Sarah K. England

Background: Spontaneous preterm birth, defined as delivery before 37 weeks of gestation, remains a global cause of neonatal illness and death, yet treatments for preterm labor remain limited. We hypothesized that K _V 7 channels in the uterus (myometrium), could be a therapeutic target for preventing or treating preterm labor. The aim was to characterize K _V 7 channel subtypes in human myometrium present after labor onset, and to use a preterm birth mouse model to provide proof-of-principal evidence that activating these channels in vivo can delay preterm delivery. Methods: This experimental study integrated studies of human myometrial tissue (term and preterm pregnancies, n = 159 across experiments), with a RU486-induced preterm birth mouse model (C57BL/6 J, n = 6-9 per experimental group), and ex vivo fetal ductus arteriosus preparations (CD-1 mice, n = 10 per group). Molecular and protein profiling, isometric tension recordings, and functional pharmacology were used to characterize K _V 7 mediated regulation of human and mouse uterine contractility. In vivo dosing studies in mice assessed the effects of K _V 7 activators (retigabine and ML213) on delivery timing ( n = 6-9). Results: We show that K _V 7 channels and ancillary units (KCNE1-5), are expressed in pregnant human myometrium, prior to and after the onset of labor. KCNQ4 and KCNE4 transcripts are also present in myometrium taken at preterm gestations ( ± labor). K _V 7.2-5 activators markedly reduce spontaneous contractions in human and mouse myometrium in vitro and significantly delay preterm birth in vivo with limited impact on fetal ductus arteriosus function. Conclusions: These findings support K _V 7 activation as a promising approach to suppress uterine contractility and hence delay preterm birth, highlighting a potential new direction for either drug repurposing or therapeutic development.

Background: Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. Prior studies suggest that sleep—including short sleep duration, sleep apnea, and poor sleep quality—are associated with PTB but rely on self-reported questionnaires and diaries and provide only brief temporal snapshots susceptible to recall bias. This study used data from wearable smartwatches to obtain continuous, objective sleep measurements, enabling more accurate characterization of sleep behaviors. Methods: In this prospective longitudinal study, we evaluated whether alterations in daily rhythms during pregnancy were associated with risk for PTB. We followed a cohort of pregnant study participants enrolled early in pregnancy (< 20 weeks pregnancy) from January 2017 to January 2020 at Washington University in St. Louis Medical Center through delivery. We measured wrist movements every minute for at least 10 days during the first and second trimesters and investigated sleep and circadian metrics with risk of PTB (82 minutes (aRR=1.75, 95% CI: 1.05-2.97). Generally similar, albeit less stable, patterns of findings were observed for PTB <32 weeks’ and <28 weeks’ gestation. Notably, earlier delivery was observed only in participants above the respective threshold, leading to infinite estimates.Interpretation: These results suggest that that daily schedules may be a potential modifiable risk factor for PTB and efforts to increase the regularity of sleep could become a therapeutic strategy to ameliorate PTB.

Prepregnancy BMI (pBMI) and gestational weight gain (GWG) may modulate maternal dyslipidemia during pregnancy, which is associated with adverse pregnancy outcomes and long-term cardiovascular risks. Studies of maternal lipid levels at delivery, when lipid burden peaks, are lacking. Our findings suggest GWG may have a stronger impact than pBMI on delivery lipid levels, with significant differences between White and Black patients, challenging the one-size-fits-all approach to pBMI and GWG recommendations in managing maternal dyslipidemia.

Emerging evidence indicates that the maternal in utero environment has enduring effects on offspring neurodevelopment. The obesity epidemic in the United States affects nearly one-third of women before pregnancy, potentially predisposing offspring to harmful developmental conditions. Glucose, the primary energy source for the brain, is highly regulated by facilitative diffusion glucose transporters (GLUTs). However, our understanding of how maternal obesity influences perinatal cerebral glucose metabolism remains limited. We hypothesized that maternal obesity is associated with altered expression of key GLUTs and dysregulated energy-sensing mechanisms in the fetal brain. Female C57BL/6J mice were randomly assigned to either a control diet (CON) or an obesogenic diet (DIO) (60% kcal from fat, 17.5% kcal from sucrose) for 10 weeks, time-mated with control males, and fed their respective diets throughout gestation. At 18.5 days post coitum, fetal brain tissue was collected for protein analysis. DIO diet did not affect litter size, offspring body weight, or brain weight when compared to CON. Whole brain GLUT1 expression was elevated only in female DIO offspring, while GLUT3 and GLUT4 expression was increased in all DIO offspring without modification by sex. However, maternal diet was not associated with differences in the activation of energy regulatory pathways adenosine monophosphate-activated protein kinase (AMPK) or the nutrient-sensing pathway mechanistic target of rapamycin (mTOR) in the fetal brain. These findings suggest that maternal obesogenic diet alters glucose transporter expression in the fetal brain, indicating a potential disruption in cerebral glucose metabolism during critical periods of perinatal development.

Understanding the spatial determinants of food intake is crucial for establishing links between maternal food environments, diet, and health outcomes. Therefore, this study aimed to identify how the distance and density of built food environments in proximity to African American pregnant women living in urban settings are associated with nutrient-dense, anti-inflammatory food intake. We hypothesized that living closer to grocery stores and farther from fast-food restaurants and convenience stores is associated with increased intake. We also hypothesized that higher grocery-store density and a lower density of fast-food restaurants and convenience stores is associated with increased intake. Using cross-sectional data from the Early Life Adversity, Biological Embedding (eLABE) and Risk for Developmental Precursors of Mental Disorders Study, as well as geographic information system (GIS) data and linear regression analyses, we examined the relationships between the built food environment and food intake in the St. Louis metropolitan area, adjusting for covariates. This analysis revealed that shorter distance to fast-food restaurants and longer distance to grocery stores were associated with higher legume intake in adjusted models. These findings highlight nuanced and counterintuitive associations, underscoring the need for additional research to understand why more distant grocery stores and closer fast-food restaurants are linked to higher legume intake among African Americans.

Circadian rhythms in gene expression and hormones are ubiquitous across species and differentiated cell types, yet their developmental origins remain poorly understood. This study aimed to determine if daily rhythms can be detected in utero and if they synchronize to the mother. We developed methods to longitudinally monitor PERIOD2 (PER2), a core circadian clock protein, from embryonic day (E)8.5 to E17.5 by restricting PER2::LUCIFERASE expression to the mouse fetoplacental unit (fetus and fetal-derived tissues). In utero fetoplacental bioluminescence imaging showed that PER2 levels increased during pregnancy, with variable daily peak times that stabilized to early night by E15.5. Interestingly, pregnancies that did not exhibit daily in utero PER2 variation were more likely to fail. Because maternal glucocorticoids have been implicated in fetal development and synchronizing other circadian tissues, we tested whether glucocorticoid injections could shift fetoplacental PER2 rhythms in utero. Daily subcutaneous corticosterone injections over 5 days of late pregnancy phase-dependently shifted the fetoplacental PER2 rhythms in utero. Blocking glucocorticoid signaling in vitro reduced synchrony between maternal and fetal placenta. We conclude that in utero daily rhythms gradually develop and synchronize with the mother prior to birth, potentially through glucocorticoid signaling.

The human maternal–fetal interface is characterized by mosaic intermingling of maternal and fetal cells ¹ . Yet the underlying cellular, molecular and spatial programmes remain incompletely defined. Here we generate a comprehensive atlas of the human maternal–fetal interface across normal pregnancies from early gestation to term by integrating large-scale paired single-nucleus transcriptomic and chromatin accessibility profiling with submicrometre-resolution spatial transcriptomics and CODEX multiplex protein imaging ² , substantially boosting the spatiotemporal resolution of prior research ³ . This framework delineates common and transient cell types, states and spatial niches across the fetal and maternal compartments, reconstructs transcriptional programmes that guide cytotrophoblast and decidual stromal cell differentiation, and resolves recurrent architecture structural units that build this interface. We identify previously unrecognized arterial endothelial state transitions during cytotrophoblast-mediated spiral artery remodelling and develop a machine learning model that predicts cytotrophoblast invasiveness from transcriptomic signatures. We further discover a decidual stromal cell subtype that suppresses cytotrophoblast invasion via endocannabinoid signalling at the human maternal–fetal interface. By integrating the atlas with genome-wide association data, we pinpoint maternal and fetal cells that are most vulnerable to pre-eclampsia, preterm birth or miscarriage. This resource provides a comprehensive spatially resolved single-cell multiomic reference of the human placenta and decidua and offers a framework for decoding their normal and disordered development.

The delta opioid receptor (DOR) is a promising target for treating pain, anxiety, and depression, yet no DOR-based drugs have reached the clinic. Here, we examine how ligands with varying therapeutic properties modulate DOR function. While full agonists rapidly internalize the receptor, partial agonists show a slower rate of internalization, and antagonists increase cell-surface DOR levels. High-resolution structures of ligand-bound DOR-G _i1 complexes, including those with antagonists engaged, reveal key interactions that account for DOR ligand selectivity, potency, and efficacy. Single-molecule fluorescence resonance energy transfer studies show that DOR dynamically samples three distinct states (active, obligate preactive, and inactive), and transition rates are tuned by both ligand efficacy and G protein coupling. The endogenous agonist, met-enkephalin, not only stabilizes the active-state conformation but also catalyzes transitions between the active and inactive states. These results reveal how ligand-specific interactions and receptor dynamics can govern pharmacological profiles and provide a framework for developing DOR-targeted therapeutics.

Circadian rhythms in gene expression and hormones are ubiquitous across species and differentiated cell types, yet their developmental origins remain poorly understood. This study aimed to determine if daily rhythms can be detected in utero and if they synchronize to the mother. We developed methods to longitudinally monitor PERIOD2 (PER2), a core circadian clock protein, from embryonic day (E)8.5 to E17.5 by restricting PER2::LUCIFERASE (PER2::LUC) expression to the mouse fetoplacental unit (fetus and fetal-derived tissues). In utero fetoplacental bioluminescence imaging showed that PER2 levels rose exponentially during pregnancy, with variable daily peak times that stabilized to dusk by E15.5. Interestingly, pregnancies that did not exhibit daily in utero PER2 variation were more likely to fail. Because maternal glucocorticoids have been implicated in fetal development and synchronizing other circadian tissues, we tested its capability to shift fetoplacental PER2 rhythms in utero . Daily subcutaneous glucocorticoid injections over five days of late pregnancy phase-dependently shifted the fetoplacental PER2 rhythms in utero . Blocking glucocorticoid signaling in vitro reduced synchrony between maternal and fetal placenta by ∼40%. We conclude that in utero daily rhythms gradually develop and synchronize with the mother prior to birth, potentially through glucocorticoid signaling.