Higher-order topological states in T-graphene and their realization in photonic crystals.

Higher-order topological states extend the power of nontrivial topological states beyond the bulk-edge correspondence. Here we study the higher-order topological states (corner states) in an open-boundary two-dimensional T-graphene lattice. Unlike the common zero-energy corner states, our findings reveal non-zero energy corner states in such lattice systems, and the energy could be controlled by modifying the hopping parameters. Moreover, the corner states could be transferred away from the lattice corners by designing the position-specific vacancy defects. The strong robustness of the corner states is also demonstrated against the uniaxial strain and vacancy defects, respectively. A plasmonic crystal is constructed to testify to the theory, in which the corner states are realized in optical modes and their higher-order topological properties are verified. Our results open the avenue of corner-states engineering, which holds significant physical implications of higher-order topological states for the design of photonic and electronic devices with specialized functionalities.

BPR3P0128, a non-nucleoside RNA-dependent RNA polymerase inhibitor, inhibits SARS-CoV-2 variants of concern and exerts synergistic antiviral activity in combination with remdesivir.

Viral RNA-dependent RNA polymerase (RdRp), a highly conserved molecule in RNA viruses, has recently emerged as a promising drug target for broad-acting inhibitors. Through a Vero E6-based anti-cytopathic effect assay, we found that BPR3P0128, which incorporates a quinoline core similar to hydroxychloroquine, outperformed the adenosine analog remdesivir in inhibiting RdRp activity (EC50 = 0.66 µM and 3 µM, respectively). BPR3P0128 demonstrated broad-spectrum activity against various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. When introduced after viral adsorption, BPR3P0128 significantly decreased SARS-CoV-2 replication; however, it did not affect the early entry stage, as evidenced by a time-of-drug-addition assay. This suggests that BPR3P0128's primary action takes place during viral replication. We also found that BPR3P0128 effectively reduced the expression of proinflammatory cytokines in human lung epithelial Calu-3 cells infected with SARS-CoV-2. Molecular docking analysis showed that BPR3P0128 targets the RdRp channel, inhibiting substrate entry, which implies it operates differently-but complementary-with remdesivir. Utilizing an optimized cell-based minigenome RdRp reporter assay, we confirmed that BPR3P0128 exhibited potent inhibitory activity. However, an enzyme-based RdRp assay employing purified recombinant nsp12/nsp7/nsp8 failed to corroborate this inhibitory activity. This suggests that BPR3P0128 may inhibit activity by targeting host-related RdRp-associated factors. Moreover, we discovered that a combination of BPR3P0128 and remdesivir had a synergistic effect-a result likely due to both drugs interacting with separate domains of the RdRp. This novel synergy between the two drugs reinforces the potential clinical value of the BPR3P0128-remdesivir combination in combating various SARS-CoV-2 variants of concern.

Associations between genetic variants of HSD17B13 and fasting plasma glucose in Chinese children.

BACKGROUND AND AIMS: Genetic variants in 17-ß hydroxysteroid dehydrogenase 13 (HSD17B13) were demonstrated to protect against NAFLD, which is highly related with insulin resistance and dyslipidemia. However, the effects of NAFLD associated HSD17B13 variants on circulating glucose and lipids have not been adequately investigated in children. This study aimed to investigate associations between single nucleotide polymorphisms (SNPs) of HSD17B13 and NAFLD or its related phenotypes, such as blood glucose and serum lipids in Chinese children. METHODS AND RESULTS: We studied 1027 Chinese Han children aged 7-18 years old, which included 162 NAFLD children and 865 controls without NAFLD. Three SNPs (rs13112695, rs7692397, rs6834314) in HSD17B13 were genotyped. The multivariable logistic and linear regression models were applied to detect the associations between three SNPs and NAFLD or its related phenotypes [alanine transaminase (ALT), fasting plasma glucose (FPG) and serum lipids]. The effect allele A of rs7692397 was negatively associated with FPG [ß (SE) = -0.088 (0.027) mmol/L, P = 0.001], whereas the effect allele G of rs6834314 was positively associated with FPG (ß (SE) = 0.060 (0.019) mmol/L, P = 0.002). After Bonferroni correction, the significant associations still remained (both P < 0.0024). No significant associations were found for NAFLD or serum lipids. CONCLUSION: The study firstly revealed the association between two HSD17B13 variants and FPG in Chinese children, providing evidence for HSD17B13 variants and abnormal glucose metabolism.

Effects of Plant-Based Diets on Anthropometric and Cardiometabolic Markers in Adults: An Umbrella Review.

We conducted an umbrella review to consolidate the evidence of adopting plant-based diets on anthropometric and cardiometabolic outcomes. Six electronic databases (CINAHL, EMBASE, PubMed, Scopus, the Cochrane Library, and Web of Science) were searched for systematic reviews with meta-analysis (SRMAs) published from each journal's inception until 1 October 2022. Effect sizes from SRMAs and primary studies were pooled separately using random effects models. Overlapping primary studies were removed for primary studies' analyses. Seven SRMAs representing 51 primary studies were included, suggesting significant benefits of plant-based diets on weight (-2.09 kg, 95% CI: -3.56, -0.62 kg, p = 0.01, I2 = 95.6%), body mass index (-0.95 kg/m2, 95% CI: -1.26, -0.63 kg/m2, p = 0.002; I2 = 45.1%), waist circumference (-2.20 cm, 95% CI: -0.08, 0.00 cm, p = 0.04; I2 = 88.4%), fasting blood glucose (-0.11 mmol/L, 95% CI: -0.13, -0.09 mmol/L, p < 0.001, I2 = 18.2%), and low-density lipoprotein cholesterol (-0.31 mmol/L, 95% CI: -0.41, -0.20 mmol/L, p < 0.001, I2 = 65.6%). Changes in high-density lipoprotein cholesterol, triglycerides, and blood pressure were not statistically significant. Generally, plant-based diets were recommended to improve anthropometry, lipid profile, and glucose metabolism. However, findings should be interpreted with caution, because most of the reviews were rated to be of low credibility of evidence and were largely based on Western eating habits and traditions, which may limit the generalizability of findings.

Association between growth differentiation factor 15 levels and gestational diabetes mellitus: A combined analysis.

Objective: Gestational diabetes mellitus (GDM) is a common glucose metabolism disease occurs in pregnancy that affects both maternal and neonatal health. Recently, increasing studies have attached importance to the relationship between growth differentiation factor 15 (GDF-15) and GDM, but the results were inconclusive. Therefore, we conducted a meta-analysis to examine the association between GDF-15 and GDM. Materials and methods: A systematical search was performed in Gene Expression Omnibus (GEO), PubMed and Google Scholar till Oct 27, 2022. We first calculated the mean and standard deviation of GDF-15 expression levels from the included eligible datasets and articles. Then, a meta-analysis was conducted to depict the difference in GDF-15 mRNA or GDF-15 protein expression between case and control groups by using conservative random effect model. Moreover, the potential publication bias was checked with the aid of Begg's test and Egger's test. Finally, sensitivity analyses were performed by changing the inclusion criteria. Results: In summary, 12 GEO datasets and 5 articles were enrolled in our study, including 789 GDM patients and 1202 non-GDM pregnant women. It was found that the expression levels of GDF-15 mRNA and GDF-15 protein in late pregnancy were significantly higher in GDM patients compared with non-GDM pregnant women, with the standard mean difference (SMD) and 95% confidence interval (95% CI) of 0.48 (0.14, 0.83) and 0.82 (0.32-1.33), respectively. Meanwhile, a slightly weakened association between GDF-15 protein levels and GDM was also observed in the middle pregnancy, with SMD (95% CI) of 0.53 (0.04-1.02). Conclusion: In all, our results suggested that the expression levels of GDF-15 were significantly higher in GDM patients compared with non-GDM pregnant women, especially in the late pregnancy.

Jinfeng pills ameliorate premature ovarian insufficiency induced by cyclophosphamide in rats and correlate to modulating IL-17A/IL-6 axis and MEK/ERK signals.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinfeng Pill (JFP) is a classical Chinese medicine formula and composed of 9 herbs, including Epimedium brevicornu Maxim (Yinyanghuo), Cervus elaphus Linnaeus (Lurong), Panax ginseng C.A.Mey. (Renshen), Equus asinus (EJiao), Ligustrum lucidum W.T.Aiton (Nvzhenzi), Reynoutria multiflora (Thunb.) Moldenke (Heshouwu), Curculigo orchioides Gaertn (Xianmao), Neolitsea cassia (L.) Kosterm. (Rougui) and Leonurus japonicus Houtt. (Yimucao). The formula is clinically used to regulate menstrual cycle and alleviate polycystic ovarian syndrome due to its capabilities of ovulation induction. It is therefore presumed that JFP could be used for the therapy of premature ovarian insufficiency (POI) but the assumed efficacy has not been fully substantiated in experiment. AIM OF STUDY: To evaluate the effectiveness of JFP on cyclophosphamide (CTX)-induced POI and preliminarily explore its potential mechanisms of action. MATERIAL AND METHODS: An experimental rat model of POI was established by using CTX induction to assess the efficacy of JFP. The potential targets of action for JFP alleviating POI were predicted by the combination of network pharmacology and transcriptomics and finally validating by RT-qPCR and Western blot. RESULTS: JFP alleviated the damages of ovarian tissue induced by CTX in the rat model of POI via significantly decreasing serum levels of FSH and LH and the ratio of FSH/LH and increasing the levels of E2 and AMH, accompanied with promoting ovarian folliculogenesis and follicle maturity and reversing the depletion of follicle pool. With the analysis of network pharmacology, pathways in cancer, proteoglycans in cancer, PI3K-AKT, TNF and FoxO signaling pathways were predicted to be influenced by JFP. The results of RNA-seq further revealed that IL-17 signaling pathway was the most important pathway regulated by both CTX and JFP, following by transcriptional misregulation in cancer and proteoglycans in cancer. Combining the two analytical methods, JFP likely targeted genes associated with immune regulation, including COX-2, HSP90AA1, FOS, MMP3 and MAPK11 and pathways, including IL-17,Th17 cell differentiation and TNF signaling pathway. Finally, JFP was validated to regulate the mRNA expression of FOS, FOSB, FOSL1, MMP3, MMP13 and COX-2 and decrease the release of IL-17A and the protein expression of IL-6 and suppress the phosphorylation of MEK1/2 and ERK1/2 in CTX induced POI rats. CONCLUSION: Jinfeng Pill is effective to ameliorate the symptoms of POI induced by CTX in the model of rats and its action is likely associated with suppressing IL-17A/IL-6 axis and the activity of MEK1/2-ERK1/2 signaling.

Metformin attenuates multiple myeloma cell proliferation and encourages apoptosis by suppressing METTL3-mediated m6A methylation of THRAP3, RBM25, and USP4.

Based on the results of epidemiological and preclinical studies, metformin can improve the prognosis of patients with malignant tumors. Studies have confirmed that metformin inhibits multiple myeloma (MM) cell proliferation and promotes apoptosis. Nevertheless, the specific mechanism remains to be elucidated. MM cells were intervened with different doses of metformin to detect cell proliferation and apoptosis. Western blotting and RT-qPCR were employed to assess the expression of METTL3, METTL14, WTAP, FTO, and ALKBH5 after metformin intervention. The microarray dataset GSE29023 was retrieved from the Gene Expression Omnibus (GEO) database and calculated using the R language (limma package) to authenticate differentially expressed genes (DEGs). The database for annotation, visualization, and integrated discovery (David) was applied for GO annotation analysis of DEGs. Subsequently, the string database and Cytoscape software were applied to construct protein-protein interaction (PPI) and DEM hub gene networks. Bioinformatics analysis and MeRIP were applied to predict and test METTL3-mediated m6A levels on mRNA of THRAP3, RBM25, and USP4 in METTL3 knocked-down cells. Then rescue experiments were performed to explore effects of METTL3 and THRAP3, RBM25, or USP4 on cell proliferation and apoptosis. The effect on MM cell xenograft tumor growth was observed by injection of metformin or/and overexpression of METTL3 in in vivo experiments. Metformin decreased cell proliferation and encouraged cell apoptosis in a dose-dependent manner. Global m6A modification was elevated in MM cells compared to normal cells, which was counteracted by metformin treatment. Furthermore, THRAP3, RBM25, and USP4 were identified as possible candidate genes for metformin treatment by GSE29023 data mining. METTL3 interference impaired m6A modification on mRNA of THRAP3, RBM25, and USP4 as well as expression levels. The mRNA stability and expression of THRAP3, RBM25, and USP4 was decreased after metformin treatment, which was reversed by METTL3 overexpression. THRAP3, RBM25 or USP4 knockdown reversed the assistance of METTL3 overexpression on the malignant behavior of MM cells. Finally, upregulation of METTL3 was shown to exert facilitative effects on xenograft tumor growth by blocking metformin injection. The present study demonstrates that metformin can repress the expression of THRAP3, RBM25, and USP4 by inhibiting METTL3-mediated m6A modification, which in turn hamper cell proliferation and promotes cell apoptosis.Abbreviations: multiple myeloma (MM), Gene Expression Omnibus (GEO), differentially expressed genes (DEGs), database for annotation, visualization and integrated discovery (David), protein-protein interaction (PPI), epithelial­mesenchymal transition (EMT), methyltransferase like 3 (METTL3), methyltransferase like 14 (METTL14), wilms tumor 1-associated protein (WTAP), methyltransferase like 16 (METTL16), acute myeloid leukemia (AML), non-small lung cancer (NSCLC), glioma stem cells (GSCs), normal bone marrow-derived plasma cells (nPCs), false discovery rate (FDR), biological process (BP), optical density (OD), horseradish peroxidase (HRP), M6A RNA immunoprecipitation assay (MeRIP).

Pediatric body mass index trajectories and the risk of hypertension among adolescents in China: a retrospective cohort study.

BACKGROUND: The impact of pediatric body mass index (BMI) trajectories on the risk of adolescent hypertension (HTN) determined by three separate visits remains unclear. This longitudinal study aims to identify potential pediatric sex-specific BMI trajectories and to assess their associations with HTN and HTN subtypes. METHODS: Based on the Health Promotion Program for Children and Adolescents (HPPCA) in Suzhou, China, a total of 24,426 participants who had initial normal blood pressure (BP) and had at least four BMI measurements during 2012-2020 were included. HTN was defined as simultaneously having three separate visits of elevated BP in 2020. Latent class growth models were used to explore sex-specific BMI trajectories, whose associations with HTN and HTN subtypes were further examined by logistic regression. RESULTS: The incidence of HTN determined through three separate visits was 3.34%. Four trajectories were identified for both sexes: low BMI increasing, medium BMI increasing, high BMI increasing, and highest BMI increasing. Compared to the medium BMI increasing group, the odds ratio (95% confidential interval) for developing adolescent HTN of the low, high, and highest BMI increasing groups among boys were 0.54 (0.39, 0.75), 1.90 (1.44, 2.51), and 2.89 (1.90, 4.39), respectively; and the corresponding values for girls were 0.66 (0.48, 0.90), 2.30 (1.72, 3.09), and 4.71 (3.06, 7.26). Similar gradually elevated associations between different trajectories with isolated systolic hypertension, systolic and diastolic hypertension were observed. CONCLUSION: Current results emphasized the adverse effects of stable high BMI on HTN and the benefits of maintaining normal weight throughout childhood.

Influence of rs2587552 polymorphism of DRD2 gene on the effect of a childhood obesity intervention: A prospective, parallel-group controlled trial / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between rs2587552 polymorphism (has a strong lin-kage disequilibrium with rs1800497 which had been found in many studies to be related to obesity, r2=0.85) of DRD2 gene and the effect of a childhood obesity intervention in Chinese population, and provide a scientific basis for future personalized childhood obesity intervention based on genetic background.@*METHODS@#From a multi-center cluster randomized controlled trial studying the effect of a childhood obesity intervention, we enrolled 382 children from 8 primary schools (192 and 190 children from intervention and control groups, respectively) in Beijing as study subjects. Saliva was collected and DNA was extracted to detect the rs2587552 polymorphism of DRD2 gene, and the interactions between the gene and study arms on childhood obesity indicators [including body weight, body mass index (BMI), BMI Z-score, waist circumference, hip circumference, waist-to-hip ratio, waist-to-height ratio, and body fat percentage] were analyzed.@*RESULTS@#No association was found between rs2587552 polymorphism and the changes in hip circumference or body fat percentage in the intervention group (P>0.05). However, in the control group, children carrying the A allele at DRD2 rs2587552 locus showed a greater increase in hip circumference and body fat percentage compared with those not carrying A allele (P < 0.001). There were interactions between rs2587552 polymorphism of DRD2 gene and study arms on the changes in hip circumference and body fat percentage (P=0.007 and 0.015, respectively). Compared with the control group, children in the intervention group carrying the A allele at DRD2 rs2587552 locus showed decrease in hip circumference by (-1.30 cm, 95%CI: -2.25 to -0.35, P=0.007) and decrease in body fat percentage by (-1.34%, 95%CI: -2.42 to -0.27, P=0.015) compared with those not carrying A allele. The results were consistent between the dominant model and the additive model (hip circumfe-rence: -0.66 cm, 95%CI: -1.28 to -0.03, P=0.041; body fat percentage: -0.69%, 95%CI: -1.40 to 0.02, P=0.056). No interaction was found between rs2587552 polymorphism and study arms on the changes in other childhood obesity-related indicators (P>0.05).@*CONCLUSION@#Children carrying the A allele at rs2587552 polymorphism of DRD2 gene are more sensitive to intervention and showed more improvement in hip circumference and body fat percentage after the intervention, suggesting that future personalized childhood obesity lifestyle intervention can be carried out based on the rs2587552 polymorphism of DRD2 gene.

Combined effect of PNPLA3 rs738409 and UGT1A1 rs10929303 gene polymorphisms on nonalcoholic fatty liver disease in children / 中华肝脏病杂志

Objective: To investigate the combined effects of patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 (C > G) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) rs10929303 (C > T) on nonalcoholic fatty liver disease (NAFLD) in children and adolescents so as to provide scientific evidence for NAFLD genetic research. Methods: 1 027 children and adolescents aged 7-18 were selected as the research subjects. The general situation, past medical history, height and body weight measurements, and B- mode ultrasound test of the liver were investigated by dedicated full-time personnel. In addition, the morning fasting venous blood was collected to measure the blood biochemical indicators. DNA was extracted and genotyped for PNPLA3 rs738409 and UGT1A1 rs10929303. Logistic regression analysis was used to analyze the association and combined effect of the two gene polymorphisms and NAFLD. Statistical analysis was performed by t-test, Mann-Whitney U test, or c2 test according to different data. Results: The GG genotype of PNPLA3 rs738409 and the CC genotype of UGT1A1 rs10929303 were associated with an increased risk of developing NAFLD in children by 89% (OR = 1.89, 95% CI: 1.11-3.23, P = 0.019) and 96% (OR = 1.96, 95% CI: 1.21-3.17, P = 0.006), respectively, while the concurrent risk of NAFLD in those who carried the above two genotypes increased by 306% compared with those who did not carry both genotypes (OR = 4.06, 95% CI: 1.90 ~ 8.66, P < 0.001). Conclusion: The combined effect of PNPLA3 and UGT1A1 gene polymorphisms can significantly increase the risk of NAFLD in children, providing new evidence for elucidating the genetic susceptibility to NAFLD.

The status and influencing factors of presenteeism among clinical nurses: a systematic review / 中华劳动卫生职业病杂志

Objective: To systematically review the status and factors influencing presenteeism among clinical nurses. Methods: In December 2021, CNKI, CBM, Wanfang, VIP, Web of Science, PubMed, Embase, The Cochrane Library, CINAHL, PsyclNFO and other databases were electronically searched to cross sectional studies on the current situation and factors influencing the occurrence of presenteeism among clinical nurses. The search terms mainly included presenteeism, sick at work, Stanford Presenteeism Scale, nurse, level, risk factor, influence, et al. And the search time was from the establishment of the database to November 30, 2021. Literature screening, data extraction and evaluation of the risk of bias in the included literature were done independently by two researchers, and meta-analysis was performed using Stata 15.1 software. Results: A total of 29 studies involving 13 535 clinical nurses were included.The results of the meta-analysis showed that the score of presenteeism was 17.99 [95% CI (17.02-18.95), P =0.000]. Subgroup analysis showed that presenteeism scores were higher in articles published before 2020 (ES=19.28, 95%CI: 18.41-20.15, P=0.000) and in the group of nurses aged 36 to 40 years (ES=19.27, 95%CI: 17.35~21.19, P=0.000), female (ES= 17.04, 95%CI: 14.70-19.39, P=0.000), secondary school education (ES=21.01, 95%CI: 17.76-24.26, P= 0.007), married (ES=17.49, 95%CI: 15.13-19.85, P=0.000), working for 5 to 10 years (ES=17.78, 95%CI: 16.54-19.02, P=0.000), contract (ES=17.05, 95%CI: 15.23-18.87, P=0.000), working in pediatrics (ES= 16.65, 95% CI: 15.31-17.99, P=0.000) and European region (ES =21.21, 95% CI: 20.50-21.93, P=0.000) . Conclusion: Current evidence suggests that clinical nurses are at high risk of presenteeism, which is affected by variety of factors. The managers should pay attention to the physical and mental health of nurses, identify high-risk factors as early as possible and take measures to reduce the occurrence of presenteeism and improve the quality of nursing.

Tobacco microbial screening and application in improving the quality of tobacco in different physical states.

The first-cured tobacco contains macromolecular substances with negative impacts on tobacco products quality, and must be aged and fermented to mitigate their effects on the tobacco products quality. However, the natural fermentation takes a longer cycle with large coverage area and low economic efficiency. Microbial fermentation is a method to improve tobacco quality. The change of chemical composition of tobacco during the fermentation is often correlated with shapes of tobacco. This study aimed to investigate the effects of tobacco microorganisms on the quality of different shapes of tobacco. Specifically, Bacillus subtilis B1 and Cytobacillus oceanisediminis C4 with high protease, amylase, and cellulase were isolated from the first-cured tobacco, followed by using them for solid-state fermentation of tobacco powder (TP) and tobacco leaves (TL). Results showed that strains B1 and C4 could significantly improve the sensory quality of TP, enabling it to outperform TL in overall texture and skeleton of tobacco products during cigarette smoking. Compared with the control, microbial fermentation could increase reducing sugar; regulate protein, starch, and cellulose, reduce nicotine, improve total aroma substances, and enable the surface of fermented TP and TL to be more loose, wrinkled, and porous. Microbial community analysis indicated that strains B1 and C4 could change the native structure of microbial community in TP and TL. LEfSe analysis revealed that the potential key biomarkers in TP and TL were Bacilli, Pseudonocardia, Pantoea, and Jeotgalicoccus, which may have cooperative effects with other microbial taxa in improving tobacco quality. This study provides a theoretical basis for improving tobacco fermentation process for better cigarettes quality.

Control of Grain Weight and Size in Rice (Oryza sativa L.) by OsPUB3 Encoding a U-Box E3 Ubiquitin Ligase.

Grain weight and size, mostly determined by grain length, width and thickness, are crucial traits affecting grain quality and yield in rice. A quantitative trait locus controlling grain length and width in rice, qGS1-35.2, was previously fine-mapped in a 57.7-kb region on the long arm of chromosome 1. In this study, OsPUB3, a gene encoding a U-box E3 ubiquitin ligase, was validated as the causal gene for qGS1-35.2. The effects were confirmed firstly by using CRISPR/Cas9-based mutagenesis and then through transgenic complementation of a Cas9-free knock-out (KO) mutant. Two homozygous KO lines were produced, each having a 1-bp insertion in OsPUB3 which caused frameshift mutation and premature termination. Compared with the recipient and a transgenic-negative control, both mutants showed significant decreases in grain weight and size. In transgenic complementation populations derived from four independent T0 plants, grain weight of transgenic-positive plants was significantly higher than transgenic-negative plants, coming with increased grain length and a less significant decrease in grain width. Based on data documented in RiceVarMap V2.0, eight haplotypes were classified according to six single-nucleotide polymorphisms (SNPs) found in the OsPUB3 coding region of 4695 rice accessions. Significant differences on grain size traits were detected between the three major haplotypes, Hap1, Hap2 and Hap3 that jointly occupy 98.6% of the accessions. Hap3 having the largest grain weight and grain length but intermediate grain width exhibits a potential for simultaneously improving grain yield and quality. In another set of 257 indica rice cultivars tested in our study, Hap1 and Hap2 remained to be the two largest groups. Their differences on grain weight and size were significant in the background of non-functional gse5, but non-significant in the background of functional GSE5, indicating a genetic interaction between OsPUB3 and GSE5. Cloning of OsPUB3 provides a new gene resource for investigating the regulation of grain weight and size.

Control of Grain Shape and Size in Rice by Two Functional Alleles of OsPUB3 in Varied Genetic Background.

Grain shape and size are key determinants of grain appearance quality and yield in rice. In our previous study, a grain shape QTL, qGS1-35.2, was fine-mapped using near-isogenic lines (NILs) derived from a cross between Zhenshan 97 (ZS97) and Milyang 46 (MY46). One annotated gene, OsPUB3, was found to be the most likely candidate gene. Here, knockout and overexpression experiments were performed to investigate the effects of OsPUB3 on grain shape and size. Four traits were tested, including grain length, grain width, grain weight, and the ratio of grain length to width. Knockout of OsPUB3 in NILZS97, NILMY46, and another rice cultivar carrying the OsPUB3MY46 allele all caused decreases in grain width and weight and increases in the ratio of grain length to width. Results also showed that the magnitude of the mutational effects varied depending on the target allele and the genetic background. Moreover, it was found that NILZS97 and NILMY46 carried different functional alleles of OsPUB3, causing differences in grain shape rather than grain weight. In the overexpression experiment, significant differences between transgenic-positive and transgenic-negative plants were detected in all four traits. These results indicate that OsPUB3 regulates grain shape and size through a complex mechanism and is a good target for deciphering the regulatory network of grain shape. This gene could be used to improve grain appearance quality through molecular breeding as well.

TREM-1 Modulates Dendritic Cells Maturation and Dendritic Cell-Mediated T-Cell Activation Induced by ox-LDL.

Atherosclerosis is a chronic inflammatory disease. The triggering receptor expressed on myeloid cells-1 (TREM-1) plays a crucial role in inflammatory diseases; recently, it was identified as a major upstream proatherogenic receptor, but its mechanism is still unclear. In this study, we explore the role of TREM-1 on dendritic cells maturation and inflammatory responses induced by ox-LDL and its possible mechanism. Human dendritic cells were differentiated from blood monocytes and treated with ox-LDL. Naive autologous T cells were cocultured with pretreated DCs or treated directly. The expression of TREM-1 and inflammatory factors were evaluated by real-time PCR, western blot, and ELISA methods. And the expression of immune factors to evaluate the DCs maturation and T-cell activation were determined by the FACS. Our study showed that ox-LDL induced TREM-1 expression, DC maturation, and T-cell activation. T cells exposed to ox-LDL-treated DCs produced interferon-γ and interleukin-17 (IL-17). Blocking TREM-1 suppressed the DC maturation, showing lower expression of CD1a, CD40, CD86, CD83, and HLA-DR, and limited their production of tumor necrosis factor-alpha (TNF-α), IL-1ß, IL-6, and monocyte chemoattractant protein-1 (MCP-1), meanwhile increased transforming growth factor-ß(TGF-ß) and IL-10 production. Ox-LDL induced miR-155, miR-27, Let-7c, and miR-185 expression; however, TREM-1 inhibiting decreased miRNA-155 expression. Furthermore, silencing miRNA-155 restores SOCS1 repression induced by ox-LDL. Experiments with T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar results. Our results uncover a new link between ox-LDL and TREM-1 and may provide insight into this interaction in the context of atherosclerosis.

Fine Mapping of the MAP2K5 Region Identified rs7175517 as a Causal Variant Related to BMI in China and the United Kingdom Populations.

Background: Genome-wide association studies (GWASs) have consistently identified MAP2K5 as an obesity susceptibility gene. To deepen our understanding of the potential causal genetic variants of this region, a fine-mapping study of MAP2K5 was conducted. Methods and Results: SNPs rs7175517 (G > A) and rs4776970 (T > A) were identified as the leading SNPs associated with BMI in both Chinese and the United Kingdom populations. Second, colocalization of GWAS and expression quantitative trait loci (eQTL) analyses and bioinformatic analyses indicated that rs7175517 is the functionally leading variant in the MAP2K5 gene region. Dual-luciferase assays indicated that the G allele of rs7175517 reduced the mRNA expression of MAP2K5 in HEK293T cells. The possible mechanism was that the G allele interacted with more RNA repressors from nuclei extracts, which was evidenced by electrophoretic mobility shift assays (EMSAs). Furthermore, the pathway enrichment analyses of the products from DNA pull-down and protein mass spectrometry demonstrated that the G allele of rs7175517 might interact with RNA catabolic or splicing transcription factors, which consequentially increased adiposity deposition. Conclusion: SNP rs7175517 of the MAP2K5 gene was the putative causal variant associated with BMI. More precisely designed in vitro or animal experiments are warranted to further delineate the function of MAP2K5 in adipogenesis.

Study on the single-mode condition for x-cut LNOI rib waveguides based on leakage losses.

Lithium niobate-on-insulator (LNOI) has recently emerged as a promising material platform for high-density and advanced photonics integrated circuits (PICs). And single-mode waveguides (SMW) are the most basic building blocks for structuring various PICs. In this paper, single-mode conditions (SMCs) for shallowly etched LNOI rib waveguides in x-cut LNOI wafer are investigated with the finite element method (FEM) in consideration of the lateral leakage and the magic width for the first time, to our best knowledge. Our results indicate that due to the lateral leakage and the magic width these shallowly etched x-cut LNOI rib waveguides have unique and complex SMCs. Our method and results provide a guidance in designing low-loss LNOI SMW and high-performance PICs.

XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX).

BACKGROUND: There is no consensus on whether triplet regimen is better than doublet regimen in the first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. METHODS: This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non-inferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. RESULTS: Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5-6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0-6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812-1.203; Pnon-inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health-related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. CONCLUSIONS: This non-inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first-line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new anti-vitiligo compounds.

Humans have been suffering from vitiligo for a long time. Target vitiligo drugs have yet been approved. Activation of Wnt/ß-catenin signalling has potential in the therapeutic use of vitiligo, so exploring new drugs that specifically directly activate Wnt is worthwhile to obtain new anti-vitiligo agents. In this work, two portions design and synthesis were put into effect. firstly, 17 phenanthridine derivatives with C-4 substitutes were designed and synthesized, which compounds 4, 6, 12, 13 served as H-acceptor with protein showed enhance melanogenesis activity; Secondly, 7 hybrid new scaffolds of compounds were designed and synthesized, scaffold hopping compound 36 that aromatic benzene was replaced pyrazole on ring C showed enhance melanogenesis and tyrosinase activity; The last and most important, a comprehensive optimization and SARs of compound 36 were carried out, compounds 41 and 43 shared phenolic hydroxyl or 3-methyl-pyridine substitutes at C-7 position remarkably improved the capacity of melanogenesis and tyrosinase activity. Compound 43 were identified as new anti-vitiligo agents that specifically activate the Wnt/ß-catenin signalling pathway by targeting Axin. Structure-activity relationship analysis implied that H-acceptor substitutions at the C-4 position and phenolic hydroxyl or pyridine substitutions at the C-7 position would improve the activities of the compounds. These findings reveal a new therapeutic strategy for vitiligo, and compounds 41 and 43 may represent potential compounds for vitiligo treatment.