaction).

Prenatal polycyclic aromatic hydrocarbon exposure and asthma at age 8-9 years in a multi-site longitudinal study.

Background And Aim: Studies suggest prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) may influence wheezing or asthma in preschool-aged children. However, the impact of prenatal PAH exposure on asthma and wheeze in middle childhood remain unclear. We investigated these associations in diverse participants from the ECHO PATHWAYS multi-cohort consortium.

Sex-specific effects of prenatal organophosphate ester (OPE) metabolite mixtures and adverse infant birth outcomes in the maternal and developmental risks from environmental and social stressors (MADRES) pregnancy cohort.

Background: Organophosphate esters (OPEs) are used as flame retardants and plasticizers in various consumer products. Limited prior research suggests sex-specific effects of prenatal OPE exposures on fetal development. We evaluated overall and sex-specific associations between prenatal OPE exposures and gestational age (GA) at birth and birthweight for gestational age (BW for GA) z-scores among the predominately low-income, Hispanic MADRES cohort.

Birth Outcomes in Relation to Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Stress in the Environmental Influences on Child Health Outcomes (ECHO) Program.

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress.

Prevalence of neonicotinoid insecticides in paired private-well tap water and human urine samples in a region of intense agriculture overlying vulnerable aquifers in eastern Iowa.

A pilot study among farming households in eastern Iowa was conducted to assess human exposure to neonicotinoids (NEOs). The study was in a region with intense crop and livestock production and where groundwater is vulnerable to surface-applied contaminants. In addition to paired outdoor (hydrant) water and indoor (tap) water samples from private wells, urine samples were collected from 47 adult male pesticide applicators along with the completions of dietary and occupational surveys.

Detected prenatal perfluorooctanoic acid (PFOA) exposure is associated with decreased fetal head biometric parameters in participants experiencing higher perceived stress during pregnancy in the MADRES cohort.

Background: Perfluoroalkyl substances (PFAS) are ubiquitous synthetic chemicals with long half-lives and are known to cross the placenta during pregnancy. We examined the influence of maternal PFAS levels on fetal growth trajectories and assessed whether maternal stress modified these associations.

Methods: Blood serum concentrations of five PFAS (PFOS, PFHxS, PFNA, PFOA, PFDA) were measured in 335 prenatal specimens (mean gestational age (GA): 21±9 weeks) in the MADRES cohort.

Prenatal polycyclic aromatic hydrocarbon (PAH) exposure in relation to placental corticotropin releasing hormone (pCRH) in the CANDLE pregnancy cohort.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous endocrine-disrupting combustion by-products that have been linked to preterm birth. One possible mechanism is through disruption of placental corticotropin releasing hormone (pCRH), a key hormone implicated in parturition. As an extension of recent research identifying pCRH as a potential target of endocrine disruption, we examined maternal PAH exposure in relation to pCRH in a large, diverse sample.