The Born in Guangzhou Cohort Study enables generational genetic discoveries.

Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health1. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study2 (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.

Trophoblast PR-SET7 dysfunction induces viral mimicry response and necroptosis associated with recurrent miscarriage.

Recurrent miscarriage (RM) is a distressing pregnancy complication. While the etiology of RM remains unclear, growing evidence has indicated the relevance of trophoblast impairment to the pathogenesis of RM. PR-SET7 is the sole enzyme catalyzing monomethylation of H4K20 (H4K20me1) and has been implicated in many pathophysiological processes. However, how PR-SET7 functions in trophoblasts and its relevance to RM remain unknown. Here, we found that trophoblast-specific loss of Pr-set7 in mice led to defective trophoblasts, resulting in early embryonic loss. Mechanistic analysis revealed that PR-SET7 deficiency in trophoblasts derepressed endogenous retroviruses (ERVs), leading to double-stranded RNA stress and subsequent viral mimicry, which drove overwhelming interferon response and necroptosis. Further examination discovered that H4K20me1 and H4K20me3 mediated the inhibition of cell-intrinsic expression of ERVs. Importantly, dysregulation of PR-SET7 expression and the corresponding aberrant epigenetic modifications were observed in the placentas of RM. Collectively, our results demonstrate that PR-SET7 acts as an epigenetic transcriptional modulator essential for repressing ERVs in trophoblasts, ensuring normal pregnancy and fetal survival, which sheds new light on potential epigenetic causes contributing to RM.

Maternal Ezh1/2 deficiency in oocyte delays H3K27me2/3 restoration and impairs epiblast development responsible for embryonic sub-lethality in mouse.

How maternal Ezh1 and Ezh2 function in H3K27 methylation in vivo in pre-implantation embryos and during embryonic development is not clear. Here, we have deleted Ezh1 and Ezh2 alone or simultaneously from mouse oocytes. H3K27me3 was absent in oocytes without Ezh2 alone, while both H3K27me2 and H3K27me3 were absent in Ezh1/Ezh2 (Ezh1/2) double knockout (KO) oocytes. The effects of Ezh1/2 maternal KO were inherited in zygotes and early embryos, in which restoration of H3K27me3 and H3K27me2 was delayed by the loss of Ezh2 alone or of both Ezh1 and Ezh2. However, the ablation of both Ezh1 and Ezh2, but not Ezh1 or Ezh2 alone, led to significantly decreased litter size due to growth retardation post-implantation. Maternal Ezh1/2 deficiency caused compromised H3K27me3 and pluripotent epiblast cells in late blastocysts, followed by defective embryonic development. By using RNA-seq, we examined crucial developmental genes in maternal Ezh1/2 KO embryos and identified 80 putatively imprinted genes. Maternal Ezh1/2-H3K27 methylation is inherited in offspring embryos and has a critical effect on fetal and placental development. Thus, this work sheds light on maternal epigenetic modifications during embryonic development.

Endogenous retrovirus-derived enhancers confer the transcriptional regulation of human trophoblast syncytialization.

Endogenous retroviruses (ERVs) have been proposed as a driving force for the evolution of the mammalian placenta, however, the contribution of ERVs to placental development and the underlying regulatory mechanism remain largely elusive. A key process of placental development is the formation of multinucleated syncytiotrophoblasts (STBs) in direct contact with maternal blood, through which constitutes the maternal-fetal interface critical for nutrient allocation, hormone production and immunological modulation during pregnancy. We delineate that ERVs profoundly rewire the transcriptional program of trophoblast syncytialization. Here, we first determined the dynamic landscape of bivalent ERV-derived enhancers with dual occupancy of H3K27ac and H3K9me3 in human trophoblast stem cells (hTSCs). We further demonstrated that enhancers overlapping several ERV families tend to exhibit increased H3K27ac and reduced H3K9me3 occupancy in STBs relative to hTSCs. Particularly, bivalent enhancers derived from the Simiiformes-specific MER50 transposons were linked to a cluster of genes important for STB formation. Importantly, deletions of MER50 elements adjacent to several STB genes, including MFSD2A and TNFAIP2, significantly attenuated their expression concomitant to compromised syncytium formation. Together, we propose that ERV-derived enhancers, MER50 specifically, fine-tune the transcriptional networks accounting for human trophoblast syncytialization, which sheds light on a novel ERV-mediated regulatory mechanism underlying placental development.

Monodispersed Molecular Phthalocyanine with Sulfur-Driven Electron Delocalization for Enhanced Electrochemical Biosensing.

Heterogenizing the molecular catalysts on conductive scaffolds to achieve the isolated molecular dispersion and expected coordination structures is significant yet still challenging. Herein, a sulfur-driving strategy to anchor monodispersed cobalt phthalocyanine on nitrogen and sulfur co-doped graphene (NSG-CoPc) is demonstrated. Experimental and theoretical analysis prove that the incorporation of S dramatically improves the adsorption capability of NSG and evokes the monodispersion of the CoPc molecule, promoting the axial Co─N coordination and the electron delocalization of the Co catalytic center. Benefiting from the reduced activation energy barrier and boosted electron transfer, as well as the maximized active site utilization, NSG-CoPc exhibits outstanding H2 O2 oxidization and sensing performance (used as a representative reaction). Moreover, the usage of NSG as a substrate can be readily extended to other metal (Ni, Cu, and Fe) phthalocyanine molecules with molecular-level dispersion. This work clarifies the mechanism of heteroatoms decoration and provides a new paradigm in devising monodispersed molecular catalysts with modulated chemical surroundings for broad applications.

An Integrated Clinical and Computerized Tomography-Based Radiomic Feature Model to Separate Benign from Malignant Pleural Effusion.

INTRODUCTION: Distinguishing between malignant pleural effusion (MPE) and benign pleural effusion (BPE) poses a challenge in clinical practice. We aimed to construct and validate a combined model integrating radiomic features and clinical factors using computerized tomography (CT) images to differentiate between MPE and BPE. METHODS: A retrospective inclusion of 315 patients with pleural effusion (PE) was conducted in this study (training cohort: n = 220; test cohort: n = 95). Radiomic features were extracted from CT images, and the dimensionality reduction and selection processes were carried out to obtain the optimal radiomic features. Logistic regression (LR), support vector machine (SVM), and random forest were employed to construct radiomic models. LR analyses were utilized to identify independent clinical risk factors to develop a clinical model. The combined model was created by integrating the optimal radiomic features with the independent clinical predictive factors. The discriminative ability of each model was assessed by receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). RESULTS: Out of the total 1,834 radiomic features extracted, 15 optimal radiomic features explicitly related to MPE were picked to develop the radiomic model. Among the radiomic models, the SVM model demonstrated the highest predictive performance [area under the curve (AUC), training cohort: 0.876, test cohort: 0.774]. Six clinically independent predictive factors, including age, effusion laterality, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 125 (CA125), and neuron-specific enolase (NSE), were selected for constructing the clinical model. The combined model (AUC: 0.932, 0.870) exhibited superior discriminative performance in the training and test cohorts compared to the clinical model (AUC: 0.850, 0.820) and the radiomic model (AUC: 0.876, 0.774). The calibration curves and DCA further confirmed the practicality of the combined model. CONCLUSION: This study presented the development and validation of a combined model for distinguishing MPE and BPE. The combined model was a powerful tool for assisting in the clinical diagnosis of PE patients.

Weight status changes from childhood to adulthood were associated with cardiometabolic outcomes in adulthood.

AIM: Few studies have assessed the association between weight changes from childhood to adulthood and cardiometabolic factors in adulthood. The aim of this study was to explore the relationships between weight changes from childhood to adulthood and cardiometabolic factors in adulthood using national Chinese data. METHODS: We included 649 participants from the China Health and Nutrition Survey from 1989 to 2009 and divided them into four groups by their body mass index from 6 to 37 years of age. They were selected using multistage random cluster sampling from 15 areas with large variations in economic and social development. Poisson regression models assessed associations between weight status changes and cardiometabolic outcomes in adulthood. RESULTS: The risk of multiple abnormal cardiometabolic outcomes in adulthood was increased in the 126 subjects with normal weight in childhood but overweight or obesity in adulthood and the 28 with obesity at both ages, compared to the 462 with normal weight at both ages. There was insufficient evidence to demonstrate that the 33 who had weight issues as children, but not as adults, had an increased risk. CONCLUSION: Being overweight or obese in both childhood and adulthood or during adulthood only increased the risk of abnormal cardiometabolic outcomes in adulthood. Larger studies need to investigate whether weight problems in childhood, but not adulthood, increase the risk.

Untangling the Effects of Doping Carbon with Diverse Heteroatoms on the Bioelectrochemistry of Glucose Oxidase.

Great enthusiasm for doping carbon materials with nonmetallic heteroatoms for promoting electrical contact of redox enzymes with electrodes in bioelectronics has been aroused. However, systematic studies of different heteroatoms on enzyme activities are still lacking. Herein, choosing glucose oxidase (GOD) as a model enzyme, carbon nanotubes (CNTs) are used as electron carriers to evaluate the effects of heteroatoms' species on the direct electron transfer and catalytic activities of GOD. Experimental data demonstrate that phosphorus (P)-doped CNTs provide the most intimate electrical contact with GOD compared to other elements (B, N, and S) doping, delivering a 3-fold increase in rate constant (ks, 2.1 s-1) and an enhanced turnover rate (kcat, 2.74 × 10-9 M cm-2 s-1) in comparison with CNTs. Meanwhile, theoretical modeling clarifies that the active center of GOD interacts more strongly with P-doped CNTs and maintains their conformation well compared to other CNTs. This study will help to understand the mechanism of heteroatom doping of carbon on the enzymatic electron transfer and shed light on the design of efficient bioelectrocatalytic interfaces.

A meta-analysis of the efficacy and toxicity of tyrosine kinase inhibitors in treating patients with different types of thyroid cancer: how to choose drugs appropriately?

PURPOSE OF REVIEW: Because the high risk of death and poor prognosis of patients with refractory thyroid cancer (TC), studies related to tyrosine kinase inhibitors (TKIs) in treating different types of refractory TC have gradually attracted attention. Thus, we conducted a meta-analysis of published randomized controlled trials and single-arm trials to evaluate tyrosine kinase inhibitors' efficacy and safety profile treatment in TC patients. RECENT FINDINGS: The studies of 29 in 287 met the criteria, 9 were randomized controlled trials and 20 were single-arm trials, involving 11 TKIs (Apatinib, Anlotinib, Cabozantinib, Imatinib, Lenvatinib, Motesanib, Pazopanib, Sorafenib, Sunitinib, Vandetanib, Vemurafenib). Treatment with TKIs significantly improved progression-free survival [hazard ratio [HR] 0.34 (95% confidence interval [CI]: 0.24, 0.48), P < 0.00001] and overall survival [OS] [HR 0.76, (95% CI: 0.64, 0.91), P = 0.003] in randomized controlled trials, but adverse events (AEs) were higher than those in the control group (P < 0.00001). The result of the objective response rate (ORR) in single-arm trials was statistically significant [odds ratio [OR] 0.49 (95% CI: 0.32, 0.75), P = 0.001]. SUMMARY: TKIs significantly prolonged progression-free survival and OS or improved ORR in patients with different types of TC (P < 0.01). Our recommendation is to select appropriate TKIs to treat different types of TC patients, and to prevent and manage drug-related AEs after using TKIs.

Timing of infant formula introduction in relation to BMI and overweight at ages 1 and 3 years: the Born in Guangzhou Cohort Study (BIGCS).

Mounting evidence suggests that the first few months of life are critical for the development of obesity. The relationships between the timing of solid food introduction and the risk of childhood obesity have been examined previously; however, evidence for the association of timing of infant formula introduction remains scarce. This study aimed to examine whether the timing of infant formula introduction is associated with growth z-scores and overweight at ages 1 and 3 years. This study included 5733 full-term (≥ 37 gestational weeks) and normal birth weight (≥ 2500 and < 4000 g) children in the Born in Guangzhou Cohort Study, a prospective cohort study with data collected at 6 weeks, 6, 12 and 36 months. Compared with infant formula introduction at 0-3 months, introduction at 4-6 months was associated with the lower BMI, weight-for-age and weight-for-length z-scores at 1 and 3 years old. Also, introduction at 4-6 months was associated with the lower odds of at-risk of overweight at age 1 (adjusted OR 0·72, 95 % CI 0·55, 0·94) and 3 years (adjusted OR 0·50, 95 % CI 0·30, 0·85). Introduction at 4-6 months also decreased the odds of overweight at age 1 year (adjusted OR 0·42, 95 % CI 0·21, 0·84) but not at age 3 years. Based on our findings, compared with introduction within the first 3 months, introduction at 4-6 months has a reduction on later high BMI risk and at-risk of overweight. However, these results need to be replicated in other well-designed studies before more firm recommendations can be made.

Incremental predictive value of platelet parameters for preeclampsia: results from a large prospective cohort study.

BACKGROUND: Platelet parameters during pregnancy were associated with the risk of preeclampsia (PE), but the predictive value of these parameters for PE remained unclear. Our aim was to clarify the individual and incremental predictive value of platelet parameters, including platelet count (PC), mean platelet volume (MPV), plateletcrit (PCT), and platelet distribution width (PDW) for PE. METHODS: This study was based on the Born in Guangzhou Cohort Study in China. Data on platelet parameters were extracted from medical records of routine prenatal examinations. Receiver operating characteristic (ROC) curve was performed to analyze the predictive ability of platelet parameters for PE. Maternal characteristic factors proposed by NICE and ACOG were used to develop the base model. Detection rate (DR), integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI) were calculated compared with the base model to assess the incremental predictive value of platelet parameters. RESULTS: A total of 30,401 pregnancies were included in this study, of which 376 (1.24%) were diagnosed with PE. Higher levels of PC and PCT were observed at 12-19 gestational weeks in women who developed PE later. However, no platelet parameters before 20 weeks of gestation reliably distinguished between PE complicated pregnancy and non-PE complicated pregnancy, with all values of the areas under the ROC curves (AUC) below 0.70. The addition of platelet parameters at 16-19 gestational weeks to the base model increased the DR for preterm PE from 22.9 to 31.4% at a fixed false positive rate of 5%, improved the AUC from 0.775 to 0.849 (p = 0.015), and yielded a NRI of 0.793 (p < 0.001), and an IDI of 0.0069 (p = 0.035). Less but significant improvement in prediction performance was also observed for term PE and total PE when all the four platelet parameters were added to the base model. CONCLUSIONS: Although no single platelet parameter at the early stage of pregnancy identified PE with high accuracy, the addition of platelet parameters to known independent risk factors could improve the prediction of PE.

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.

Efficacy and safety of immune checkpoint inhibitors in colorectal cancer: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitor (ICI) therapies have shown promising prospects in colorectal cancer (CRC) immunotherapy; many clinical trials have been carried out. In this study, we sought to evaluate the efficacy and safety of ICI therapies in CRC by presenting a meta-analysis of relevant studies. METHODS: Databases including PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for studies concerning the efficacy and safety of ICI in colorectal cancer. The reported odds ratio (OR) or weighted mean difference (WMD) with 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAEs), and TRAEs ≥ 3 in the included studies were analyzed by fixed effects/random effects models. RESULTS: Three studies involving 667 patients with colorectal cancer were included in our meta-analysis. No significant difference between the immune checkpoint inhibitor therapies and conventional therapies in OS (WMD = 0.73, 95% CI - 3.09, 4.54; p = 0.71), in ORR (OR = 1.54, 95% CI 0.98, 2.40; p = 0.06), and in DCR (OR = 0.97, 95% CI 0.36, 2.61; p = 0.95). The median PFS of the ICI therapy group was shorter than that of the conventional therapy group (WMD = - 0.10, 95% CI - 0.18, - 0.02; p = 0.02). At the same time, we also could not find a significant difference between the immune checkpoint inhibitor therapies and conventional therapies in TRAEs (OR = 1.56, 95% CI 0.11, 22.09; p = 0.74) and in TRAEs ≥ 3 (OR = 0.94, 95% CI 0.16, 5.65; p = 0.95). CONCLUSION: Immune checkpoint inhibitor therapies could not improve all survival endpoints to advanced or metastatic colorectal cancer patients. Whether immune checkpoint inhibitors should be the first choice of therapies for colorectal cancer patients with undetermined microsatellite status or not able to determine microsatellite status needs more related studies to prove.

Single-cell RNA-seq revealed diverse cell types in the mouse placenta at mid-gestation.

The mammalian placenta consists of a set of cells to ensure normal placental functions throughout gestation. Dysfunctional placentae are considered as the origin of a series of pregnancy complications. Therefore, it is urgent for detailed information about the molecular recipes of the cell types within the normal placenta. In the past years, gene expression analysis via single-cell RNA-seq (scRNA-seq) offers opportunities to identify new cell types in a variety of organs and tissues. In this study, scRNA-seq was used to explore the cell heterogeneity within the E10.5 mouse placenta and unravel their discrepancies in cell composition and communications. We identified sixteen cell clusters, including some cell clusters that originated from the maternal tissue. Moreover, we traced the developmental trajectories of trophoblasts and Hofbauer-like cells. Further analysis revealed cell connections between the endothelial cells and pericytes, syncytiotrophoblasts, as well as decidual cells. Besides, we highlighted several signaling pathways, such as the EGF, FGF, canonical, and non-canonical WNT signaling pathways, which mediated the potential crosstalk between different cell types within placenta. Our research provides an in-depth understanding of placental development, cellular composition, and communications at the maternal-fetal interface.

Combined effects of air pollutants on gestational diabetes mellitus: A prospective cohort study.

Exposures to multiple air pollutants during pregnancy have been associated with the risk of gestational diabetes mellitus (GDM). However, their combined effects are unclear. We aimed to evaluate the combined associations of five air pollutants from pre-pregnancy to the 2nd trimester with GDM. This study included 20,113 participants from the Born in Guangzhou Cohort Study (BIGCS). The inverse distance-weighted models were used to estimate individual air pollutant exposure, namely ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter less than 10 µm in diameter (PM10), and less than 2.5 µm in diameter (PM2.5). We estimated stage-specific associations of air pollutants with GDM using generalized estimating equation, and departures from additive joint effects were assessed using the relative excess risk (RERI) and the joint relative risk (JRR). Of the 20,113 participants, 3440 women (17.1%) were diagnosed with GDM. In the adjusted model, increased concentrations of O3 and SO2 3-6 months before pregnancy were associated with GDM occurrence, as well as O3 and PM10 in the 1st trimester, the adjusted relative risk (95% confident intervals) [RRs (95%CI)] ranged from 1.05 (1.00, 1.09) to 1.21 (1.04, 1.40). The largest JRR for GDM was the combination of SO2, NO2, and PM10 in the 1st trimester (JRR = 1.32, 95% CI: 1.10, 1.59). The JRR for O3 and SO2 was less than their additive joint effects [RERI = -0.25 (-0.47, -0.04), P for interaction = 0.048]. Associations of air pollutants with GDM differed somewhat by pre-pregnancy BMI and season. This study added new evidence to the current understanding of the combined effects of multiple air pollutants on GDM. Public health strategies were needed to reduce the adverse effects of air pollution exposure on pregnant women.

Platelet parameters and risk of hypertension disorders of pregnancy: a propensity score adjusted analysis.

While the role of platelets in cardiovascular diseases among the general population has been widely reported, evidence is inconsistent regarding the association between platelet indices with hypertension in pregnant women. In this study, we explored the associations between platelet parameters before 20 gestational weeks, an understudied period, with hypertensive disorders of pregnancy (HDP), including preeclampsia/eclampsia (PEEC) and gestational hypertension (GH). Based on the Born in Guangzhou Cohort Study, 12053 singleton pregnant women with platelet parameters, including platelet count (PC), mean platelet volume (MPV), plateletcrit (PCT), and platelet distribution width (PDW) measured at 14-19 gestational weeks were included. Conventional multivariable adjustment and propensity score analysis were used to control for confounders. The restricted cubic spline showed that the risk of PEEC increased linearly for PC, and non-linearly for PCT. For GH, the risk increased linearly for PC, MPV, and PCT, and non-linearly for PDW. When these indices were categorized into quintiles, women with higher PC and PCT were associated with increased risk of both PEEC and GH. Women with MPV exceeding the second quintile (≥ 8.8 fL) had a greater risk for GH, but not for PEEC. When HDP was classified into two groups (early- vs late-onset) based on the occurrence time, significant associations persisted for early-onset PEEC, early-onset GH, and late-onset GH. In conclusion, increased PC and PCT before 20 weeks of gestation were both associated with higher risk of PEEC and GH, while elevated MPV was only linked to GH.

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.

Blastocyst activation engenders transcriptome reprogram affecting X-chromosome reactivation and inflammatory trigger of implantation.

Implantation of the blastocyst into the uterus is the gateway for further embryonic development in mammals. Programming of blastocyst to an implantation-competent state known as blastocyst activation is the determining factor for implantation into the receptive uterus. However, it remains largely unclear how the blastocyst is globally programmed for implantation. Employing a delayed implantation mouse model, we show here that the blastocyst undergoes extensive programming essential for implantation. By analyzing the transcriptional profile of blastocysts with different implantation competency, we reveal the dynamic change in the biosynthesis, metabolism, and proliferation during blastocyst reactivation from diapause. We also demonstrate that reactivation of the X chromosome, one of the most important events during periimplantation of female embryonic development, is not completed even in blastocysts under conditions of dormancy, despite long term suspension in the uterus. Moreover, the mural trophectoderm (TE), but not the polar TE, differentiates to be more invasive through the weakened cell-cell tight junctions and extracellular matrices (ECMs). By analyzing the differentially expressed profile of secretory proteins, we further demonstrate that the blastocyst functions as a proinflammatory body to secrete proinflammatory signals, such as TNFα and S100A9, thereby triggering embryo-uterine attachment reaction during implantation. Collectively, our data systematically and comprehensively disclose the programming of blastocyst reactivation from diapause for implantation and uncover previously undefined roles of blastocyst during implantation.

All Si3 N4 Nanowires Membrane Based High-Performance Flexible Solid-State Asymmetric Supercapacitor.

Recently, much attention has been drawn in the development of flexible energy storage devices due to the increasing demands for flexible/portable electronic devices with high energy density, low weight, and good flexibility. Herein, vertically oriented graphene nanosheets (VGNs) are in situ fabricated on the surface of free-standing and flexible Si3 N4 nanowires (NWs) membrane by plasma-enhanced chemical vapor deposition (PECVD), which are directly used as flexible nanoscale conductive substrates. NiCo2 O4 hollow nanospheres (HSs) and FeOOH amorphous nanorods (NRs) are finally prepared on Si3 N4NWs @VGNs, which are served as the positive and negative electrodes, respectively. Profiting from the structural merits, the synthesized Si3 N4NWs @VGNs@NiCo2 O4HSs and Si3 N4NWs @VGNs@FeOOHNRs membrane electrodes exhibit remarkable electrochemical performance. Using Si3 N4NWs membrane as the separator, the assembled all Si3 N4NWs membrane-based flexible solid-state asymmetric supercapacitor (ASC) with a wide operating potential window of 1.8 V yields the outstanding energy density of 96.3 Wh kg-1 , excellent cycling performance (91.7% after 6000 cycles), and good mechanical flexibility. More importantly, this work provides a rational design strategy for the preparation of flexible electrode materials and broadens the applications of Si3 N4NWs in the field of energy storage.

The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments.

The immune system must distinguish viable cells from cells damaged by physical and infective processes. The damaged cell-recognition molecule Clec9A is expressed on the surface of the mouse and human dendritic cell subsets specialized for the uptake and processing of material from dead cells. Clec9A recognizes a conserved component within nucleated and nonnucleated cells, exposed when cell membranes are damaged. We have identified this Clec9A ligand as a filamentous form of actin in association with particular actin-binding domains of cytoskeletal proteins. We have determined the crystal structure of the human CLEC9A C-type lectin domain and propose a functional dimeric structure with conserved tryptophans in the ligand recognition site. Mutation of these residues ablated CLEC9A binding to damaged cells and to the isolated ligand complexes. We propose that Clec9A provides targeted recruitment of the adaptive immune system during infection and can also be utilized to enhance immune responses generated by vaccines.