Inverse association between maternal serum concentrations of trace elements and risk of spontaneous preterm birth: a nested case-control study in China.

Few studies have evaluated the joint effect of trace elements on spontaneous preterm birth (SPTB). This study aimed to examine the relationships between the individual or mixed maternal serum concentrations of Fe, Cu, Zn, Se, Sr and Mo during pregnancy, and risk of SPTB. Inductively coupled plasma MS was employed to determine maternal serum concentrations of the six trace elements in 192 cases with SPTB and 282 controls with full-term delivery. Multivariate logistic regression, weighted quantile sum regression (WQSR) and Bayesian kernel machine regression (BKMR) were used to evaluate the individual and joint effects of trace elements on SPTB. The median concentrations of Sr and Mo were significantly higher in controls than in SPTB group (P < 0·05). In multivariate logistic regression analysis, compared with the lowest quartile levels of individual trace elements, the third- and fourth-quartile Sr or Mo concentrations were significantly associated with reduced risk of SPTB with adjusted OR (aOR) of 0·432 (95 CI < 0·05). In multivariate logistic regression analysis, compared with the lowest quartile levels of individual trace elements, the third- and fourth-quartile Sr or Mo concentrations were significantly associated with reduced risk of SPTB with adjusted aOR of 0·432 (95 % CI 0·247, 0·756), 0·386 (95 % CI 0·213, 0·701), 0·512 (95 % CI 0·297, 0·883) and 0·559 (95 % CI 0·321, 0·972), respectively. WQSR revealed the inverse combined effect of the trace elements mixture on SPTB (aOR = 0·368, 95 % CI 0·228, 0·593). BKMR analysis confirmed the overall mixture of the trace elements was inversely associated with the risk of SPTB, and the independent effect of Sr and Mo was significant. Our findings suggest that the risk of SPTB decreased with concentrations of the six trace elements, with Sr and Mo being the major contributors.

Biomarkers for congenital ventricular outflow tract malformations based on maternal serum lipid metabolomics analysis.

BACKGROUND: The congenital ventricular outflow tract malformations (CVOTMs) is a major congenital heart diseases (CHDs) subtype, and its pathogenesis is complex and unclear. Lipid metabolic plays a crucial role in embryonic cardiovascular development. However, due to the limited types of detectable metabolites in previous studies, findings on lipid metabolic and CHDs are still inconsistent, and the possible mechanism of CHDs remains unclear. METHODS: The nest case-control study obtained subjects from the multicenter China Teratology Birth Cohort (CTBC), and maternal serum from the pregnant women enrolled during the first trimester was utilized. The subjects were divided into a discovery set and a validation set. The metabolomics of CVOTMs and normal fetuses were analyzed by targeted lipid metabolomics. Differential comparison, random forest and lasso regression were used to screen metabolic biomarkers. RESULTS: The lipid metabolites were distributed differentially between the cases and controls. Setting the selection criteria of P value < 0.05, and fold change (FC) > 1.2 or < 0.833, we screened 70 differential metabolites. Within the prediction model by random forest and lasso regression, DG (14:0_18:0), DG (20:0_18:0), Cer (d18:2/20:0), Cer (d18:1/20:0) and LPC (0:0/18:1) showed good prediction effects in discovery and validation sets. Differential metabolites were mainly concentrated in glycerolipid and glycerophospholipids metabolism, insulin resistance and lipid & atherosclerosis pathways, which may be related to the occurrence and development of CVOTMs. CONCLUSION: Findings in this study provide a new metabolite data source for the research on CHDs. The differential metabolites and involved metabolic pathways may suggest new ideas for further mechanistic exploration of CHDs, and the selected biomarkers may provide some new clues for detection of COVTMs.

Association of maternal phthalates exposure and metabolic gene polymorphisms with congenital heart diseases: a multicenter case-control study.

BACKGROUND: The majority of congenital heart diseases (CHDs) are thought to result from the interactions of genetics and the environment factors. This study aimed to assess the association of maternal non-occupational phthalates exposure, metabolic gene polymorphisms and their interactions with risk of CHDs in offspring. METHODS: A multicenter case-control study of 245 mothers with CHDs infants and 268 control mothers of health infant was conducted from six hospitals. Maternal urinary concentrations of eight phthalate metabolites were measured by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Twenty single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and 19 (CYP2C19), uridine diphosphate (UDP) glucuronosyl transferase family 1 member A7 (UGT1A7), family 2 member B7 (UGT2B7) and B15(UGT2B15) genes were genotyped. The multivariate logistic regressions were used to estimate the association between maternal phthalates exposure or gene polymorphisms and risk of CHDs. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-gene and gene-phthalates exposure interactions. RESULTS: There was no significant difference in phthalate metabolites concentrations between the cases and controls. No significant positive associations were observed between maternal exposure to phthalates and CHDs. The SNPs of UGT1A7 gene at rs4124874 (under three models, log-additive: aOR = 1.74, 95% CI:1.28-2.37; dominant: aOR = 1.86, 95% CI:1.25-2.78; recessive: aOR = 2.50, 95% CI: 1.26-4.94) and rs887829 (under the recessive model: aOR = 13.66, 95% CI: 1.54-121) were significantly associated with an increased risk of CHDs. Furthermore, the associations between rs4124874 (under log-additive and dominant models) of UGT1A7 were statistically significant after the false discovery rate correction. No significant gene-gene or gene-phthalate metabolites interactions were observed. CONCLUSIONS: The polymorphisms of maternal UGT1A7 gene at rs4124874 and rs887829 were significantly associated with an increased risk of CHDs. More large-scale studies or prospective study designs are needed to confirm or refute our findings in the future.

A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability.

Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired adaptive behavior and cognitive capacity. High throughput sequencing approaches have revealed the genetic etiologies for 25-50% of ID patients, while inherited genetic mutations were detected in <5% cases. Here, we investigated the genetic cause for non-syndromic ID in a Han Chinese family. Whole genome sequencing was performed on identical twin sisters diagnosed with ID, their respective children, and their asymptomatic parents. Data was filtered for rare variants, and in silico prediction tools were used to establish pathogenic alleles. Candidate mutations were validated by Sanger sequencing. In silico modeling was used to evaluate the mutation's effects on the protein encoded by a candidate coding gene. A novel heterozygous variant in the ZBTB18 gene c.1323C>G (p.His441Gln) was identified. This variant co-segregated with affected individuals in an autosomal dominant pattern and was not detected in asymptomatic family members. Molecular studies reveal that a p.His441Gln substitution disrupts zinc binding within the second zinc finger and disrupts the capacity for ZBTB18 to bind DNA. This is the first report of an inherited ZBTB18 mutation for ID. This study further validates WGS for the accurate molecular diagnosis of ID.

m6A-dependent mevalonate kinase in juvenile hormone synthesis pathway regulates the diapause process of bivoltine silkworm (Bombyx mori).

BACKGROUND: Research has shown that epigenetic modification are involved the regulation of diapause in bivoltine silkworms (Bombyx mori), but it remains unclear how epigenetic modification in response to environmental signals precisely to regulate the diapause processing of bivoltine B. mori. METHODS AND RESULTS: In this study, the diapause terminated eggs of bivoltine B. mori, Qiufeng (QF) were divided into two groups: a QFHT group incubated at 25 °C with a natural day/night cycle to produce diapause eggs, and a QFLT group incubated at 16.5 °C in darkness to produce non-diapause eggs. On the 3rd day of the pupal stage, the total RNAs of the eggs were extracted and their N6-adenosine methylation (m6A) abundances were analyzed to explore the effects of m6A methylation on diapause in the silkworm. The results showed that 1984 m6A peaks are shared, 1563 in QFLT and 659 in QFHT. The m6A methylation level of the QFLT group was higher than that of the QFHT one in various signaling pathways. The m6A methylation rate of mevalonate kinase (MK) in the insect hormone synthesis pathway was significantly different between the two groups. The knockdown of MK by RNA interference in the pupae of QFLT resulted in females laying diapause eggs rather than non-diapause eggs after mating. CONCLUSIONS: m6A methylation involves in the diapause regulation of bivoltine B. mori by changing the expression levels of MK. This result provides a clearer image of the environmental signals on the regulation of diapause in bivoltine silkworms.

PHLDA1 promotes glioblastoma cell growth via sustaining the activation state of Ras.

Activation of the Ras signaling pathway promotes the growth of malignant human glioblastoma multiforme (GBM). Mutations in Ras are rare in GBM, elevated levels of activated Ras are prevalently observed in GBM. However, the potential mechanism of how Ras is activated in GBM remains unclear. In this study, we screened a new interacted protein of Ras, PHLDA1. Our findings confirmed that PHLDA1 acted as an oncogene and promoted glioma progression and recurrence. We demonstrated that PHLDA1 was upregulated in GBM tissues and cells. PHLDA1 overexpression promoted cell proliferation and tumor growth. In terms of mechanism, PHLDA1 promoted cell proliferation by regulating Ras/Raf/Mek/Erk signaling pathway. Moreover, Src promotes GTPase activity of Ras via tyrosine 32 phosphorylation. PHLDA1 and Src competed for binding with Ras, inhibiting Ras phosphorylation by Src and rescuing Ras activity. This study may provide a new idea of the molecular mechanism underlying glioma progression and a novel potential therapeutic target for comprehensive glioblastoma treatment.

RNA N6-methyladenosine of DHAPAT and PAP involves in regulation of diapause of Bombyx mori via the lipid metabolism pathway.

Environment-induced epigenetics are involved in diapause regulation, but the molecular mechanism that epigenetically couples nutrient metabolism to diapause regulation remains unclear. In this study, we paid special attention to the significant differences in the level of N6-adenosine methylation (m6A) of dihydroxyacetone phosphate acyltransferase (DHAPAT) and phosphatidate phosphatase (PAP) genes in the lipid metabolism pathway of the bivoltine silkworm (Bombyx mori) strain Qiufeng developed from eggs incubated at a normal temperature (QFHT, diapause egg producer) compared to those from eggs incubated at a low temperature (QFLT, non-diapause egg producer). We knocked down DHAPAT in the pupal stage of the QFLT group, resulting in the non-diapause destined eggs becoming diapausing eggs. In the PAP knockdown group, the colour of the non-diapause destined eggs changed from light yellow to pink 3 days after oviposition, but they hatched as normal. Moreover, we validated that YTHDF3 binds to m6A-modified DHAPAT and PAP mRNAs to promote their stability and translation. These results suggest that RNA m6A methylation participates in the diapause regulation of silkworm by changing the expression levels of DHAPAT and PAP and reveal that m6A epigenetic modification can be combined with a lipid metabolism signal pathway to participate in the regulation of insect diapause traits, which provides a clearer image for exploring the physiological basis of insect diapause.

The allocation and fairness of health human resources in Chinese maternal and child health care institutions: a nationwide longitudinal study.

BACKGROUND: In response to an aging population, the Chinese government implemented the three-child policy in 2021 based on the comprehensive two-child policy. With the implementation of the new birth policy, people's maternal and child health (MCH) needs will also increase. The allocation and fairness of MCH human resources directly affect people's access to MCH services. The purpose of this study is to analyze the allocation of health human resources in Chinese maternal and child health care institutions, evaluate the fairness of the allocation, to provide a reference for the rational allocation of MCH human resources. METHODS: The data of health technicians, licensed (assistant) physicians, and registered nurses in maternal and child health care institutions nationwide from 2016 to 2020 were included. The health resource density index (HRDI) is used to evaluate the allocation level of MCH human resources. The Gini coefficient (G) and Theil index (T) are used to evaluate the fairness of the allocation of MCH human resources from the perspectives of population and geographic area. RESULTS: From 2016 to 2020, the average annual growth rate of the number of health technicians, licensed (assistant) physicians, and registered nurses in Chinese maternal and child health care institutions was 7.53, 6.88, and 9.12%, respectively. The Gini coefficient (G) of the three types of MCH human resources allocated by population were all below 0.23, and the Gini coefficient (G) allocated by geographical area were all above 0.65. The Theil index (T) of the three types of MCH human resources allocated by population was all lower than 0.06, and the Theil index (T) allocated by geographical area was all higher than 0.53. In addition, the three types of MCH human resources allocated by population and geographic area contributed more than 84% of the Theil index within the group (Tintra) to the Theil index (T). CONCLUSIONS: China's MCH human resources were fair in terms of population allocation, but unfair in terms of geographical area allocation. In the future, more attention should be paid to the geographical accessibility of MCH human resources, and the allocation of resources should comprehensively consider the two factors of serving the population and geographical area.

Evaluation of nausea and vomiting in the first trimester on the risk of adverse birth outcomes and the contribution of genetic polymorphisms: a pilot prospective study.

PURPOSE: To evaluate the impact of Nausea and Vomiting in Pregnancy (NVP) on the risk of Preterm Birth (PTB) and Low Birth Weight (LBW), and explore the effect of genetic polymorphisms on the severity of NVP. METHODS: A prospective study was conducted. Participants' experience of NVP prior to 12 gestational weeks were evaluated by a Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) scale. 11 Single Nucleotide Polymorphisms (SNPs) loci located in growth differentiation factor 15 (GDF15) and leucine-rich repeat containing 25 (LRRC25) gene of chr19p13.11 and intergenic region of chr4q12 were genotyped, which were implicated as genetic risk factors for NVP. Logistic regression models were applied to determine the effect of NVP in the first trimester on the risk of PTB and LBW, and genetic polymorphisms on the risk of NVP. RESULTS: Among 413 pregnant women, the incidence of nausea and vomiting was 85.5% (n = 353) in the first trimester, including 38.7% (n = 160) mild vomiting, 42.6% (n = 176) moderate vomiting and 4.1% (n = 17) severe vomiting. 33 were PTB, 20 were LBW. Compared with pregnant women without NVP, women with mild, moderate or severe NVP in the first trimester were not associated with the risk of PTB and LBW. Besides, the polymorphisms of 11 SNPs loci were not associated with the risk of NVP. CONCLUSIONS: Our study indicated that symptoms of nausea and vomiting in the first trimester were not significantly associated with PTB and LBW, and there were also no associations between GDF15 and LRRC25 polymorphisms and NVP.

A Study on the Prediction of Reproductive Outcomes in Frozen Embryo Transfer Cycles by Calculating the Volume of Uterine Junctional Zone with Three-Dimensional Ultrasound.

PURPOSE: To prospectively study the influence of the volume of the uterine junctional zone (JZ) as a novel predictor of reproductive outcomes in frozen embryo transfer cycles. METHODS: Among the first 30 patients, intra- and interobserver repeatability was evaluated and expressed as a coefficient of repeatability. The same classification system was used to evaluate the JZ of 142 infertility patients undergoing in vitro fertilization (IVF). Ultrasonography was performed on the day before transplantation. The three-dimensional (3D) volume images were then analyzed to obtain the volume of the endometrium (EV), the average thickness of the JZ on the coronal plane, and the volume of the JZ (JZV). The JZV was then divided by the EV. These parameters were compared with the outcomes of clinical pregnancy. RESULTS: The 3D image showed that the JZ achieved a good intra- and interobserver consistency (k = 0.862, k = 0.694). The total pregnancy rate was 47%. There was a highly significant difference between pregnant and non-pregnant women with respect to age (p < 0.001), JZV (p = 0.003), and JZV/EV (p < 0.001) on the day before transplantation. Age and JZV/EV were independent factors for predicting the success of IVF transplantation (p = 0.010, p = 0.016). The area under the ROC curve of JZV/EV in predicting clinical pregnancy was 0.688, the cut-off value was 0.54, the sensitivity was 83.8%, and the specificity was 50.0%. CONCLUSION: Age and JZV/EV are independent factors for predicting the success of frozen embryo transfer cycles in IVF. A smaller JZV/EV was more beneficial for clinical pregnancy.

Exorista sorbillans (Diptera: Tachinidae) parasitism shortens host larvae growth duration by regulating ecdysone and juvenile hormone titers in Bombyx mori (Lepidoptera: Bombycidae).

The tachinid fly, Exorista sorbillans, is a notorious ovolarviparous endoparasitoid of the silkworm, Bombyx mori, causing severe damage to silkworm cocoon industry. Silkworm larvae show typically precocious wandering behavior after being parasitized by E. sorbillans; however, the underlying molecular mechanism remains unexplored. Herein, we investigated the changes in the levels of 20-hydroxyecdysone (20E) and juvenile hormone (JH) titer, and they both increased in the hemolymph of parasitized silkworms. Furthermore, we verified the expression patterns of related genes, which showed an upregulation of 20E signaling and biosynthesis genes but a significant downregulation of ecdysone oxidase (EO), a 20E inactivation enzyme, in parasitized silkworms. In addition, related genes of the JH signaling were activated in parasitized silkworms, while related genes of the JH degradation pathway were suppressed, resulting in an increase in JH titer. Notably, the precocious wandering behavior of parasitized silkworms was partly recoverable by silencing the transcriptions of BmCYP302A1 or BmCYP307A1 genes. Our findings suggest that the developmental duration of silkworm post parasitism could be shortened by regulation of 20E and JH titers, which may help silkworm to resist the E. sorbillans infestation. These findings provide a basis for deeper insight into the interplay between silkworms and E. sorbillans and may serve as a reference for the development of a novel approach to control silkworm myiasis.

Biomarkers for isolated congenital heart disease based on maternal amniotic fluid metabolomics analysis.

INTRODUCTION: Congenital heart disease (CHD) is one of the most prevalent birth defects in the world. The pathogenesis of CHD is complex and unclear. With the development of metabolomics technology, variations in metabolites may provide new clues about the causes of CHD and may serve as a biomarker during pregnancy. METHODS: Sixty-five amniotic fluid samples (28 cases and 37 controls) during the second and third trimesters were utilized in this study. The metabolomics of CHD and normal fetuses were analyzed by untargeted metabolomics technology. Differential comparison and randomForest were used to screen metabolic biomarkers. RESULTS: A total of 2472 metabolites were detected, and they were distributed differentially between the cases and controls. Setting the selection criteria of fold change (FC) ≥ 2, P value < 0.01 and variable importance for the projection (VIP) ≥ 1.5, we screened 118 differential metabolites. Within the prediction model by random forest, PE(MonoMe(11,5)/MonoMe(13,5)), N-feruloylserotonin and 2,6-di-tert-butylbenzoquinone showed good prediction effects. Differential metabolites were mainly concentrated in aldosterone synthesis and secretion, drug metabolism, nicotinate and nicotinamide metabolism pathways, which may be related to the occurrence and development of CHD. CONCLUSION: This study provides a new database of CHD metabolic biomarkers and mechanistic research. These results need to be further verified in larger samples.

The effect of maternal polycyclic aromatic hydrocarbons exposure and methylation levels of congenital heart diseases-candidate genes on the risk of congenital heart diseases.

OBJECTIVE: To evaluate the impact of maternal exposure to polycyclic aromatic hydrocarbons (PAHs) and methylation levels of CHDs-candidate genes on the risk of congenital heart diseases (CHDs), and the effect of PAHs exposure on DNA methylation states. METHODS: A case-control study involving 60 mother -fetus pairs was performed by measuring 1-OHPG concentration in maternal urine and methylation levels of 20 CHDs-candidate genes in cord bloods. Logistic regression models were applied to determine the effect of maternal PAHs exposure and fetal methylation levels on the risk of CHDs. Spearman correlation was performed to correlate PAHs exposure and methylation levels. RESULTS: Maternal higher PAHs exposure was associated with the risk of CHDs (aOR = 3.245, 95% CI: 1.060, 9.937) or some subtypes. The methylation levels of 23 amplicons within 11 genes exhibited significant differences between CHDs and controls. Higher methylation of NKX2-5_M1 was associated with decreased risk of CHDs (aOR = 0.182, 95% CI:0.034, 0.983). No significant correlations were found between 1-OHPG concentration and methylation levels of NKX2-5_M1. CONCLUSIONS: Maternal PAHs exposure was linked with CHDs. Higher methylation of the upstream sequence of NKX2-5 promoter decreased the risk of CHDs. There was no correlation between maternal PAHs exposure and the methylation level of NKX2-5.

Mixture toxicity effects of chloramphenicol, thiamphenicol, florfenicol in Daphnia magna under different temperatures.

Acute toxicities of chloramphenicol (CAP), thiamphenicol (TAP), and florfenicol (FLO) and their mixtures on Daphnia magna under two representative temperatures of the aquatic environment (20 and 25 °C) have been examined. Their toxicities depicted with an order of 72-h EC50 values were as follows: CAP > FLO > TAP and CAP ≈ FLO > TAP under 20 and 25 °C, separately. Furthermore, the acute toxicity significantly increased with the rise of temperature from 20 to 25 °C in nearly all separate and mixture phenicol antibiotics. Meanwhile, the most toxic combination under two different temperatures was diverse. The nature of toxicological interactions of phenicol antibiotic mixtures was analyzed by Combination Index (CI) equation. In general, a dual synergism-antagonism effect was dominant in nearly all mixtures at both temperatures. The prediction suitability of Concentration Addition (CA), Independent Action (IA) models, and CI method was compared, suggesting that the CI equation seems to be more appropriate for predicting the toxicity values of phenicol drugs than CA and IA models. In brief, phenicol antibiotic mixtures with temperature variation may pose more significant hazards and risks to aquatic organisms; hence, the environment.

Unintended pregnancy-related factors and the occurrence of offspring congenital heart disease: a multi-site case-control study in China.

OBJECTIVES: The aim of this study was to explore the association between unintended pregnancy and related factors among congenital heart defects (CHDs) in infants. METHODS: A total of 1197 cases with isolated CHDs and 1125 controls without any abnormalities were analysed in this multicentre study at seven hospitals in China. According to the pregnancy intention, cases were divided into two groups: planned and unintended pregnancies. The adjusted odds ratio (AOR) was calculated by logistic regression analysis to assess the association between unintended pregnancy and CHD occurrence. The time to prepare for pregnancy and the influencing factors were also compared in this article. RESULTS: The risk for CHD occurrence was significantly associated with unintended pregnancy (AOR: 1.42; 95%CI: 1.16-1.73), which may increase the risks for each subtype of CHD occurrence. Risks such as parental smoking, housing renovation, accidental alcohol consumption, lack of health check-ups, and no folic acid supplementation before pregnancy were distributed differently among the planned and unintended pregnancy groups and were associated with CHD occurrence. However, there was no significant association between the duration of planned pregnancy and the risk of CHDs. CONCLUSIONS: Unintended pregnancy increased the risk of CHDs in infants. This risk may be related to some known and unknown factors. SYNOPSIS: Some unintended pregnancy related factors may increase the risk for foetal CHDs. The duration of planning pregnancy may not be associated with the risk of CHDs.

Seasonal and spatial variations in the phytoplankton community and their correlation with environmental factors in the Jinjiang River Estuary in Quanzhou, China.

The seasonal and spatial variation in the phytoplankton community structure and the environmental variables were investigated in December (the dry season) 2016 and July (the rainy season) 2017 in the Jinjiang River Estuary, China. We identified a total of 138 species of phytoplankton, which were mainly Chlorophyta, Bacillariophyta, and Cryptophyta in the dry season; however, in the rainy season, only Bacillariophyta were found. In the Jinjiang River Estuary, the species evenness and the biodiversity index were higher in the rainy season and that the species diversity was higher in the dry season. Redundancy analysis (RDA) revealed that the dominant species were statistically related to many of the environmental variables, including the water temperature (WT), pH, salinity (Sal), dissolved oxygen (DO), total phosphorus (TP), and total nitrogen (TN). Among the variables, the Sal, DO, TP, and TN had a significant influence on the dominant species distribution, and the WT and pH also affected the dominant species distribution to some extent.

CELF2 suppresses non-small cell lung carcinoma growth by inhibiting the PREX2-PTEN interaction.

The phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway is important in the regulation of cell proliferation through its production of phosphatidylinositol 3,4,5-triphosphate (PIP3). Activation of this pathway is frequently observed in human cancers, including non-small cell lung carcinoma. The PI3-K/Akt pathway is negatively regulated by the dual-specificity phosphatase and tensin homolog (PTEN) protein. PTEN acts as a direct antagonist of PI3-K by dephosphorylating PIP3. Studies have shown that PTEN phosphatase activity is inhibited by PREX2, a guanine nucleotide exchanger factor (GEF). Multiple studies revealed that CELF2, an RNA binding protein, cooperates synergistically with PTEN as a tumor suppressor in multiple cancers. However, the underlying mechanism as to how CELF2 enhances PTEN activity remains unclear. Here, we report that CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN. Consistent with this observation, PTEN phosphatase activity is upregulated with CELF2 overexpression. In addition, overexpression of CELF2 represses both Akt phosphorylation and cell proliferation only in the presence of PTEN. In an ex vivo study, CELF2 gene delivery could significantly inhibit patient-derived xenografts (PDX) tumor growth. To further investigate the clinical relevance of this finding, we analyzed 87 paired clinical lung adenocarcinoma samples and the results showed that CELF2 protein expression is downregulated in tumor tissues and associated with poor prognosis. The CELF2 gene is located on the chromosome 10p arm, a region frequently lost in human cancers, including breast invasive carcinoma, low-grade glioma and glioblastoma. Analysis of TCGA datasets showed that CELF2 expression is also associated with shorter patient survival time in all these cancers. Overall, our work suggests that CELF2 plays a novel role in PI3-K signaling by antagonizing the oncogenic effect of PREX2.

Social and environmental risk factors for the accidental drowning of children under five in China.

BACKGROUND: Accidental drowning of children under five is a serious problem in China. The present study analyzed data on environmental and sociodemographic factors and on primary caregivers of drowned children to understand factors that may contribute to this problem. METHODS: The present study collected information on 563 cases of drowning in children under five from October 1, 2015, to September 30, 2016, in 334 sampling districts in China. Primary caregivers were interviewed individually using the Drowning Mortality among Children under 5 Questionnaire. RESULTS: Most drowned children under 5 years old were boys, and 71.6% lived within 100 m of a body of water. The drownings primarily occurred in ponds, canals, rivers, and wells, and over 90% of these water bodies had no safety measures. There were 28.1% of primary caregivers who did not provide full-time care for the children, and 83.1% of them had no knowledge of first aid skills for drowning. CONCLUSION: Encouraging kindergarten enrollment and providing safety education for children may reduce drowning in children under 5 years of age. Public water body protection measures should be strengthened to prevent children from drowning. Encouraging primary caregivers to care full-time for the children and learning first aid skills for drowning may also help reduce fatalities.

ECDYSTEROID AND CHITINASE FLUCTUATIONS IN THE WESTERN TARNISHED PLANT BUG (Lygus hesperus) PRIOR TO MOLT INDICATE ROLES IN DEVELOPMENT.

Vital physiological processes that drive the insect molt represent areas of interest for the development of alternative control strategies. The western tarnished plant bug (Lygus hesperus Knight) is a pest of numerous agronomic and horticultural crops but the development of novel control approaches is impeded by limited knowledge of the mechanisms regulating its molt. To address this deficiency, we examined the fundamental relationship underlying the hormonal and molecular components of ecdysis. At 27°C L. hesperus exhibits a temporally controlled nymph-adult molt that occurs about 4 days after the final nymph-nymph molt with ecdysteroid levels peaking 2 days prior to the final molt. Application of exogenous ecdysteroids when endogenous levels had decreased disrupted the nymphal-adult molt, with treated animals exhibiting an inability to escape the old exoskeleton and resulting in mortality compared to controls. Using accessible transcriptomic data, we identified 10 chitinase-like sequences (LhCht), eight of which had protein motifs consistent with chitinases. Phylogenetic analyses revealed orthologous relationships to chitinases critical to molting in other insects. RT-PCR based transcript profiling revealed that expression changes to four of the LhChts was coordinated with the molt period and ecdysteroid levels. Collectively, our results support a role for ecdysteroid regulation of the L. hesperus molt and suggest that cuticle clearance is mediated by LhCht orthologs of chitinases that are essential to the molt process. These results provide the initial hormonal and molecular basis for future studies to investigate the specific roles of these components in molting.

BMDREDD REGULATES THE APOPTOSIS COORDINATING WITH BMDAXX, BMCIDE-B, BMFADD, AND BMCREB IN BMN CELLS.

The apoptosis mechanisms in mammals were investigated relatively clearly. However, little is known about how apoptosis is achieved at a molecular level in silkworm cells. We cloned a caspase homologous gene named BmDredd (where Bm is Bombyx mori and Dredd is death-related ced-3/Nedd2-like caspase) in BmN cells from the ovary of Bm and analyzed its biological information. We constructed the N-terminal, C-terminal, and overexpression vector of BmDredd, respectively. Our results showed that the transcriptional expression level of BmDredd was increased in the apoptotic BmN cells. Furthermore, overexpression of BmDredd increased the caspase-3/7 activity. Simultaneously, RNAi of BmDredd could save BmN cells from apoptosis. The immunofluorescence study showed that BmDredd located at the cytoplasm in normal cell otherwise is found at the nucleus when cells undergo apoptosis. Moreover, we quantified the transcriptional expressions of apoptosis-related genes including BmDredd, BmDaxx (where Daxx is death-domain associated protein), BmCide-b (where Cide-b is cell death inducing DFF45-like effector), BmFadd (Fadd is fas-associated via death domain), and BmCreb (where Creb is cAMP-response element binding protein) in BmN cells with dsRNA interferences to detect the molecular mechanism of apoptosis. In conclusion, BmDredd may function for promoting apoptosis and there are various regulatory interactions among these apoptosis-related genes.