Tripartite motif-containing protein 21 is involved in IFN-γ-induced suppression of hepatitis B virus by regulating hepatocyte nuclear factors.

The antiviral role of the tripartite motif-containing (TRIM) protein family , a member of the E3-ubiquitin ligase family, has recently been actively studied. Hepatitis B virus (HBV) infection is a major contributor to liver diseases; however, the host factors regulated by cytokine-inducible TRIM21 to suppress HBV remain unclear. In this study, we showed the antiviral efficacy of TRIM21 against HBV in hepatoma cell lines, primary human hepatocytes isolated from patient liver tissues, and mouse model. Using TRIM21 knock-out cells, we confirmed that the antiviral effects of interferon-gamma, which suppress HBV replication, are diminished when TRIM21 is deficient. Northern blot analysis confirmed a reduction of HBV RNA levels by TRIM21. Using Luciferase reporter assay, we also discovered that TRIM21 decreases the activity of HBV enhancers, which play a crucial role in covalently closed circular DNA transcription. The participation of the RING domain and PRY-SPRY domain in the anti-HBV effect of TRIM21 was demonstrated through experiments using deletion mutants. We identified a novel interaction between TRIM21 and hepatocyte nuclear factor 4α (HNF4α) through co-immunoprecipitation assay. More specifically, ubiquitination assay revealed that TRIM21 promotes ubiquitin-mediated proteasomal degradation of HNF4α. HNF1α transcription is down-regulated as a result of the degradation of HNF4α, an activator for the HNF1α promoter. Therefore, the reduction of key HBV enhancer activators, HNF4α and HNF1α, by TRIM21 resulted in a decline in HBV transcription, ultimately leading to the inhibition of HBV replication.IMPORTANCEDespite extensive research efforts, a definitive cure for chronic hepatitis B remains elusive, emphasizing the persistent importance of this viral infection as a substantial public health concern. Although the risks associated with hepatitis B virus (HBV) infection are well known, host factors capable of suppressing HBV are largely uncharacterized. This study elucidates that tripartite motif-containing protein 21 (TRIM21) suppresses HBV transcription and consequently inhibits HBV replication by downregulating the hepatocyte nuclear factors, which are host factors associated with the HBV enhancers. Our findings demonstrate a novel anti-HBV mechanism of TRIM21 in interferon-gamma-induced anti-HBV activity. These findings may contribute to new strategies to block HBV.

GLIS3 expression in the thyroid gland in relation to TSH signaling and regulation of gene expression.

Loss of GLI-Similar 3 (GLIS3) function in mice and humans causes congenital hypothyroidism (CH). In this study, we demonstrate that GLIS3 protein is first detectable at E15.5 of murine thyroid development, a time at which GLIS3 target genes, such as Slc5a5 (Nis), become expressed. This, together with observations showing that ubiquitous Glis3KO mice do not display major changes in prenatal thyroid gland morphology, indicated that CH in Glis3KO mice is due to dyshormonogenesis rather than thyroid dysgenesis. Analysis of GLIS3 in postnatal thyroid suggested a link between GLIS3 protein expression and blood TSH levels. This was supported by data showing that treatment with TSH, cAMP, or adenylyl cyclase activators or expression of constitutively active PKA enhanced GLIS3 protein stability and transcriptional activity, indicating that GLIS3 activity is regulated at least in part by TSH/TSHR-mediated activation of PKA. The TSH-dependent increase in GLIS3 transcriptional activity would be critical for the induction of GLIS3 target gene expression, including several thyroid hormone (TH) biosynthetic genes, in thyroid follicular cells of mice fed a low iodine diet (LID) when blood TSH levels are highly elevated. Like TH biosynthetic genes, the expression of cell cycle genes is suppressed in ubiquitous Glis3KO mice fed a LID; however, in thyroid-specific Glis3 knockout mice, the expression of cell cycle genes was not repressed, in contrast to TH biosynthetic genes. This indicated that the inhibition of cell cycle genes in ubiquitous Glis3KO mice is dependent on changes in gene expression in GLIS3 target tissues other than the thyroid.

Genotype of dengue virus serotype 1 in relation to severe dengue in Guangzhou, China.

Guangzhou has been the city most affected by the dengue virus (DENV) in China, with a predominance of DENV serotype 1 (DENV-1). Viral factors such as dengue serotype and genotype are associated with severe dengue (SD). However, none of the studies have investigated the relationship between DENV-1 genotypes and SD. To understand the association between DENV-1 genotypes and SD, the clinical manifestations of patients infected with different genotypes were investigated. A total of 122 patients with confirmed DENV-1 genotype infection were recruited for this study. The clinical manifestations, laboratory tests, and levels of inflammatory mediator factors were statistically analyzed to investigate the characteristics of clinical manifestations and immune response on the DENV-1 genotype. In the case of DENV-1 infection, the incidence of SD with genotype V infection was significantly higher than that with genotype I infection. Meanwhile, patients infected with genotype V were more common in ostealgia and bleeding significantly. In addition, levels of inflammatory mediator factors including IFN-γ, TNF-α, IL-10, and soluble vascular cell adhesion molecule 1 were higher in patients with SD infected with genotype V. Meanwhile, the concentrations of regulated upon activation normal T-cell expressed and secreted and growth-related gene alpha were lower in patients with SD infected with genotype V. The higher incidence of SD in patients infected with DENV-1 genotype V may be attributed to elevated cytokines and adhesion molecules, along with decreased chemokines.

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.

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.

[Comparison of in vivo pharmacokinetics of twelve constituents in Qihe Fenqing Yin in normal rats and diabetic rats].

This paper aims to study the pharmacokinetic differences of twelve effective constituents(succinic acid, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, protocatechuic aldehyde, caffeic acid, 5-O-ferulogeninic acid, p-coumaric acid, nuciferine, quercetin, oleanolic acid, and ursolic acid) in Qihe Fenqing Yin in normal and diabetic rats. The diabetic rat model was established by a high-fat diet combined with intraperitoneal injection of streptozocin. A UHPLC-QTRAP-MS/MS method was established for the simultaneous determination of 12 constituents in the plasma of normal rats and model rats after a single intragastric administration of Qihe Fenqing Yin. The results show that the established analytical method has a good linear relationship with the 12 components, and the specificity, accuracy, precision, and stability meet the requirements. The computational pharmacokinetic parameters are fitted by DAS 3.2.8 software, and the results show that the half-life time(t_(1/2)) of the other nine components in the model group was longer than that in the normal group except for caffeic acid, 5-O-ferulogeninic acid, and oleanolic acid. The area under curve(AUC_(0-t)) of cryptochlorogenic acid, p-coumaric acid, ursolic acid, and oleanolic acid increases compared with the normal group. Meanwhile, mean residence time(MRT) delays. The "double peaks" of quercetin and nuciferine in the normal group are not observed in the model group, suggesting that the pharmacokinetic parameters of the drugs in the disease state are significantly different.

Dual-Salt Electrolyte Additive Enables High Moisture Tolerance and Favorable Electric Double Layer for Lithium Metal Battery.

The carbonate electrolyte chemistry is a primary determinant for the development of high-voltage lithium metal batteries (LMBs). Unfortunately, their implementation is greatly plagued by sluggish electrode interfacial dynamics and insufficient electrolyte thermodynamic stability. Herein, lithium trifluoroacetate-lithium nitrate (LiTFA-LiNO3 ) dual-salt additive-reinforced carbonate electrolyte (LTFAN) is proposed for stabilizing high-voltage LMBs. We reveal that 1) the in situ generated inorganic-rich electrode-electrolyte interphase (EEI) enables rapid interfacial dynamics, 2) TFA- preferentially interacts with moisture over PF6 - to strengthen the moisture tolerance of designed electrolyte, and 3) NO3 - is found to be noticeably enriched at the cathode interface on charging, thus constructing Li+ -enriched, solvent-coordinated, thermodynamically favorable electric double layer (EDL). The superior moisture tolerance of LTFAN and the thermodynamically stable EDL constructed at cathode interface play a decisive role in upgrading the compatibility of carbonate electrolyte with high-voltage cathode. The LMBs with LTFAN realize 4.3 V-NCM523/4.4 V-NCM622 superior cycling reversibility and excellent rate capability, which is the leading level of documented records for carbonate electrode.

Enzymatic Assembly of DNA Nanostructures and Fragments with Sequence Overlaps.

Homologous recombination, an evolutionarily conserved DNA double-strand break repair pathway to protect genome stability, has long been exploited for the in vivo and in vitro assembly of multiple DNA duplex fragments in molecular cloning. Whether such methods can also be applied in the self-assembly of DNA nanostructures remains underexplored. Here, we report an enzymatic approach for the self-assembly of high-order DNA constructs with overlapping segments. In our system, a DNA polymerase with exonuclease activity was introduced to produce ssDNA overhangs for specific sticky end cohesion, and as many as 25 DNA structural units were designed to be hierarchically assembled. Using this approach, we successfully constructed a variety of high-order DNA nanostructures, including tubes and extended oligomers, from homogeneous assembly and custom multimers from heterogeneous assembly. Our strategy expands the construction toolbox of complex DNA nanostructures and highlights the potential to enhance the assembly of duplex fragments in molecular cloning.

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.

Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza.

The multifunctional influenza virus protein PB1-F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 PB1-F2 protein not only interferes with the mitochondria-dependent pathway of type I interferon (IFN) signaling, but also acquired a novel IFN antagonist function by targeting the DEAD-box helicase DDX3, a key downstream mediator in antiviral interferon signaling, toward proteasome-dependent degradation. Interactome analysis revealed that 1918 PB1-F2, but not PR8 PB1-F2, binds to DDX3 and causes its co-degradation. Consistent with intrinsic protein instability as basis for this gain-of-function, internal structural disorder is associated with the unique cytotoxic sequences of the 1918 PB1-F2 protein. Infusing mice with recombinant DDX3 protein completely rescued them from lethal infection with the 1918 PB1-F2-producing virus. Alongside NS1 protein, 1918 PB1-F2 therefore constitutes a potent IFN antagonist causative for the severe pathogenicity of the 1918 influenza strain. Our identification of molecular determinants of pathogenesis should be useful for the future design of new antiviral strategies against influenza pandemics.

Synthesis and biological evaluation of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine as a novel, potent ALK5 receptor inhibitor.

Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. In this work, a novel series of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine (11), a potential clinical candidate, was synthesized by strategic incorporation of deuterium at potential metabolic soft spots and identified as ALK5 inhibitors. This compound has a low potential for CYP-mediated drug-drug interactions as a CYP450 inhibitor (IC50 = >10 µM) and showed potent inhibitory effects in cellular assay (IC50 = 3.5 ± 0.4 nM). The pharmacokinetic evaluation of 11 in mice demonstrated moderate clearance (29.0 mL/min/kg) and also revealed high oral bioavailability in mice (F = 67.6%).

The electronic structure of a strongly bound sandwich MoS2-WS2 heterobilayer.

First of all, we show that two kinds of sandwich bilayers (BLs) are dynamically, thermally, and mechanically stable, which are degenerate p-type materials with intercalated Ca atoms, i.e., Nb-doped MoS2 homobilayers (HoBLs) and Nb-doped WS2-MoS2 heterobilayers (HtBLs) with 25% Nb content. Specifically, their interlayer bindings are five times stronger than van der Waals interactions in their pristine counterparts. Both of them are semiconductors with indirect band gaps in the visible region within the HSE06 exchange-correlation functional. Depending upon the presence and absence of centrosymmetry, they display interesting spin-valley coupling effects in such a way that opposite hidden spin polarization or opposite spin splitting is observed at opposite k-points. They can be easily engineered into direct gap materials under compressive (>2%) strain along the zigzag direction even with an explicit consideration of giant spin splitting. Under strain, they satisfy thermodynamic conditions for bifunctional catalysis in photocatalytic water splitting. In addition, the photoholes of the BLs can be subjected to lower overpotentials than those of pristine BLs for the oxygen evolution reaction. Electrons and holes in the sandwich HtBL can be separated into different layers under photon irradiation, allowing it to be more efficient than the corresponding HoBL in solar energy harvesting.

Single-molecule dynamics of Dishevelled at the plasma membrane and Wnt pathway activation.

Dvl (Dishevelled) is one of several essential nonenzymatic components of the Wnt signaling pathway. In most current models, Dvl forms complexes with Wnt ligand receptors, Fzd and LRP5/6 at the plasma membrane, which then recruits the destruction complex, eventually leading to inactivation of ß-catenin degradation. Although this model is widespread, direct evidence for the individual steps is lacking. In this study, we tagged mEGFP to C terminus of dishevelled2 gene using CRISPR/Cas9-induced homologous recombination and observed its dynamics directly at the single-molecule level with total internal reflection fluorescence (TIRF) microscopy. We focused on two questions: 1) What is the native size and what are the dynamic features of membrane-bound Dvl complexes during Wnt pathway activation? 2) What controls the behavior of these complexes? We found that membrane-bound Dvl2 is predominantly monomer in the absence of Wnt (observed mean size 1.1). Wnt3a stimulation leads to an increase in the total concentration of membrane-bound Dvl2 from 0.12/µm2 to 0.54/µm2 Wnt3a also leads to increased oligomerization which raises the weighted mean size of Dvl2 complexes to 1.5, with 56.1% of Dvl still as monomers. The driving force for Dvl2 oligomerization is the increased concentration of membrane Dvl2 caused by increased affinity of Dvl2 for Fzd, which is independent of LRP5/6. The oligomerized Dvl2 complexes have increased dwell time, 2 ∼ 3 min, compared to less than 1 s for monomeric Dvl2. These properties make Dvl a unique scaffold, dynamically changing its state of assembly and stability at the membrane in response to Wnt ligands.

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.

Basic Helix-Loop-Helix Transcription Factors: Regulators for Plant Growth Development and Abiotic Stress Responses.

Plant basic helix-loop-helix (bHLH) transcription factors are involved in many physiological processes, and they play important roles in the abiotic stress responses. The literature related to genome sequences has increased, with genome-wide studies on the bHLH transcription factors in plants. Researchers have detailed the functionally characterized bHLH transcription factors from different aspects in the model plant Arabidopsis thaliana, such as iron homeostasis and abiotic stresses; however, other important economic crops, such as rice, have not been summarized and highlighted. The bHLH members in the same subfamily have similar functions; therefore, unraveling their regulatory mechanisms will help us to identify and understand the roles of some of the unknown bHLH transcription factors in the same subfamily. In this review, we summarize the available knowledge on functionally characterized bHLH transcription factors according to four categories: plant growth and development; metabolism synthesis; plant signaling, and abiotic stress responses. We also highlight the roles of the bHLH transcription factors in some economic crops, especially in rice, and discuss future research directions for possible genetic applications in crop breeding.

[Development and Application of Ontology of Cancer Hallmarks].

Objective To develop a traceable cancer hallmark ontology with terminology including gene mutation,cancer hallmark,and cell line for knowledge integration,standardization,correlation,and discovery.Methods The Ontology Development 101 and the current ontology development methods were employed to determine the content coverage,structural layers,reusable terms,and new terms of the cancer hallmark ontology.Taking colorectal cancer as a study case,we extracted the knowledge related with colorectal cancer hallmarks using text mining and text classification technology from PubMed,and then formalized the extracted knowledge into the cancer hallmark ontology.Moreover,we made use of existing cancer hallmark evidence in Catalogue of Somatic Mutations in Cancer and further semantic retrieval to discover new knowledge.Results The established cancer hallmark ontology comprised 9910 classes and 6138 instances,which realized the semantic representation of 2310 article abstracts about colorectal cancer and 26 pieces of evidence about genes and their cancer hallmarks.Compared with the Catalogue of Somatic Mutations in Cancer,new evidence for more genes associated with colorectal cancer hallmarks was found based on cancer hallmark ontology.Conclusion This study is of great significance to the research on the cancer pathogenesis at the molecular level,the revealing of specific roles of genes and mutations in the occurrence of cancer,and the rapid knowledge discovery of cancer hallmarks.

The nuclear receptor RORα preserves cardiomyocyte mitochondrial function by regulating caveolin-3-mediated mitophagy.

Preserving optimal mitochondrial function is critical in the heart, which is the most ATP-avid organ in the body. Recently, we showed that global deficiency of the nuclear receptor RORα in the "staggerer" mouse exacerbates angiotensin II-induced cardiac hypertrophy and compromises cardiomyocyte mitochondrial function. However, the mechanisms underlying these observations have not been defined previously. Here, we used pharmacological and genetic gain- and loss-of-function tools to demonstrate that RORα regulates cardiomyocyte mitophagy to preserve mitochondrial abundance and function. We found that cardiomyocyte mitochondria in staggerer mice with lack of functional RORα were less numerous and exhibited fewer mitophagy events than those in WT controls. The hearts of our novel cardiomyocyte-specific RORα KO mouse line demonstrated impaired contractile function, enhanced oxidative stress, increased apoptosis, and reduced autophagic flux relative to Cre(-) littermates. We found that cardiomyocyte mitochondria in "staggerer" mice with lack of functional RORα were upregulated by hypoxia, a classical inducer of mitophagy. The loss of RORα blunted mitophagy and broadly compromised mitochondrial function in normoxic and hypoxic conditions in vivo and in vitro. We also show that RORα is a direct transcriptional regulator of the mitophagy mediator caveolin-3 in cardiomyocytes and that enhanced expression of RORα increases caveolin-3 abundance and enhances mitophagy. Finally, knockdown of RORα impairs cardiomyocyte mitophagy, compromises mitochondrial function, and induces apoptosis, but these defects could be rescued by caveolin-3 overexpression. Collectively, these findings reveal a novel role for RORα in regulating mitophagy through caveolin-3 and expand our currently limited understanding of the mechanisms underlying RORα-mediated cardioprotection.

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.

Light-Designed Shark Skin-Mimetic Surfaces.

Sharks, marine creatures that swim fast and have an antifouling ability, possess dermal denticle structures of micrometer-size. Because the riblet geometries on the denticles reduce the shear stress by inducing the slip of fluid parallel to the stream-wise direction, shark skin has the distinguished features of low drag and antifouling. Although much attention has been given to low-drag surfaces inspired from shark skin, it remains an important challenge to accurately mimic denticle structures in the micrometer scale and to finely control their structural features. This paper presents a novel method to create shark skin-mimetic denticle structures for low drag by exploiting a photoreconfigurable azopolymer. The light-designed denticle structure exhibits superior hydrophobicity and an antifouling effect as sharks do. This work suggests that our novel photoreconfiguration technology, mimicking shark skin and systematically manipulating various structural parameters, can be used in a reliable manner for diverse applications requiring low-drag surfaces.