Comparative pharmacokinetics of multi-components in normal and stomach cold syndrome rats after oral administration of Zingiberis Rhizoma - Jujubae Fructus herb pair and its single herb extracts by UHPLC-MS/MS.

The Zingiberis Rhizoma - Jujubae Fructus herb pair (ZJHP) is a classic herb pair in traditional Chinese medicine. The herb pair shows the effect of dispelling cold, harmonizing the middle and improving gastrointestinal function, and is widely used for patients with stomach cold syndrome (SCS), stomachache and anemofrigid cold. The gingerols, shogaols, flavonoids and triterpenic acids are the important bioactive ingredients of ZJHP. However, few pharmacokinetic studies have been investigated in vivo for the above compounds. To comprehend the kinetics of active components and promote their curative application, a fast and sensitive ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS) method was established for simultaneous determination of 12 analytes in normal and SCS rats in this study. The results showed that the pharmacokinetic parameters (Cmax, Tmax, t1/2z, MRT0-t, AUC0-t and AUC0-∞) in SCS model were significantly different from those in normal rats. In addition, the pharmacokinetics of rats given ZJHP were also varied from single herb oral administration, especially in model condition. These results indicated that the in vivo processes of the above analytes changed under pathological conditions and the compatibility of the herb pair could significantly influence the absorption of active components, which might provide an insight and further supports for the clinical application of ZJHP.

De novo variation in ARID1B gene causes Coffin-Siris syndrome 1 in a Chinese family with excessive early-onset high myopia.

Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS.

Maternal fasting glucose levels throughout the pregnancy and risk of adverse birth outcomes in newborns: a birth cohort study in Foshan city, Southern China.

OBJECTIVE: We aimed to investigate the associations between maternal fasting plasma glucose (FPG) levels and glycemic fluctuations during different trimesters and adverse birth outcomes among newborns. METHODS: This cohort study used data from 63 213 pregnant women and their offspring in Foshan city from November 2015 to January 2019. Associations between maternal FPG and glycemic fluctuations during different trimesters and adverse birth outcomes [congenital heart defect (CHD), macrosomia, small/large for gestational age (SGA/LGA), and preterm birth (PTB)] in newborns were estimated using mixed-effects logistic regression models. RESULTS: A total of 45 516 participants accepted at least one FPG test throughout pregnancy, and 7852 of whom had glycemic trajectory data. In the adjusted model, higher maternal FPG throughout the pregnancy was associated with an increased risk of adverse birth outcomes (except for SGA). Each 1 mmol/L increase in maternal FPG during trimester 1 was associated with higher odds of CHD (OR = 1.14 (95% CI: 1.02, 1.26)). The same increase in maternal FPG during trimester 3 was associated with a higher risk of PTB (OR = 1.05 (95% CI: 1.01, 1.10)). Increment of maternal FPG during trimester 2 and trimester 3 was associated with a higher risk of macrosomia and LGA. Increase in FPG throughout the pregnancy was associated with slightly lower odds of SGA. Similar results were observed when analyzing the associations between glycemic fluctuations during different trimesters and adverse birth outcomes. CONCLUSIONS: Our findings indicate higher maternal FPG levels during different trimesters were associated with different adverse birth outcomes, which suggests the importance of glycemic management throughout the pregnancy.

Xp21 DNA microdeletion syndrome in a Chinese family: clinical features show retinitis pigmentosa and chronic granuloma.

Xp21 DNA microdeletion syndrome is a very rare disease characterized by retinitis pigmentosa (RP), chronic granulomatous disease (CGD), and McLeod syndrome (MLS). Due to the complex and diverse clinical manifestations, early diagnosis remains a challenge for many physicians. In this study, for the purpose of determining the pathogenic gene variants and definitive diagnosis in a patient medically backgrounded with RP and CGD from a normal Chinese family, whole-exome sequencing (WES) was performed in this proband and copy number variation (CNV) was further verified in other family members by qPCR. A genetic evaluation revealed that the short arm of the X chromosome in the proband had a deletion CNV Xp21.1p11.4 (37431123-38186681) of approximately 0.755 Mb in size, and contained three contiguous OMIM genes as X-linked Kx blood group antigen (XK), cytochrome b-245 beta chain (CYBB), and RP GTPase regulator (RPGR). The qPCR results confirmed the copy number loss in Xp21.1p11.4 present in the proband and his unaffected mother. According to the American College of Medical Genetics and Genomics (ACMG) guidelines for the CNV interpretation, the deletion of this segment was a pathogenic variant. Our results provided evidence that CNV deletion of Xp21.1p11.4 in the short arm of the X chromosome was a pathogenic variant in such Chinese RP and CGD family, and the McLeod phenotype was not yet available. This study suggests that genetic testing is essential for a definitive diagnosis, which should better assist physicians in prediction, diagnosis, genetic counseling, and guidance for Xp21 DNA microdeletion syndrome.

Evaluation of the tolerance and forage quality of different ecotypes of seashore paspalum.

Seashore paspalum is a halophytic, warm-season grass with wide applications. It is noted for its superior salt tolerance in saline environments; however, the nutritive value of seashore paspalum and the effect of salinity remains to be determined. Therefore, this study aimed to evaluate the relationship between agronomic traits and forage quality and identified the effects of short-term high-salt stress (1 week, 700 mM NaCl) on the growth and forage nutritive value of 16 ecotypes of seashore paspalum. The salt and cold tolerances of the seashore paspalum ecotypes were assessed based on the survival rate following long-term high-salt stress (7 weeks, 700 mM NaCl) and exposure to natural low temperature stress. There were significant genetic (ecotype-specific) effects on plant height, leaf-stem ratio, and survival rate of seashore paspalum following salt or low temperature stress. Plant height was significantly negatively correlated with the leaf-stem ratio (r = -0.63, P<0.01), but the heights and leaf-stem ratios were not significantly correlated with the fresh weight (FW) and dry weight (DW) of the shoots. High salinity decreased the FW and DW of the shoots by 50.6% and 23.6%, respectively, on average. Seashore paspalum exhibited outstanding salt tolerance and forage quality at high salinity. The survival rate of the different ecotypes of seashore paspalum varied from 6.5% to 49.0% following treatment with 700 mM NaCl for 7 weeks. The crude protein (CP) content of the control and treatment groups (700 mM NaCl) was 17.4% and 19.3%, respectively, of the DW on average, and the CP content of most ecotypes was not significantly influenced by high salinity. The average ether extract (EE) content ranged from 4.6% to 4.4% of the DW under control and saline conditions, respectively, indicating that the influence was not significant. The neutral detergent fiber (NDF) and acid detergent fiber (ADF) contents of the control group were 57.4% and 29.8%, respectively, of the DW on average. Salt stress reduced the content of NDF and ADF to 50.2% and 25.9%, respectively, of the DW on average. Altogether, the results demonstrated that stress did not have any significant effects on the CP and EE content of most ecotypes, but reduced the NDF and ADF content and improved relative feed value (RFV). The results obtained herein support the notion that seashore paspalum is a good candidate for improving the forage potential of saline soils and can provide useful guidelines for livestock producers.

Strained Lattice Gold-Copper Alloy Nanoparticles for Efficient Carbon Dioxide Electroreduction.

Electrocatalytic conversion of carbon dioxide (CO2) into specific renewable fuels is an attractive way to mitigate the greenhouse effect and solve the energy crisis. AunCu100-n/C alloy nanoparticles (AunCu100-n/C NPs) with tunable compositions, a highly active crystal plane and a strained lattice were synthesized by the thermal solvent co-reduction method. Transmission electron microscopy (TEM) and X-ray diffraction (XRD) results show that AunCu100-n/C catalysts display a subtle lattice strain and dominant (111) crystal plane, which can be adjusted by the alloy composition. Electrochemical results show that AunCu100-n/C alloy catalysts for CO2 reduction display high catalytic activity; in particular, the Faradaic efficiency of Au75Cu25/C is up to 92.6% for CO at -0.7 V (vs. the reversible hydrogen electrode), which is related to lattice shrinkage and the active facet. This research provides a new strategy with which to design strong and active nanoalloy catalysts with lattice mismatch and main active surfaces for CO2 reduction reaction.

Effect of Light Intensity on Morphology, Photosynthesis and Carbon Metabolism of Alfalfa (Medicago sativa) Seedlings.

To understand how light intensity influences plant morphology and photosynthesis in the forage crop alfalfa (Medicago sativa L. cv. Zhongmu 1), we investigated changes in leaf angle orientation, chlorophyll fluorescence, parameters of photosynthesis and expression of genes related to enzymes involved in photosynthesis, the Calvin cycle and carbon metabolism in alfalfa seedlings exposed to five light intensities (100, 200, 300, 400 and 500 µmol m-2 s-1) under hydroponic conditions. Seedlings grown under low light intensities had significantly increased plant height, leaf hyponasty, specific leaf area, photosynthetic pigments, leaf nitrogen content and maximal PSII quantum yield, but the increased light-capturing capacity generated a carbon resource cost (e.g., decreased carbohydrates and biomass accumulation). Increased light intensity significantly improved leaf orientation toward the sun and upregulated the genes for Calvin cycle enzymes, thereby increasing photosynthetic capacity. Furthermore, high light (400 and 500 µmol m-2 s-1) significantly enhanced carbohydrate accumulation, accompanied by gene upregulation and increased activity of sucrose and starch-synthesis-related enzymes and those involved in carbon metabolism. Together, these results advance our understanding of morphological and physiological regulation in shade avoidance in alfalfa, which would guide the identification of suitable spatial planting patterns in the agricultural system.

Nanoparticle-Based Lateral Flow Biosensor Integrated With Loop-Mediated Isothermal Amplification for Rapid and Visual Identification of Chlamydia trachomatis for Point-of-Care Use.

Chlamydial infection, caused by Chlamydia trachomatis, is the most common bacterial sexually transmitted infection and remains a major public health problem worldwide, particularly in underdeveloped regions. Developing a rapid and sensitive point-of-care (POC) testing for accurate screening of C. trachomatis infection is critical for earlier treatment to prevent transmission. In this study, a novel diagnostic assay, loop-mediated isothermal amplification integrated with gold nanoparticle-based lateral flow biosensor (LAMP-LFB), was devised and applied for diagnosis of C. trachomatis in clinical samples. A set of LAMP primers based on the ompA gene from 14 C. trachomatis serological variants (serovar A-K, L1, L2, L3) was successfully designed and used for the development of C. trachomatis-LAMP-LFB assay. The optimal reaction system can be performed at a constant temperature of 67°C for 35 min. The total assay process, including genomic DNA extraction (~15 min), LAMP reaction (35 min), and LFB readout (~2 min), could be finished within 60 min. The C. trachomatis-LAMP-LFB could detect down to 50 copies/ml, and the specificity was 100%, no cross-reactions with other pathogens were observed. Hence, our C. trachomatis-LAMP-LFB was a rapid, reliable, sensitive, cost-effective, and easy-to-operate assay, which could offer an attractive POC testing tool for chlamydial infection screening, especially in resource starvation settings.

Fusion Bonding Possibility for Incompatible Polymers by the Novel Ultrasonic Welding Technology: Effect of Interfacial Compatibilization.

Fusion bonding for polymers has been successfully welded for the same and dissimilar materials. However, it is difficult to bond incompatible polymers due to poor interfacial adhesion. Usually, interfacial compatibilization can resolve this problem. According to the mechanism, an interlayer solder sheet (ISS) consisting of maleic anhydride-functionalized polypropylene (PP-g-MAH) and polyamide6 (PA6) was introduced into the ultrasonic welding (USW) device. In this way, it successfully realized the weldability between PP and PA6. The welding strength of PP-PA6 reached 22.3 MPa, about 84% welding strength for the PP body and 63% tensile strength for PP. Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and scanning electron microscopy (SEM) showed the formation of PP-g-PA6 copolymer in blends. This copolymer played the role of an emulsifier, which enhanced the interfacial adhesion between PP and PA6 in two phases, leading to micron-scale homogeneity. In the USW process, the copolymer could act as a bridge between PP and PA6 molecular chains to realize the fusion bonding of incompatible polymers. Finally, we proposed the fusion bonding model for PP-PA6 interfaces.

Salvianolic acid B alleviates diabetic endothelial and mitochondrial dysfunction by down-regulating apoptosis and mitophagy of endothelial cells.

Endothelial dysfunction is a critical mediator in the pathogenesis of vascular complications of diabetes. Herein, this study was conducted to investigate the therapeutic effects of Salvianolic acid B (Sal B) on diabetes-induced endothelial dysfunction and the underlying mechanisms. Diabetic models were established both in db/db mice and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs). Moreover, HUVECs were exposed to carbonyl cyanide m-chlorophenyl hydrazone (CCCP) to induce endothelial cell damage. Following Sal B treatment, pathological changes of thoracic aorta were investigated by hematoxylin and eosin, alcian blue (AB), elastic fiber, Masson, and reticular fiber staining. BCL2-associated X (BAX), B-cell lymphoma-2 (Bcl-2), Beclin1, Parkin and PTEN Induced Kinase 1 (Pink1) expression was detected by Western blot, immunohistochemistry, and immunofluorescence in thoracic aorta, HG- and CCCP-induced HUVECs. Cell scratch test, MitoTracker Red CMXRos staining and Flou-4 AM staining were separately presented to detect migration, mitochondrial activity and intracellular Ca2+ in HUVECs. Our results showed that Sal B significantly ameliorated hyperlipidemia, hyperglycemia, hyperinsulinemia, and insulin resistance in db/db mice. Furthermore, it significantly alleviated diabetes-induced vascular endothelial dysfunction according to histopathology analysis. In diabetic thoracic aorta, HG- and CCCP-induced HUVECs, Sal B distinctly increased Bcl-2 expression and reduced BAX, Beclin1, Parkin and Pink1 expression, thereby protecting endothelial cells from apoptosis and mitophagy. Moreover, Sal B markedly enhanced migration, mitochondrial activity and intracellular Ca2+ levels both in HG- and CCCP-induced HUVECs. Collectively, Sal B exhibited a potential to improve diabetes-induced endothelial and mitochondrial dysfunction through down-regulating apoptosis and mitophagy of endothelial cells.Abbreviations: DM: diabetes mellitus; T2DM: type 2 diabetes mellitus; Sal B: Salvianolic acid B; HG: high glucose; FBG: fasting blood glucose; TC: total cholesterol; TG: triglycerides; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; FINS: fasting insulin; HOMA-IR: homeostasis model assessment insulin resistance; QUICKI: quantitative insulin-sensitivity check index; H&E: hematoxylin and eosin; HUVECs: human umbilical vein endothelial cells; IHC: immunohistochemistry; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; FCM: flow cytometry; CCK-8: cell counting kit-8.

Phenylalanine 4-Hydroxylase Contributes to Endophytic Bacterium Pseudomonas fluorescens' Melatonin Biosynthesis.

Melatonin acts both as an antioxidant and as a growth regulatory substance in plants. Pseudomonas fluorescens endophytic bacterium has been shown to produce melatonin and increase plant resistance to abiotic stressors through increasing endogenous melatonin. However, in bacteria, genes are still not known to be melatonin-related. Here, we reported that the bacterial phenylalanine 4-hydroxylase (PAH) may be involved in the 5-hydroxytryptophan (5-HTP) biosynthesis and further influenced the subsequent production of melatonin in P. fluorescens. The purified PAH protein of P. fluorescens not only hydroxylated phenylalanine but also exhibited l-tryptophan (l-Trp) hydroxylase activity by converting l-Trp to 5-HTP in vitro. However, bacterial PAH displayed lower activity and affinity for l-Trp than l-phenylalanine. Notably, the PAH deletion of P. fluorescens blocked melatonin production by causing a significant decline in 5-HTP levels and thus decreased the resistance to abiotic stress. Overall, this study revealed a possible role for bacterial PAH in controlling 5-HTP and melatonin biosynthesis in bacteria, and expanded the current knowledge of melatonin production in microorganisms.

A CRISPR-Cas12b-Based Platform for Ultrasensitive, Rapid, and Highly Specific Detection of Hepatitis B Virus Genotypes B and C in Clinical Application.

Hepatitis B virus (HBV) is one of the most dangerous and prevalent agents that causes acute and chronic liver diseases in humans. Genotyping plays an important role in determining clinical outcomes and response to antiviral treatment in HBV-infected patients. Here, we first devised a CRISPR-based testing platform, termed "CRISPR-HBV," for ultrasensitive, highly specific, and rapid detection of two major HBV genotypes (HBV-B and HBV-C) in clinical application. The CRISPR-HBV employed multiple cross displacement amplification (MCDA) for rapid preamplification and then Cas12b-based detection for decoding the targets. Finally, the detection result was read out with real-time fluorescence and a lateral flow biosensor. The sensitivity of CRISPR-HBV was 10 copies per test. The specificity was one hundred percent, and no cross reactions were observed in other HBV genotypes and pathogens. The whole detection process, including DNA template extraction (15 min), preamplification reaction of MCDA (30 min at 65°C), CRISPR-Cas12b-based detection (5 min at 37°C), and results readout (∼2 min), could be completed within 1 h. The feasibility of the CRISPR-HBV assay for genotyping HBV-B and -C as successfully validated with clinical samples. Hence, the CRISPR-HBV assay has remarkable potential to develop a point-of-care testing for identifying and distinguishing HBV genotypes B and C in clinical settings, especially in resource-scarcity countries.

Visual and Rapid Diagnosis of Neisseria gonorrhoeae Using Loop-Mediated Isothermal Amplification Combined With a Polymer Nanoparticle-Based Biosensor in Clinical Application.

Neisseria gonorrhoeae is a host-adapted human pathogen that causes sexually transmitted gonorrhea and remains to be a serious global public health challenge, especially in low- and middle-income regions. It is vital to devise a reliable, simple, cost-saving, and easy-to-use assay for detecting the N. gonorrhoeae agent. In the current study, we firstly report a novel approach, loop-mediated isothermal amplification linked with a polymer nanoparticle-based biosensor (LAMP-PNB), that was used for identifying N. gonorrhoeae in clinical samples. The results showed that the LAMP primers based on the orf1 gene were valid for development of the N. gonorrhoeae-LAMP-PNB assay. The detection system with optimal conditions could be performed at a fixed temperature of 64°C for 40 min. The whole process, including genomic DNA preparation (approximately 10 min), LAMP reaction (40 min), and PNB reporting (approximately 2 min), could be accomplished within 60 min. The limit of detection (LoD) of the N. gonorrhoeae-LAMP-PNB assay was 50 copies per test. The specificity of the current assay was 100%, and no cross-reactions to non-N. gonorrhoeae isolates were observed. These results confirmed that the N. gonorrhoeae-LAMP-PNB technique is a reliable, specific, sensitive, rapid, low-cost, and easy-to-use method for detecting gonococci isolates. More importantly, this assay has great potential to develop a point-of-care (POC) testing method in clinical practice, especially in resource-constrained regions.

Multiple Cross Displacement Amplification Linked with Nanoparticles-Based Lateral Flow Biosensor in Screening of Hepatitis B Virus in Clinical Application.

BACKGROUND: Hepatitis B virus (HBV) is a common pathogen that predominantly causes severe liver disease, and remains one of a huge challenge worldwide, especially in many resource-constrained areas. Developing a low-cost, sensitive, specific, and rapid approach for screening HBV is critical for its treatment and prevention. In the current study, a novel molecular detection approach, multiple cross displacement amplification (MCDA) coupled with polymer nanoparticle-based lateral flow biosensor (MCDA-LFB), was applied for detection of HBV in blood samples. METHODS: HBV standard substance and clinical donor serum samples were collected and used for the establishment and confirmation of the HBV-MCDA-LFB assay. A set of 10 MCDA primers was designed according to HBV-specific gene S. The HBV-MCDA-LFB assay conditions, including genomic template concentration, MCDA reaction temperature and time were optimized. The sensitivity and specificity of the HBV-MCDA -LFB assay were evaluated in this report. The HBV-MCDA-LFB assay was applied to detect the HBV agent from clinical samples. RESULTS: The HBV-MCDA primers based on the S gene were valid for establishment of MCDA assay. The HBV-MCDA reaction with optimized conditions could be carried out at a constant temperature 64°C for 35 min. The whole process, including sample preparation (5 min), genomic template extraction (~30 min), MCDA amplification (35 min), and LFB reading (~2 min), could be completed within 80 min. The sensitivity of this assay was 5 IU per reaction. The specificity was 100% for HBV-MCDA-LFB assay. CONCLUSION: These results confirmed that the HBV-MCDA-LFB is a low-cost, sensitive, specific, simple, and rapid method for detecting HBV agents. This technique has great potential to develop a point-of-care testing (POCT) method in clinical practice, especially in endemic and resource-constrained regions.

Ambient air pollution exposure associated with glucose homeostasis during pregnancy and gestational diabetes mellitus.

BACKGROUND: To investigate the effects of air pollution exposure during pregnancy on the indicators of glucose homeostasis and gestational diabetes mellitus (GDM). METHODS: We conducted a birth cohort study in Foshan, China during 2015-2019. Oral glucose tolerance test (OGTT) was administered to each participant during pregnancy. GDM was defined according to the International Association of Diabetes and Pregnancy Study Groups criteria (IADPSG). Air pollutant (fine particulate matter (PM2.5), particulate matter with an aerodynamic diameter of 10 µm or less (PM10), sulfate dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3)) concentrations from the air monitoring stations in Foshan were used to estimate individual air pollutant exposure during the first two trimesters. Linear and logistic regression models were employed to estimate the associations between air pollution exposure during the first two trimesters and OGTT glucose levels and GDM. RESULTS: Of 12,842 pregnant women, 3055 (23.8%) had GDM. A 10 µg/m3 increase in PM2.5, PM10 and SO2 during trimester 1, trimester 2 and two trimesters were associated with 0.07 mmol/L to 0.29 mmol/L increment in OGTT-fasting glucose levels in single-pollutant model. A 10 µg/m3 increase in NO2 and O3 during two trimesters were associated with 0.15 mmol/L and 0.12 mmol/L decrease in OGTT-fasting glucose in single-pollutant model. However, no significant or weaker effects of O3 during two trimesters on OGTT-fasting glucose were observed in two-pollutant models. Moreover, exposure to PM2.5, PM10 and SO2 were associated with increased risk of GDM in both single- and two-pollutant models. CONCLUSIONS: Our study suggests PM2.5, PM10 and SO2 exposure during the first two trimesters might increase the risk of GDM.

The mediation effect of maternal glucose on the association between ambient air pollution and birth weight in Foshan, China.

Maternal blood glucose level is associated with fetal growth, therefore, its role in the associations between air pollution and birth weight deserves investigation. We examined the mediation effect of maternal blood glucose on the associations between maternal air pollution exposure and birth weight. A total of 10,904 pregnant women in Foshan, China during 2015-2019 were recruited. Oral glucose tolerance test (OGTT) was administered to each participant after late trimester 2. Air pollution data at the monitoring stations in residential districts was used to estimate exposures of each participant during trimester 1 and trimester 2. Mixed-effects linear models were used to estimate the associations between air pollution and birth weight. After controlling for ten covariates, the direct effect of PM2.5 and SO2 (each 10 µg/m3 increment) on birth weight was -15.7 g (95% CI: -29.4, -4.8 g) and -83.6 g (95% CI: -134.8, -33.0 g) during trimester 1. The indirect effect of PM2.5 and SO2 (each 10 µg/m3 increment) on birth weight by increasing maternal fasting glucose level was 6.6 g (95% CI: 4.6, 9.1 g) and 22.0 g (95% CI: 4.1, 44.0 g) during trimester 1. Our findings suggest that air pollution might affect the birth weight through direct and indirect pathway, and the indirect effect might be mediated by maternal blood glucose.

Cross-sectional study reveals that HLA-C*07:02 is a potential biomarker of early onset/lesion severity of psoriasis.

Psoriasis is a common chronic autoimmune skin disease, with T cells playing a predominant role in its pathogenesis. Here, we aimed to investigate the relation of T-cell repertoires (TCR) and major histocompatibility complex (MHC) in psoriatic patients to further understand mechanisms in disease pathogenesis. We conducted a cross-sectional study involving nine pairs of monozygotic twins with inconsistent psoriasis and examined the TCR diversity and MHC haplotype of the individuals using multiple-PCR and high-throughput sequencing. Additionally, 665 psoriatic patients were applied to validate the relation of human leucocyte antigen (HLA) class I allele HLA-C*07:02 and early onset or lesion severity of psoriasis. The immune diversity was lower in psoriatic patients compared with unaffected individuals within the twin pairs, although the difference was not significant. The clonotypes of TCR significantly decreased in psoriatic patients with high PASI score and early onset. HLA-C*07:02, a haplotype associated with psoriasis, was positively correlated with the diversity of the TCRV gene. Moreover, HLA-C*07:02 clustered in patients with high PASI and early onset. In the replication stage, we found that the PASI and onset age in psoriasis with HLA-C*07:02 were significantly different from those without HLA-C*07:02 and without HLA-C*06:02. Our observations indicate that HLA-C*07:02 is positively correlated with the diversity of TCRV gene in psoriasis and maybe a potential biomarker of early onset/severe lesions of psoriasis.

The potential DPP-4 inhibitors from Xiao-Ke-An improve the glucolipid metabolism via the activation of AKT/GSK-3ß pathway.

Dipeptidyl Peptidase-4 (DPP-4) is a specific enzyme hydrolyzing the incretin hormone glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) to reduce insulin secretion, meanwhile DPP-4 inhibitors play an important role in diabetic therapy. In present study, 14 potential inhibitors were screened with an inhibition over 50% on DPP-4 activity from Xiao-Ke-An formula (XKA) and 12 of them exhibited a dose-dependently inhibitory effect at concentrations of 5-50 µmol/l. We found 10 DPP-4 inhibitors restrained differentiation of 3T3-L1 pre-adipocytes as well as reducing the triglycerides and total cholesterol content in 3T3-L1 adipocytes. Furthermore, 7 DPP-4 inhibitors promoted the glucose consumption in insulin-resistance BNL CL.2 cells. Thereinto, ginsenoside Rk1 up-regulated the protein kinase B (AKT) and glycogen synthase kinase-3 (GSK-3ß) phosphorylation expression, while kukoamine B and coptisine hydrochloride obviously increased the phosphorylation of AKT protein and columbamine, panaxadiol, ginsenoside Ro, timosaponin AI significantly promoted the phosphorylation of GSK-3ß protein. It's our first effort to confirm those seven compounds could serve as DPP-4 inhibitors to attenuate DPP-4 activities, accompanied with the ability to adjust glucolipid metabolism. Moreover, activating the AKT/GSK-3ß signaling pathway to ameliorate insulin resistant may be the anti-diabetic mechanism of XKA.

Maternal air pollution exposure associated with risk of congenital heart defect in pre-pregnancy overweighted women.

OBJECTIVES: Prenatal exposure to air pollutant has been associated with congenital heart defect (CHD). However, no study has investigated this effect in pre-pregnancy overweighted women. This study aimed to evaluate gestational exposure to particulate pollutant (PM2.5) and gaseous air pollutants (O3 and NO2) on the risk of CHD, and explore the potential effect modifiers including maternal age, pre-pregnancy BMI and pregestational diseases. METHODS: In this birth cohort study, a total of 63,213 pregnant women in Foshan, China were initially recruited and followed from their first hospital visit for pregnancy to delivery during 2015-2019. CHD cases were confirmed by the records in hospital- and population- based birth defect surveillance systems. Air pollutant exposures were estimated by the daily concentrations measured in air monitoring stations in each participant's residential county. Mixed-effects regression models, adjusted for potential confounding factors were applied to estimate the associations between air pollutant and CHD during the first three months of the pregnancy. RESULTS: A total of 985 (1.6%) newborns were identified as CHD cases. For each 10 µg/m3 increase in ambient O3 during the 1st month, the OR values for CHD were 1.03 (95% CI: 0.94, 1.13) in pre-pregnancy normal weighted women and 1.24 (95% CI: 1.01, 1.53) in pre-pregnancy overweighted women. For each 10 µg/m3 increase in NO2 during the 3rd month, the OR values for CHD were 1.09 (95% CI: 1.01, 1.18) in pre-pregnancy normal weighted women and 1.27 (95% CI: 1.07, 1.51) in pre-pregnancy overweighted women. No significant associations were found between PM2.5 exposure and CHD in our analysis. CONCLUSIONS: This study demonstrates that gaseous air pollutants (O3 and NO2) exposure during the cardiac embryogenesis period is associated with an increased risk of CHD, particularly for pre-pregnancy overweighted women.

Multi-omics study in monozygotic twins confirm the contribution of de novo mutation to psoriasis.

BACKGROUND: Genome-wide association studies have identified over 120 risk loci for psoriasis. However, most of the variations are located in non-coding region with high frequency and small effect size. Pathogenetic variants are rarely reported except HLA-C*0602 with the odds ratio being approximately 4.0 in Chinese population. Although rare variations still account for a small proportion of phenotypic variances in complex diseases, their effect on phenotypes is large. Recently, more and more studies focus on the low-frequency functional variants and have achieved a certain amount of success. METHOD: Whole genome sequencing and sanger sequencing was performed on 8 MZ twin pairs discordant for psoriasis to scan and verified the de novo mutations (DNMs). Additionally, 665 individuals with about 20 years' medical history versus 2054 healthy controls and two published large population studies which had about 8 years' medical history (including 10,727 cases versus 10,582 controls) were applied to validate the enrichment of rare damaging mutations in two DNMs genes. Besides, to verify the pathogenicity of candidate DNM in C3, RNA-sequencing for CD4+, CD8+ T cells of twins and lesion, non-lesion skin of psoriasis patients were carried out. Meanwhile, the enzyme-linked immunosorbent assay kit was used to detect the level of C3, C3b in the supernatant of peripheral blood. RESULT: A total of 27 DNMs between co-twins were identified. We found six of eight twins carry HLA-C∗0602 allele which have large effects on psoriasis. And it is interesting that a missense mutation in SPRED1 and a splice region mutation in C3 are found in the psoriasis individuals in the other two MZ twin pairs without carrying HLA-C*0602 allele. In the replication stage, we found 2 loss-of-function (LOF) variants of C3 only in 665 cases with about 20 years' medical history and gene-wise analysis in 665 cases and 2054 controls showed that the rare missense mutations in C3 were enriched in cases (OR = 1.91, P = 0.0028). We further scanned the LOF mutations of C3 in two published studies (about 8 years' medical history), and found one LOF mutation in the case without carrying HLA-C*0602. In the individual with DNM in C3, RNA sequencing showed the expression level of C3 in skin was significant higher than healthy samples in public database (TPM fold change = 1.40, P = 0.000181) and ELISA showed protein C3 in peripheral blood was higher (~2.2-fold difference) than the other samples of twins without DNM in C3. CONCLUSION: To the best of our knowledge, this is the first report that DNM in C3 is the likely pathological mutations, and it provided a better understanding of the genetic etiology of psoriasis and additional treatments for this disease.