Environmental and genetic predictors of whole blood mercury and selenium concentrations in pregnant women in a UK birth cohort.

There is evidence that tissue concentrations of mercury (Hg) and selenium (Se) are predicted by numerous dietary, sociodemographic, environmental, and genetic factors. This study aimed to estimate the relative importance of predictors of Hg and Se concentrations in blood samples taken from pregnant women. The Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK measured whole blood Hg and Se concentrations in 3,972 pregnant women. We identified 30 potential predictors of Hg and 24 of Se, which were evaluated using cross-validated random forests to identify the optimal models for predictive power. The relative importance of individual variables was estimated by averaging the added-R2 per predictor. Linkage disequilibrium score regression was used to estimate the variance explained by genotype. A multivariable model of 14 predictors explained 22.4% of Hg variance (95% CI: 13.0 to 37.1), including 6.9% from blood Se and 3.2% from white fish consumption. There were 11 predictors which explained 15.3% of Se variance (CI: 8.9 to 25.9), including 6.4% from blood Hg, 1.3% from blood lead, and 1.3% from oily fish. Measured genetic variation explained 30% of Hg variance (CI: 8.4 to 51.5) and 37.5% of Se (CI: 10.4 to 64.5). A high proportion of Hg and Se variance could be explained from dietary, sociodemographic, metabolic, and genetic factors. Seafood consumption was less predictive of Hg than may be expected and other factors should be considered when determining risk of exposure. There was tentative evidence that genotype is a major contributor to Hg and Se variation, possibly by modifying the efficacy of internal metabolism.

Using an ER-specific optogenetic mechanostimulator to understand the mechanosensitivity of the endoplasmic reticulum.

The ability of cells to perceive and respond to mechanical cues is essential for numerous biological activities. Emerging evidence indicates important contributions of organelles to cellular mechanosensitivity and mechanotransduction. However, whether and how the endoplasmic reticulum (ER) senses and reacts to mechanical forces remains elusive. To fill the knowledge gap, after developing a light-inducible ER-specific mechanostimulator (LIMER), we identify that mechanostimulation of ER elicits a transient, rapid efflux of Ca2+ from ER in monkey kidney COS-7 cells, which is dependent on the cation channels transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and polycystin-2 (PKD2) in an additive manner. This ER Ca2+ release can be repeatedly stimulated and tuned by varying the intensity and duration of force application. Moreover, ER-specific mechanostimulation inhibits ER-to-Golgi trafficking. Sustained mechanostimuli increase the levels of binding-immunoglobulin protein (BiP) expression and phosphorylated eIF2α, two markers for ER stress. Our results provide direct evidence for ER mechanosensitivity and tight mechanoregulation of ER functions, placing ER as an important player on the intricate map of cellular mechanotransduction.

Toroidic phase transitions in a direct-kagome artificial spin ice.

Ferrotoroidicity-the fourth form of primary ferroic order-breaks both space and time-inversion symmetry. So far, direct observation of ferrotoroidicity in natural materials remains elusive, which impedes the exploration of ferrotoroidic phase transitions. Here we overcome the limitations of natural materials using an artificial nanomagnet system that can be characterized at the constituent level and at different effective temperatures. We design a nanomagnet array as to realize a direct-kagome spin ice. This artificial spin ice exhibits robust toroidal moments and a quasi-degenerate ground state with two distinct low-temperature toroidal phases: ferrotoroidicity and paratoroidicity. Using magnetic force microscopy and Monte Carlo simulation, we demonstrate a phase transition between ferrotoroidicity and paratoroidicity, along with a cross-over to a non-toroidal paramagnetic phase. Our quasi-degenerate artificial spin ice in a direct-kagome structure provides a model system for the investigation of magnetic states and phase transitions that are inaccessible in natural materials.

Unconventional Superconducting Diode Effects via Antisymmetry and Antisymmetry Breaking.

Symmetry breaking plays a pivotal role in unlocking intriguing properties and functionalities in material systems. For example, the breaking of spatial and temporal symmetries leads to a fascinating phenomenon: the superconducting diode effect. However, generating and precisely controlling the superconducting diode effect pose significant challenges. Here, we take a novel route with the deliberate manipulation of magnetic charge potentials to realize unconventional superconducting flux-quantum diode effects. We achieve this through suitably tailored nanoengineered arrays of nanobar magnets on top of a superconducting thin film. We demonstrate the vital roles of inversion antisymmetry and its breaking in evoking unconventional superconducting effects, namely a magnetically symmetric diode effect and an odd-parity magnetotransport effect. These effects are nonvolatilely controllable through in situ magnetization switching of the nanobar magnets. Our findings promote the use of antisymmetry (breaking) for initiating unconventional superconducting properties, paving the way for exciting prospects and innovative functionalities in superconducting electronics.

Impact of closed-off management due to COVID-19 rebound on maternal depression during pregnancy.

BACKGROUND: This study aimed to assess the impacts of closed-off measures with different strictness levels (lockdown, partial lockdown and non-lockdown) and geographic proximity to patients with coronavirus disease 2019 (COVID-19) on prenatal depression during an epidemic rebound of COVID-19. METHODS: This was a cross-sectional web-based survey including 880 pregnant women. Depressive symptoms were measured by Self-Rating Depression Scale (SDS) and geographic proximity was calculated using Geographic Information Systems. Linear and logistic regression were used to assess the associations of closed-off measures and geographic proximity with SDS scores and depressive symptoms. Restricted cubic splines were used to model non-linear associations between geographic proximity and depression symptoms. RESULTS: Compared with those living in non-lockdown areas, women in lockdown areas had higher SDS scores (adjusted ß: 3.51, 95% CI: 1.80, 5.21) and greater risk of depressive symptoms (adjusted OR: 4.00, 95% CI: 2.18, 7.35), but evidence for partial lockdown was not obvious. A progressive increase in the risk of depressive symptoms was found with decreasing distance to COVID-19 patients when geographic proximity was <8 kilometers. Compared to those in the 5th quintile of geographic proximity, women in the first, second and third quintiles had at least 6 times higher risk of depressive symptoms. CONCLUSIONS: Pregnant women under strict closed-off management during COVID-19 epidemic have high risk of depression. A specific range around the residences of reported COVID-19 patients should be underlined as potential clustering of high prenatal depression levels. Our findings highlight the importance of enhancing mental health management during the COVID-19 epidemic for pregnant women.

Comparison of freezing and heating treatment sequence on biochemical properties and flavor of swimming crabs (Portunus Trituberculatus) meat during freeze-thaw cycles.

The objective of this study was to compare the effect of freezing and heating treatment sequences on the biochemical properties and flavor of crab (Portunus trituberculatus) meat during freeze-thaw cycles. The results showed that pH, color, K and microstructure changes in the H-F group were not significant with increasing number of freeze-thaw cycles, but TVB-N values increased and WHC values decreased. However, with the increase in the number of freeze-thaw cycles, pH and WHC significantly decreased and TVB-N, L* and K values significantly increased in the C and F-H groups. Proteins were degraded in all groups, but the lower degree of degradation occurred in the H-F group. Although the total free amino acid content decreased with increasing number of freeze-thaw cycles in each group, the high content of AMP and IMP in the H-F group suggested that it still had a better flavor.

Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation: an epigenome-wide association study meta-analysis.

Background: Prenatal caffeine exposure may influence offspring health via DNA methylation, but no large studies have tested this. Materials & methods: Epigenome-wide association studies and differentially methylated regions in cord blood (450k or EPIC Illumina arrays) were meta-analyzed across six European cohorts (n = 3725). Differential methylation related to self-reported caffeine intake (mg/day) from coffee, tea and cola was compared with assess whether caffeine is driving effects. Results: One CpG site (cg19370043, PRRX1) was associated with caffeine and another (cg14591243, STAG1) with cola intake. A total of 12-22 differentially methylated regions were detected with limited overlap across caffeinated beverages. Conclusion: We found little evidence to support an intrauterine effect of caffeine on offspring DNA methylation. Statistical power limitations may have impacted our findings.

Current guidelines recommend pregnant women to limit caffeine intake to less than 200 mg daily, even though there is no clear proof of its effects on human development. A biological explanation for how exposure to caffeine during pregnancy influences development would help clarify if recommended limits are justified. An epigenetic mechanism, called DNA methylation (DNAm), has been suggested as a potential biological explanation for how caffeine intake during pregnancy influences health development. DNAm can switch genes 'on' or 'off' in response to environmental influences and therefore act as a bridge between genes and the environment. Studies have found that smoking during pregnancy is connected to over 6000 changes in DNAm at birth, with lasting effects into adulthood. To explore the link between caffeine intake during pregnancy and DNAm at birth, we analyzed data from 3725 mother­child pairs living in different European countries. We looked at effects from coffee, tea and cola intake during pregnancy on children's DNAm at birth. We found one change in DNAm to be connected to total caffeine and another to cola consumption during pregnancy. These few connections do not provide convincing evidence that caffeine intake during pregnancy impacts children's DNAm at birth. However, because mothers in our study consumed little caffeine, it is possible that results would be different in studies with participants consuming high amounts of caffeine during pregnancy. Potentially, our study did not include enough people to find very small changes in DNAm that are connected to caffeine consumption during pregnancy.

A high mass loading flexible electrode with a sheet-like Mn3O4/NiMoO4@NiCo LDH on a carbon cloth for supercapacitors.

Mass loading is an important parameter to evaluate the application potential of active materials in high-capacity supercapacitors. Synthesizing active materials with high mass loading is a promising strategy to improve high performance energy storage devices. Preparing electrode materials with a porous structure is of significance to overcome the disadvantages brought by high mass loading. In this work, a Mn3O4/NiMoO4@NiCo layered double hydroxide (MO/NMO/NiCo LDH) positive electrode is fabricated on a carbon cloth with a high mass loading of 20.4 mg cm-2. The MO/NMO/NiCo LDH presents as a special three-dimensional porous nanostructure and exhibits a high specific capacitance of 815 F g-1 at 1 A g-1. Impressively, the flexible supercapacitor based on the MO/NMO/NiCo LDH positive electrode and an AC negative electrode delivers a maximum energy density of 22.5 W h kg-1 and a power density of 8730 W kg-1. It also retains 60.84% of the original specific capacitance after bending to 180° 600 times. Moreover, it exhibits 76.92% capacitance retention after 15 000 charge/discharge cycles. These results make MO/NMO/NiCo LDH one of the most attractive candidates of positive electrode materials for high-performance flexible supercapacitors.

Machine Learning-Based Integration Develops a Macrophage-Related Index for Predicting Prognosis and Immunotherapy Response in Lung Adenocarcinoma.

BACKGROUND: Macrophages play a critical role in tumor immune microenvironment (TIME) formation and cancer progression in lung adenocarcinoma (LUAD). However, few studies have comprehensively and systematically described the characteristics of macrophages in LUAD. METHODS: This study identified macrophage-related markers with single-cell RNA sequencing data from the GSE189487 dataset. An integrative machine learning-based procedure based on 10 algorithms was developed to construct a macrophage-related index (MRI) in The Cancer Genome Atlas (TCGA), GSE30219, GSE31210, and GSE72094 datasets. Several algorithms were used to evaluate the associations of MRI with TIME and immunotherapy-related biomarkers. The role of MRI in predicting the immunotherapy response was evaluated with the GSE91061 dataset. RESULTS: The optimal MRI constructed by the combination of the Lasso algorithm and plsRCox was an independent risk factor in LUAD and showed a stable and powerful performance in predicting the overall survival rate of patients with LUAD. Those with low MRI scores had a higher TIME score, a higher level of immune cells, a higher immunophenoscore, and a lower Tumor Immune Dysfunction and Exclusion (TIDE) score, indicating a better response to immunotherapy. The IC50 value of common drugs for chemotherapy and target therapy with low MRI scores was higher compared to high MRI scores. Moreover, the survival prediction nomogram, developed from MRI, had good potential for clinical application in predicting the 1-, 3-, and 5-year overall survival rate of LUAD. CONCLUSION: Our study constructed for the first time a consensus MRI for LUAD with 10 machine learning algorithms. The MRI could be helpful for risk stratification, prognosis, and selection of treatment approach in LUAD.

Epilepsy and long-term risk of arrhythmias.

BACKGROUND AND AIMS: Previous evidence has mainly supported transient changes in cardiac function during interictal or peri-ictal phases in people with epilepsy, but the long-term risk of cardiac arrhythmias is poorly described. This study aimed to assess the long-term association of epilepsy with cardiac arrhythmias, considering the potential role of genetic predisposition and antiseizure medications (ASMs) in any associations observed. METHODS: This population-based study evaluated UK Biobank data for individuals recruited between 2006 and 2010. Cox proportional hazards models and competing risk models were used to examine the association of epilepsy history with the long-term incidence risk of cardiac arrhythmias and arrhythmias subtypes. Polygenic risk scores (PRS) were calculated to investigate the effect of genetic susceptibility. The role of ASMs was also evaluated by integrating observational and drug target Mendelian randomization (MR) evidence. RESULTS: The study included 329 432 individuals, including 2699 people with epilepsy. Compared with those without epilepsy, people with epilepsy experienced an increased risk of all cardiac arrhythmias [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.21-1.53], atrial fibrillation (HR 1.26, 95% CI 1.08-1.46), and other cardiac arrhythmias (HR 1.56, 95% CI 1.34-1.81). The associations were not modified by genetic predisposition as indicated by PRS. Competing and sensitivity analyses corroborated these results. Individuals with epilepsy using ASMs, especially carbamazepine and valproic acid, were at a higher risk for cardiac arrhythmias. This observation was further supported by drug target MR results (PSMR < .05 and PHEIDI > .05). CONCLUSION: This study revealed the higher risk of cardiac arrhythmias persists long term in people with epilepsy, especially among those using carbamazepine and valproic acid. These findings highlight the need for regular heart rhythm monitoring and management in people with epilepsy in order to reduce the risk of further cardiovascular complications.

Mendelian randomization study of maternal coffee consumption and its influence on birthweight, stillbirth, miscarriage, gestational age and pre-term birth.

BACKGROUND: Coffee consumption has been associated with several adverse pregnancy outcomes, although data from randomized-controlled trials are lacking. We investigate whether there is a causal relationship between coffee consumption and miscarriage, stillbirth, birthweight, gestational age and pre-term birth using Mendelian randomization (MR). METHODS: A two-sample MR study was performed using summary results data from a genome-wide association meta-analysis of coffee consumption (N = 91 462) from the Coffee and Caffeine Genetics Consortium. Outcomes included self-reported miscarriage (N = 49 996 cases and 174 109 controls from a large meta-analysis); the number of stillbirths [N = 60 453 from UK Biobank (UKBB)]; gestational age and pre-term birth (N = 43 568 from the 23andMe, Inc cohort) and birthweight (N = 297 356 reporting own birthweight and N = 210 248 reporting offspring's birthweight from UKBB and the Early Growth Genetics Consortium). Additionally, a one-sample genetic risk score (GRS) analysis of coffee consumption in UKBB women (N up to 194 196) and the Avon Longitudinal Study of Parents and Children (N up to 6845 mothers and 4510 children) and its relationship with offspring outcomes was performed. RESULTS: Both the two-sample MR and one-sample GRS analyses showed no change in risk of sporadic miscarriages, stillbirths, pre-term birth or effect on gestational age connected to coffee consumption. Although both analyses showed an association between increased coffee consumption and higher birthweight, the magnitude of the effect was inconsistent. CONCLUSION: Our results suggest that coffee consumption during pregnancy might not itself contribute to adverse outcomes such as stillbirth, sporadic miscarriages and pre-term birth or lower gestational age or birthweight of the offspring.

Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer's disease risk in the general population: a Mendelian randomisation study.

AIMS/HYPOTHESIS: Metformin use has been associated with reduced incidence of dementia in diabetic individuals in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomisation (MR) to investigate the causal effect of metformin targets on Alzheimer's disease and potential causal mechanisms in the brain linking the two. METHODS: Genetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA1c level (N=344,182) and expression level of the corresponding gene (N≤31,684). The cognitive outcomes were derived from genome-wide association studies comprising 527,138 middle-aged Europeans, including 71,880 with Alzheimer's disease or Alzheimer's disease-by-proxy. MR estimates representing lifelong metformin use on Alzheimer's disease and cognitive function in the general population were generated. Effect of expression level of 22 metformin-related genes in brain cortex (N=6601 donors) on Alzheimer's disease was further estimated. RESULTS: Genetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA1c, was associated with 4% lower odds of Alzheimer's disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10-4) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on Alzheimer's disease (OR 0.88, p=4.73×10-4) that was independent of AMP-activated protein kinase. MR of expression in brain cortex tissue showed that decreased MCI-related gene (NDUFA2) expression was associated with lower Alzheimer's disease risk (OR 0.95, p=4.64×10-4) and favourable cognitive function. CONCLUSIONS/INTERPRETATION: Metformin use may cause reduced Alzheimer's disease risk in the general population. Mitochondrial function and the NDUFA2 gene are plausible mechanisms of action in dementia protection.

Blood pressure trajectories during pregnancy and preterm delivery: A prospective cohort study in China.

Women's blood pressure (BP) changes throughout pregnancy. The effect of BP trajectories on preterm delivery is not clear. The authors aim to evaluate the association between maternal BP trajectories during pregnancy and preterm delivery. The authors studied pregnant women included in the Born in Guangzhou Cohort Study in China between February 2012 and June 2016. Maternal BP was measured at antenatal visits between 13 and 40 gestational weeks, and gestational age of delivery data was collected. The authors used linear mixed models to capture the BP trajectories of women with term, and spontaneous and iatrogenic preterm delivery. BP trajectories of women with various gestational lengths (34, 35, 36, 37, 38, 39, 40 weeks) were compared. Of the 17 426 women included in the analysis, 618 (3.55%) had spontaneous preterm delivery; 158 (.91%) had iatrogenic preterm delivery; and 16 650 (95.55%) women delivered at term. The BP trajectories were all J-shaped curves for different delivery types. Women with iatrogenic preterm delivery had the highest mean BP from 13 weeks till delivery, followed by those with spontaneous preterm delivery and term delivery (p < .001). Trajectory analysis stratified by maternal parity showed similar results for nulliparous and multiparous women. Excluding women with pre-eclampsia and gestational hypertension (GH) significantly attenuated the aforementioned association. Also, women with shorter gestational length tend to have higher BP trajectories during pregnancy. In conclusion, Women with spontaneous preterm delivery have a higher BP from 13 weeks till delivery than women with term delivery, while women with iatrogenic preterm delivery have the highest BP.

Gestational weight gain rates in the first and second trimesters are associated with small for gestational age among underweight women: a prospective birth cohort study.

BACKGROUND: Despite the well-studied effects of gestational weight gain (GWG) on offspring health, little is known about the association of trimester-specific GWG with offspring birth weight among underweight pregnant women. This study aimed to explore the association of trimester-specific GWG rate with small for gestational age (SGA) in underweight women. METHODS: The GWG rate of underweight pregnant women (pre-pregnancy body mass index [BMI] lower than 18.5 kg/m2) of the Born in Guangzhou Cohort Study was calculated as the weight gain during a specific trimester divided by the corresponding duration of week. Total GWG was calculated as the weight difference between pre-pregnancy and delivery, and was categorized into inadequate, adequate, and excessive weight gain based on the 2009 Institute of Medicine (IOM) weight gain recommendation. The INTERGROWTH-21st standards were used to define SGA. Logistic regression models were used to examine the associations of total GWG and trimester-specific GWG rates with SGA. Associations between trimester-specific GWG rates and SGA were also analyzed separately based on different total GWG categories (i.e. inadequate and adequate/excessive GWG). RESULTS: Of the 3839 participants, SGA births occurred in 397 (10.3%), and mean GWG was 14.9 kg (SD 3.9). A lower risk of SGA was observed among women with higher GWG rate (per 0.5 kg/week increase) during the first (adjusted OR [aOR] 0.74, 95%CI 0.57, 0.96) and second (adjusted OR [aOR] 0.40, 95%CI 0.30, 0.55) but not third trimester. Similar association between higher GWG rate during the second trimester and a decreased risk of SGA were observed among women with inadequate (< 12.5 kg) and adequate/excessive (≥12.5 kg) total GWG, respectively. Compared to women with adequate GWG rate, women with inadequate GWG rate during the second trimester had a significantly increased risk of SGA (aOR 1.58, 95% CI 1.14, 2.20). CONCLUSIONS: Second-trimester GWG might be the key driver for the association between inadequate GWG and increased risk of SGA births in underweight women.

Assessment of causal effects of visceral adipose tissue on risk of cancers: a Mendelian randomization study.

BACKGROUND: Despite the established association between obesity and cancer risk, it remains unclear whether visceral obesity is causally related to cancer risk and whether it is more pro-oncogenic than total body fat. METHODS: We conducted two-sample Mendelian randomization (MR) analysis to assess the causal effects of visceral adipose tissue (VAT) on six common cancers. For exposure data, 221 genetic variants associated with the predicted volume of VAT in 325 153 Europeans from UK Biobank were used as instrumental variables. Genetic association data of six common cancers (breast, lung, colorectal, ovarian, pancreatic and prostate cancers) were obtained from large-scale consortia with an average of 19 576 cases and 43 272 controls. We performed univariable MR with five MR methods [inverse-variance weighted (IVW), MR-Egger regression, weighted median, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and Radial MR] and multivariable MR to estimate the effect of VAT independent of body mass index (BMI). Finally, we performed a series of sensitivity analyses as validation of primary MR results. RESULTS: Two associations survived the false discovery rate correction for multiple testing (q-value < 0.05): in IVW, the odds ratios (95% CIs) per unit increase in genetically determined VAT were 1.65 (1.03 to 2.62) for pancreatic cancer and 1.47 (1.20 to 1.82) for lung squamous-cell carcinoma, respectively, which showed the same directions and overlapped confidence intervals with MR-Egger regression and weighted median results. There were no outlier variants identified by MR-PRESSO and no evidence supporting the presence of heterogeneity and pleiotropy in sensitivity analyses, although with wider confidence intervals that included the null, multivariable MR results for these two cancers showed the same directions and similar effect sizes as in IVW, which were independent of the effect from BMI. There was no evidence for a causal effect of VAT on the risk of other types of cancer. CONCLUSION: Our findings suggest that lifelong exposure to elevated volumes of VAT might increase the risk of pancreatic cancer and lung squamous-cell carcinoma, highlighting the importance of revealing the underlying mechanisms for intervention targets.

Optogenetic activation of intracellular signaling based on light-inducible protein-protein homo-interactions.

Dynamic protein-protein interactions are essential for proper cell functioning. Homo-interaction events-physical interactions between the same type of proteins-represent a pivotal subset of protein-protein interactions that are widely exploited in activating intracellular signaling pathways. Capacities of modulating protein-protein interactions with spatial and temporal resolution are greatly desired to decipher the dynamic nature of signal transduction mechanisms. The emerging optogenetic technology, based on genetically encoded light-sensitive proteins, provides promising opportunities to dissect the highly complex signaling networks with unmatched specificity and spatiotemporal precision. Here we review recent achievements in the development of optogenetic tools enabling light-inducible protein-protein homo-interactions and their applications in optical activation of signaling pathways.

Light-inducible deformation of mitochondria in live cells.

Mitochondria, the powerhouse of the cell, are dynamic organelles that undergo constant morphological changes. Increasing evidence indicates that mitochondria morphologies and functions can be modulated by mechanical cues. However, the mechano-sensing and -responding properties of mitochondria and the relation between mitochondrial morphologies and functions are unclear due to the lack of methods to precisely exert mechano-stimulation on and deform mitochondria inside live cells. Here, we present an optogenetic approach that uses light to induce deformation of mitochondria by recruiting molecular motors to the outer mitochondrial membrane via light-activated protein-protein hetero-dimerization. Mechanical forces generated by motor proteins distort the outer membrane, during which the inner mitochondrial membrane can also be deformed. Moreover, this optical method can achieve subcellular spatial precision and be combined with different optical dimerizers and molecular motors. This method presents a mitochondria-specific mechano-stimulator for studying mitochondria mechanobiology and the interplay between mitochondria shapes and functions.

Associations of maternal weight status with the risk of offspring atopic dermatitis and wheezing by 1 year of age.

BACKGROUND: Maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) have been linked to offspring allergic disorders. However, associations observed in previous studies were inconsistent and might be confounded by unmeasured familial factors. We aimed to examine the associations of maternal weight with offspring allergic disorders by using paternal BMI as a negative control exposure. METHODS: We included the data of 10,522 children from the Born in Guangzhou Cohort Study, 2012-2017. Data on maternal weight were obtained from questionnaires and obstetric records, and paternal weight was collected from questionnaires. Atopic dermatitis (AD) and wheezing at the age of 1 year were defined according to parent-reported physician diagnosis. Risk ratios (RRs) were estimated by log-binominal regression with mutual adjustment for maternal and paternal weight status. RESULTS: By the age of 1 year, 16.2% and 7.9% of children were diagnosed with AD and wheezing, respectively. While maternal pre-pregnancy BMI as a continuous variable was not associated with offspring AD, infants of pre-pregnancy overweight/obese women had a higher risk of AD than those born to normal weight women; no such associations were observed for paternal BMI. Both maternal pre-pregnancy BMI and paternal BMI were positively associated with the risk of offspring wheezing. Maternal GWG was not associated with AD or wheezing. CONCLUSIONS: Our findings suggest that maternal pre-pregnancy overweight/obesity might increase the risk of infant AD via intrauterine mechanisms, whereas the association with wheezing might be confounded by uncontrolled familial factors. These findings may be valuable in early-life prevention for offspring allergic diseases.

Association Between the COVID-19 Pandemic and Infant Neurodevelopment: A Comparison Before and During COVID-19.

Aim: To investigate the association between the experience of the coronavirus disease 2019 (COVID-19) pandemic and neurodevelopment of 6-month-old and 1-year-old children and explore the differences in the association by birth order. Methods: This comparison study was embedded in the Born in Guangzhou Cohort Study in China. The exposed group included 546 6-month-old and 285 1-year-old children who attended neurodevelopment assessments between March 1 and May 15, 2020, and the non-exposed group included 3,009 6-month-old and 2,214 1-year-old children during the same months from 2015 to 2019. Neurodevelopment at age 6 months and 1 year was assessed by trained clinical staff using the Ages and Stages Questionnaires, third edition (ASQ-3) and the Gesell Developmental Schedules (GDS). Results: The experience of the pandemic in 2020 was associated with a higher risk of delay in the fine motor (adjusted OR: 2.50, 95% CI: 1.25, 4.99; estimated by logistic regression) and communication (adjusted RR [aRR]: 1.13, 95% CI: 1.02, 1.25; estimated by log-binomial regression) domains at age 1 year. The association between the experience of the pandemic and communication delay at age 1 year only existed in first-born children (aRR: 1.15, 95% CI: 1.03, 1.30) but not in later-born children (aRR: 1.02, 95% CI: 0.84, 1.25). No associations were observed in any domain among 6-month-olds. Conclusion: Experiencing the COVID-19 pandemic and related public health strategies might be associated with a higher risk of delay in the development of fine motor and communication in 1-year-old children; the association observed in the communication domain only existed in first-born children.

m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in hepatocellular carcinoma.

BACKGROUND: There is increasing evidence of the epigenetic regulation of the immune response in cancer. However, the specific functions and mechanisms of RNA N6-methyladenosine (m6A) modification in the cell infiltration in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) is unknown. METHODS: We systematically analyzed the m6A-modification patterns of 371 HCC samples based on 23 m6A regulators, and determined their correlation with TME cell-infiltrating characteristics. Principal-component analysis algorithms was used to calculate the m6Ascore and clarify the m6A-modification patterns of individual tumors. RESULTS: Three different m6A-modification patterns were identified in HCC, wherein the m6Acluster B and m6Acluster A had the best and worst prognosis, respectively. These three patterns had different TME cell infiltration characteristics and biological behavior. An m6A-scoring signature was constructed to evaluate the m6A-modification patterns within individual tumors. A low m6Ascore was associated with a low overall survival and high clinical stage. Moreover, the m6A-scoring signature was characterized by distinct immunotherapeutic landscapes; a high m6A score indicated a higher immune checkpoint inhibitor score in the anti-PD-1 treatment alone, anti-CTLA-4 treatment alone, or combined anti-CTLA-4/PD-1 treatment cohorts, which reflected significant treatment and clinical benefits. CONCLUSIONS: Our study highlights the significant role of the m6A modification in the HCC TME. A scoring signature to clarify the individual m6A-modification pattern would help us understand the HCC TME infiltration characterization and, thus, would guide the selection of more effective immunotherapeutic strategies.