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Liquid-liquid phase separation (LLPS) underlies diverse biological processes. Because most LLPS studies were performed in vitro using recombinant proteins or in cells that overexpress protein, the physiological relevance of LLPS for endogenous protein is often unclear. PERIOD, the intrinsically disordered domain-rich proteins, are central mammalian circadian clock components and interact with other clock proteins in the core circadian negative feedback loop. Different core clock proteins were previously shown to form large complexes. Circadian clock studies often rely on experiments that overexpress clock proteins. Here, we show that when Per2 transgene was stably expressed in cells, PER2 protein formed nuclear phosphorylation-dependent slow-moving LLPS condensates that recruited other clock proteins. Super-resolution microscopy of endogenous PER2, however, revealed formation of circadian-controlled, rapidly diffusing nuclear microbodies that were resistant to protein concentration changes, hexanediol treatment, and loss of phosphorylation, indicating that they are distinct from the LLPS condensates caused by protein overexpression. Surprisingly, only a small fraction of endogenous PER2 microbodies transiently interact with endogenous BMAL1 and CRY1, a conclusion that was confirmed in cells and in mice tissues, suggesting an enzyme-like mechanism in the circadian negative feedback process. Together, these results demonstrate that the dynamic interactions of core clock proteins are a key feature of mammalian circadian clock mechanism and the importance of examining endogenous proteins in LLPS and circadian clock studies.

Aim: To assess the validity of the Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations–Questionnaire (ESSENCE‐Q), a simple screening tool for neurodevelopmental problems, in Japan. Method: Parents/caregivers completed the 11‐item ESSENCE‐Q for 77 612 children aged 2 years 6 months included in a national birth cohort study. Information about neurodevelopmental disorders (NDDs: autism spectrum disorder; intellectual disability and/or developmental language disorder; motor delay/motor disorder) was collected at age 3 years. Each ESSENCE‐Q item was scored on a binary (0,1) scale, with a total score range of 0 to 11. Total scores and individual items were compared across children with and without NDDs. Results: NDDs were recorded in 854 children (1.1%). With a total ESSENCE‐Q score cut‐off of ≥3, receiver operating characteristic curve analysis showed an area under the curve of 0.91, with sensitivity 84.9%, specificity 84.8%, positive predictive value 5.9%, and negative predictive value 99.8%. The proportion of parental concerns at 2 years 6 months differed significantly by NDD status for communication (89.5% vs 14.2%) and general development (80.2% vs 7.4%). ESSENCE‐Q total scores were moderately negatively correlated (−0.36, p < 0.001) with Japanese Ages and Stages Questionnaire scores. Interpretation: The parent/caregiver‐completed ESSENCE‐Q is useful as a tool for screening out children with neurotypical development at this early age. Further research into longer‐term predictive validity will be possible as more NDD diagnoses are given as the children grow up. [ABSTRACT FROM AUTHOR]

Purpose: The effects of general anesthesia on neurodevelopment in children remain controversial. We explored the relationship between general anesthesia and neurodevelopment in children participating in the Japan Environment and Children's Study (JECS). Methods: This study enrolled children born between 37 and 41 weeks of pregnancy via single-vaginal delivery to pregnant women registered in the JECS between January 2011 and March 2014. Data were collected from mother-completed questionnaires and medical transcripts. Neurodevelopment in five domains was assessed every 6 months between 12 and 48 months of age, using the Ages and Stages Questionnaires. The associations between general anesthesia exposure during early childhood and neurodevelopment in children were evaluated at each time point. Adjusted odds ratios and 95% confidence intervals were estimated after covariate adjustment using logistic regression models. Results: Children who received general anesthesia before age 1 year had higher risks of neurodevelopmental delay in all five domains throughout the observational period. The largest risk was for gross motor delay at 18 months (adjusted odds ratio: 3.51; 95% confidence interval: 2.75–4.49). The effects on the incidence of neurodevelopmental delays after age 3 were not observed except for problem solving at 48 months. The risk of neurodevelopmental delay in children who first received general anesthesia after age 1 was considerably small. Conclusions: This study suggests that general anesthesia administration before age 1 is associated with neurodevelopmental delay during 1–4 years of age. The risk of general anesthesia after age 1 may be small. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the association between atopic dermatitis in pregnant women and preterm births, accounting for maternal ritodrine hydrochloride administration status. Methods: Data of 83,796 women with singleton pregnancies at and after 22 weeks of gestation (enrolled between 2011 and 2014) were analyzed. These data were obtained from the Japan Environment and Children's Study. Atopic dermatitis was defined based on self-reported questionnaire responses obtained during the first trimester. The primary outcome measures were preterm births before 37, 32, and 28 weeks of gestation. Using a multivariable logistic regression model, odds ratios for preterm births in pregnant women with atopic dermatitis were calculated, with women without atopic dermatitis included in the reference group. This analysis considered confounding factors and maternal ritodrine hydrochloride administration. Results: Among pregnant women with atopic dermatitis, the adjusted odds ratios (95% confidence intervals) for preterm births before 37, 32, and 28 weeks of gestation were 0.89 (0.81–0.98), 0.98 (0.74–1.30), and 0.88 (0.50–1.55), respectively. This trend remained consistent after excluding participants who received ritodrine hydrochloride. Conclusions for practice: Atopic dermatitis in pregnant women was significantly associated with a decreased incidence of preterm births before 37 weeks of gestation, even after accounting for the effects of maternal ritodrine hydrochloride administration. Significance: What is already known on this subject?: Atopic dermatitis is among the most prevalent chronic dermatological conditions in pregnant women. The association between atopic dermatitis in pregnant women and obstetric outcomes remains unclear owing to conflicting research findings. What this study adds?: Atopic dermatitis in pregnant women was significantly associated with a decreased incidence of preterm births before 37 weeks of gestation. The trend was the same in participants without maternal ritodrine hydrochloride administration. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate differences in maternal characteristics and obstetric and offspring childhood outcomes between births at and after 37 weeks of gestation (referred to as term and post-term births) according to the use of tocolytic treatment. Methods: Data for 63,409 women with singleton births at and after 37 weeks of gestation were analyzed using data from the Japan Environment and Children's Study (JECS). We compared maternal characteristics, obstetric outcomes, and offspring childhood outcomes between term and post-term births exposed and not exposed to tocolytic treatment. Additionally, multivariable logistic regression models were used to calculate adjusted odds ratios for offspring childhood outcomes with significant between-group differences in the univariable analysis, with term and post-term births without tocolytic agents as the reference group. Results: We observed differences in maternal characteristics and obstetric outcomes between term and post-term births exposed and not exposed to tocolytic treatment. The incidence of offspring childhood developmental disorders showed no significant between-group differences. However, participants exposed to tocolytic agents had higher incidence of offspring childhood allergic disorders. The adjusted odds ratio for any of the offspring childhood allergic disorders in term and post-term births with tocolytic agents was 1.08 (95% confidence interval, 1.03–1.13). Conclusion: This study found no significant difference in the incidence of offspring developmental disorders between term and post-term births exposed and not exposed to tocolytic treatment. However, tocolytic treatment was associated with differences in maternal characteristics and obstetric outcomes, along with a marginal increase in the incidence of childhood allergic disorders in offspring. [ABSTRACT FROM AUTHOR]

Microtubule (MT)-dependent transport is a critical means of intracellular movement of cellular cargo by kinesin and dynein motors. MT-dependent transport is tightly regulated by cellular MT-associated proteins (MAPs) that directly bind to MTs and either promote or impede motor protein function. Viruses have been widely shown to usurp MT-dependent transport to facilitate their virion movement to sites of replication and/or for exit from the cell. However, it is unclear if viruses also negatively regulate MT-dependent transport. Using single-molecule motility and cellular transport assays, we show that the vaccinia virus (VV)-encoded MAP, A51R, inhibits kinesin-1-dependent transport along MTs in vitro and in cells. This inhibition is selective as the function of kinesin-3 is largely unaffected by VV A51R. Interestingly, we show that A51R promotes the perinuclear accumulation of cellular cargo transported by kinesin-1 such as lysosomes and mitochondria during infection. Moreover, A51R also regulates the release of specialized VV virions that exit the cell using kinesin-1-dependent movement. Using a fluorescently tagged rigor mutant of kinesin-1, we show that these motors accumulate on A51R-stabilized MTs, suggesting these stabilized MTs may form a "kinesin-1 sink" to regulate MT-dependent transport in the cell. Collectively, our findings uncover a new mechanism by which viruses regulate host cytoskeletal processes. [ABSTRACT FROM AUTHOR]

Background: Food allergy children and their families tend to have emotional distress and anxiety. There have been few reports of differences in parenting stress and a child's food allergy phenotypes. Methods: We examined the associations between food allergy phenotypes in children and parenting stress assessed by the Parenting Stress Index‐Short Form (PSI‐SF) from a national birth cohort (Japan Environment and Children's Study). Results: We included 65,805 children for statistical analysis. Of them, 7.2% of children had a food allergy diagnosis at 2 years old. The means of the total PSI‐SF (39.9 ± 10.3, 39.1 ± 9.9), CD‐SF (19.5 ± 5.4, 19.1 ± 5.2), and PD‐SF (20.5 ± 6.3, 20.0 ± 6.1) scores are similar for caregivers in the with and without food allergy groups. Food allergy diagnosis resulted in significantly higher total PSI scores (coefficient.47, 95% CI 0.19–0.75, p =.001), CD‐SF (coefficient.22, 95% CI 0.07–0.38, p =.004), and PD‐SF (coefficient.24, 95% CI 0.08–0.41, p =.004). A similar trend was observed for allergy reactions to hen's egg. However, there was no clear relationship between allergic reactions to milk, wheat, nuts, and PSI‐SF. Conclusions: Parental stress was significantly related to a child's food allergy. Furthermore, hen's egg allergy increased parental stress. Multiple food avoidance might also increase parental stress. Healthcare providers need to be aware of parental stress in our daily clinic. [ABSTRACT FROM AUTHOR]

Background: To our knowledge, the association of maternal exposure to metallic elements with weight trajectory pattern from the neonatal period has not been investigated. Objectives: The goals of this study were to identify infant growth trajectories in weight in the first 3 y of life and to determine the associations of maternal blood levels of lead, cadmium, mercury, selenium, and manganese with growth trajectory. Methods: This longitudinal study, part of the Japan Environment and Children Study, enrolled 103,099 pregnant women at 15 Regional Centres across Japan between 2011 and 2014. Lead, cadmium, mercury, selenium, and manganese levels were measured in blood samples collected in the second (14-27 wk gestational age) or third trimester ([greater than or equal to] 28 wk). Growth trajectory of 99,014 children was followed until age 3 y. Raw weight values were transformed to age- and sex-specific weight standard deviation (SD) scores, and latent-class group-based trajectory models were estimated to determine weight trajectories. Associations between maternal metallic element levels and weight trajectory were examined using multinomial logistic regression models after confounder adjustment. Results: We identified 5 trajectory patterns based on weight SD score: 4.74% of infants were classified in Group I, very small to small; 31.26% in Group II, moderately small; 21.91% in Group III, moderately small to moderately large; 28.06% in Group IV, moderately large to normal; and 14.03% in Group V, moderately large to large. On multinomial logistic regression, higher maternal lead and selenium levels tended to be associated with increased odds ratios (ORs) of poor weight SD score trajectories (Groups I and II), in comparison with Group III. Higher levels of mercury were associated with decreased ORs, whereas higher levels of manganese were associated with increased ORs of 'moderately large' trajectories (Groups IV and V). Discussion: Maternal lead, mercury, selenium, and manganese blood levels affect infant growth trajectory pattern in the first 3 y of life. https://doi.org/10.1289/EHP10321, Introduction The World Health Organization (WHO) estimates that 15%20% of all births have low birth weight (LBW) (1); in particular, 6% of infants born in East Asia and the Pacific, [...]

Otitis media, one of the most common childhood diseases, is characterized by inflammation or infection of the middle ear. Due to their ease of access, daily probiotics are recommended for the prevention of early childhood otitis media. This study aimed to assess the impact of probiotics on the incidence of otitis media using a dataset (n = 95,380) from the Japan Environment and Children's Study, a nationwide birth cohort study. After multiple imputations, the association between the incidence of otitis media in early childhood and the daily frequency of yogurt intake in children and mothers was examined using a generalized linear model after adjusting for several confounders. Repeated incidence of otitis media during the 2 years after birth was found in 14,874 participants (15.6%). Based on participants with the lowest frequency of yogurt intake ("almost never") as the reference group, risk ratios for otitis media incidence decreased with higher frequencies of yogurt intake in children at one year of age, but also independently in mothers during pregnancy. The lowest risk ratio (95% confidence interval) for otitis media incidence at six months of age was observed with the most frequent yogurt intake (once/day or more) (0.54 [0.46–0.63]). Additionally, although a similar association was observed in the subgroup of those with cleft lip and/or palate (CL/P), a high-risk group for severe recurrent otitis media, no statistical significance was observed. Thus, increased regular yogurt intake in both children and mothers was associated with a decrease of otitis media during early childhood. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting young children, with an unclear etiology. We investigated the link between maternal heavy metal exposure and KD incidence in children using the Japan Environment and Children's Study, a large-scale nationwide prospective cohort with approximately 100,000 mother–child pairs. Maternal blood samples collected during the second/third trimester were analyzed for heavy metals [mercury (Hg), cadmium (Cd), lead (Pb), selenium (Se), manganese (Mn)], divided into four quartiles based on concentration levels. KD incidence within the first year of life was tracked via questionnaire. Among 85,378 mother–child pairs, 316 children (0.37%) under one year were diagnosed with KD. Compared with the lowest concentration group (Q1), the highest (Q4) showed odds ratios (95% confidence interval) for Hg, 1.29 (0.82–2.03); Cd, 0.99 (0.63–1.58); Pb, 0.84 (0.52–1.34); Se, 1.17 (0.70–1.94); Mn, 0.70 (0.44–1.11), indicating no concentration-dependent increase. Sensitivity analyses with logarithmic transformation and extended outcomes up to age 3 yielded similar results. No significant association was found between maternal heavy metal levels and KD incidence, suggesting that heavy metal exposure does not increase KD risk. [ABSTRACT FROM AUTHOR]