The atrial fibrillation (AF) associated microRNAs (miRNAs) were found in the right atrium (RA) and left atrium (LA) from patients with rheumatic mitral valve disease (RMVD). However, most studies only focus on the RA; and the potential differences of AF-associated miRNAs between the RA and LA are still unknown. The aim of this study was to perform miRNA expression profiles analysis to compare the potential differences of AF-associated miRNAs in the right atrial appendages (RAA) and left atrial appendages (LAA) from RMVD patients.

The purpose of this study is to evaluate the efficacy of composite doxorubicinloaded micelles for enhancing doxorubicin radiosensitivity in multicellular spheroids from a non-small cell lung cancer cell line.

Structural changes of the left and right atria associated with atrial fibrillation (AF) in mitral stenosis (MS) patients are well known, and alterations in microRNA (miRNA) expression profiles of the right atria have also been investigated. However, miRNA changes in the left atria still require delineation. This study evaluated alterations in miRNA expression profiles of left atrial tissues from MS patients with AF relative to those with normal sinus rhythm (NSR).

Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. PD-L1 could promote the expression of stemness markers (OCT4 and Nanog) in breast cancer stem cells. However, the mechanisms by which PD-L1 regulates the stemness of breast cancer cells and PD-L1 is regulated in breast cancer cells are still unclear.

BACKGROUND CCL11 is an important inflammatory cytokine associated with inflammation-related diseases such as atherosclerosis and stroke. The aim of this study was to investigate the relationship between CCL11 gene polymorphism with subtypes of ischemic stroke in Xinjiang Han populations. MATERIAL AND METHODS The improved multiple ligase detection reaction (iMLDR) method was used to analyze the genotypes of 6 tag SNPs in the CCL11 gene (rs1129844, rs17809012, rs1860183, rs1860184, rs4795898, and rs4795895) in a case-control study of 406 lacunar stroke patients, 214 large-artery atherosclerotic (LAA) stroke patients, and 425 controls. RESULTS We found the GG genotype of rs4795895 was significantly associated with increased risk of lacunar stroke (adjusted OR=1.676, 95%CI=1.117-2.515), and the GA genotype of rs17809012 was associated with a significant increase in risk of LAA stroke (adjusted OR=1.337, 95%CI=1.127-1.585). Hypertension stratification analyses showed that the GA genotype of rs17809012 was significantly associated with LAA stroke in the hypertensive group (adjusted OR=1.274, 95%CI=1.015-1.601). In the non-hypertensive group, the GA genotype of rs17809012 was significantly associated with LAA stroke (adjusted OR=1.361, 95%CI=1.041-1.780). The GG genotype of rs4795895 (adjusted OR=1.147, 95%CI=1.115-4.134) and the TT genotype of rs1860184 were significantly associated with lacunar stroke (adjusted OR=2.440, 95%CI=1.550-3.840). CONCLUSIONS This study demonstrates that the CCL11 gene could play an important role in the pathogenesis of lacunar stroke and LAA stroke in the Han population of China.

Radiotherapy and cisplatin-based chemotherapy are currently considered as standard treatments employed for advanced cervical cancer (CC). However, patients with local recurrence or distant metastasis continue to have poor outcomes. EGFR overexpression correlated with chemo/radioresistance, and disease failure has been well proved in the previous studies. Hence, the aim of this study was to explore the therapeutic efficacy and underlying mechanism of the sensitization to radiation or cisplatin of icotinib hydrochloride (IH), a high-selective EGFR tyrosine kinase inhibitor (TKI), in the Hela S3 human CC cell line.

In this paper, owing to the electrostatic interaction between graphene and h-BN, a facile liquid phase exfoliation method was carried out to fabricate h-BN/graphene based van der Waals heterostructure nanocomposites without additional chemical cross-linkers. The physicochemical properties of as-prepared composites were characterized by several electron microscopic and spectroscopic measurements. The h-BN/graphene heterostructure composites were employed to use as the anodes of asymmetric supercapacitor, and exhibited exceptional capacitive performance due to their synergistic effects. It is expected that the as-prepared h-BN/graphene materials can boost scalable heterostructure electrodes in supercapacitors, and our liquid phase exfoliation method can be used for the construction of the other energy storage and electronics.

Background: miR-29a, a downstream factor of Wnt/β-catenin signaling, promotes the activity of the Wnt/β-catenin signaling in a positive feedback loop. Our previous work showed that 5,7,3',4'-tetramethoxyflavone (TMF), a major constituent from Murraya exotica L., exhibited chondroprotective activity by inhibiting the activity of Wnt/β-catenin signaling. Purpose: To investigate whether TMF showed the inhibitory effects on miR-29a/β-catenin signaling by up regulation of Foxo3a expression. Methods: Rat knee OA models were duplicated by using Hulth's method. TMF (5 μg/mL and 20 μg/mL) was used for administration to cultured cells, which were isolated from the rat cartilages. Analysis of chondrocytes apoptosis, gene expression, and protein expression were conducted. In addition, miR-29a mimics and pcDNA3.1(+)-Foxo3a vector were used for transfection, luciferase reporter assay for detecting the activity of Wnt/β-catenin signaling, and co-immunoprecipitation for determining proteins interaction. Results: TMF down regulated miR-29a/β-catenin signaling activity and cleaved caspase-3 expression and up regulated Foxo3a expression in OA rat cartilages. In vitro, miR-29a mimics down regulated the expression of Foxo3a and up regulated the activity of Wnt/β-catenin signaling and cleaved caspase-3 expression. TMF ameliorated miR-29a/β-catenin-induced chondrocytes apoptosis by up regulation of Foxo3a expression. Conclusion: TMF exhibited chondroprotective activity by up regulating Foxo3a expression and subsequently inhibiting miR-29a/Wnt/β-catenin signaling activity.

The gene tms5, which controls thermo-sensitive genic male sterility (TGMS), has been widely used in two-line hybrid rice breeding in China. The tms5 lines have two sources, namely, AnnongS-1 (AnS) and Zhu1S (ZhS) and, interestingly, are commonly subject to an alteration at cds.71. However, whether cds.71 acts as a mutation hotspot is unknown. Herein, another tms5 mutant named T98S (induced from T98B by irradiation) was used to explore this. First, the gene of tms(t) responsible for T98S was fine-mapped on chromosome 2 based on an F2 group of T98S/R893. In T98S, the candidate gene TMS5 (LOC_Os02g12290.1) mutated at cds.71 with a transversion from cytosine (C) to adenine (A), as also observed in AnS and ZhS. Moreover, the entire coding sequence of TMS5 from T98B converted T98S from sterile to fertile by Agrobacterium tumefaciens-mediated transformation, confirming that T98S is controlled by tms5. Next, detection on nearly 40,000 single nucleotide polymorphisms (SNPs) on Rice 56K SNP Array revealed T98S was 99.99% similar to T98B but only 72.84% and 77.47% similar to AnS and ZhS, respectively, demonstrating that T98S originated from T98B rather than from existing tms5 lines. Furthermore, the cds.70 was found to exist as a T/G haplotype, and it was T rather than G that helped to induce a TGMS trait. The T frequency was 67.52% in indica rice but decreased to 1.75% in japonica rice in 2,644 cultivars tested, which partly explains why tms5 mutants were mostly found in indica lines. Our findings provide evidence that cds.71 may act as a mutation hotspot and clues for breeding TGMS lines in a more efficient way.

Radiotherapy and chemotherapy are the main clinical treatments for biliary tract cancers (BTCs). Patients with advanced disease have a very poor prognosis, yet no molecular targets have been proven effective for the adjuvant therapy of BTCs. In this study, we aimed to explore the effect of combination treatment with icotinib hydrochloride (IH) and fluzoparib (FZ) on radiosensitivity and clarify its underlying mechanism in the HCCC-9810 and GBC-SD human BTC cell lines.

Cell death is a vital and ubiquitous process that is tightly controlled in all organisms. However, the mechanisms underlying precise cell death control remain fragmented. As an important shared module in plant growth, development, and immunity, Arabidopsis thaliana BRASSINOSTEROID INSENSITIVE 1-associated receptor kinase 1 (BAK1) and somatic embryogenesis receptor kinase 4 (SERK4) redundantly and negatively regulate plant cell death. By deploying an RNAi-based genetic screen for bak1/serk4 cell death suppressors, we revealed that cyclic nucleotide-gated channel 20 (CNGC20) functions as a hyperpolarization-activated Ca2+-permeable channel specifically regulating bak1/serk4 cell death. BAK1 directly interacts with and phosphorylates CNGC20 at specific sites in the C-terminal cytosolic domain, which in turn regulates CNGC20 stability. CNGC19, the closest homolog of CNGC20 with a low abundance compared with CNGC20, makes a quantitative genetic contribution to bak1/serk4 cell death only in the absence of CNGC20, supporting the biochemical data showing homo- and heteromeric assembly of the CNGC20 and CNGC19 channel complexes. Transcripts of CNGC20 and CNGC19 are elevated in bak1/serk4 compared with wild-type plants, further substantiating a critical role of homeostasis of CNGC20 and CNGC19 in cell death control. Our studies not only uncover a unique regulation of ion channel stability by cell-surface-resident receptor kinase-mediated phosphorylation but also provide evidence for fine-tuning Ca2+ channel functions in maintaining cellular homeostasis by the formation of homo- and heterotetrameric complexes.

Nicotine, the most abundant pyridine alkaloid in cultivated tobacco (Nicotiana tabacum L.), is a potent inhibitor of insect and animal herbivory and a neurostimulator of human brain function. Nicotine biosynthesis is controlled developmentally and can be induced by abiotic and biotic stressors via a jasmonic acid (JA)-mediated signal transduction mechanism involving members of the APETALA 2/ethylene-responsive factor (AP2/ERF) and basic helix-loop-helix (bHLH) transcription factor (TF) families. AP2/ERF and bHLH TFs work combinatorically to control nicotine biosynthesis and its subsequent accumulation in tobacco leaves. Here, we demonstrate that overexpression of the tobacco NtERF32, NtERF221/ORC1, and NtMYC2a TFs leads to significant increases in nicotine accumulation in T2 transgenic K326 tobacco plants before topping. Up to 9-fold higher nicotine production was achieved in transgenics overexpressing NtERF221/ORC1 under the control of a constitutive GmUBI3 gene promoter compared to wild-type plants. The constitutive 2XCaMV35S promoter and a novel JA-inducible 4XGAG promoter were less effective in driving high-level nicotine formation. Methyljasmonic acid (MeJA) treatment further elevated nicotine production in all transgenic lines. Our results show that targeted manipulation of NtERF221/ORC1 is an effective strategy for elevating leaf nicotine levels in commercial tobacco for use in the preparation of reduced risk tobacco products for smoking replacement therapeutics.

Radiation-induced oral mucositis (RIOM) is one of the most common side effects of radiotherapy in cancer patients, especially in almost all head and neck cancer patients. It presents as severe pain and ulceration. The development of RIOM is composed of five stages: initiation, primary damage response, signal amplification, ulceration, and healing. However, the key regulators involved in the RIOM pathogenesis remain largely unknown. In this study, we reveal a novel role of miR-200c, a member of the miR-200 family, in modulating RIOM pathogenesis. Using a mouse model mimicking RIOM, we found that the miR-200 family numbers (miR-141, miR-200a, miR-200b, and miR-200c) except miR-429 were significantly induced during the RIOM formation. Besides, in RIOM mice, miR-200c expression level was also increased dramatically in the normal human keratinocytes (NHKs) after irradiation. Knockdown of miR-200c expression with miR-200c-3p-shRNA significantly reduced senescence phenotype and enhanced cell proliferation in NHKs after irradiation. The generation of reactive oxygen species (ROS) and p47 enzyme involved in ROS production was increased after irradiation but both were markedly reduced in NHKs by miR-200c inhibition. Knockdown of miR-200c expression in NHKs increased DNA double-strand break repair after irradiation compared with control NHKs. Furthermore, miR-200c inhibition repressed the production of proinflammatory cytokines (TGF-β, TNF-α, and IL-1α) via inhibiting NF-κB and Smad2 activation in NHKs exposed to IR. Additionally, miR-200c inhibition promoted NHK migration and increased the expression of molecules that regulate epithelial to mesenchymal transition, including Snail, Vimentin, Zeb1, and Bmi-1. These results not only identify the key role of miR-200c in the pathogenesis of RIOM but also provide a novel therapeutic target to treat RIOM.

With their photosynthetic ability and established genetic modification systems, cyanobacteria are essential for fundamental and biotechnological research. Till now, hundreds of cyanobacterial genomes have been sequenced, and transcriptomic analysis has been frequently applied in the functional genomics of cyanobacteria. However, the massive omics data have not been extensively mined and integrated. Here, we describe CyanoOmicsDB (http://www.cyanoomics.cn/), a database aiming to provide comprehensive functional information for each cyanobacterial gene. CyanoOmicsDB consists of 8 335 261 entries of cyanobacterial genes from 928 genomes. It provides multiple gene identifiers, visualized genomic location, and DNA sequences for each gene entry. For protein-encoding genes, CyanoOmicsDB can provide predicted gene function, amino acid sequences, homologs, protein-domain super-families, and accession numbers for various public protein function databases. CyanoOmicsDB integrates both transcriptional and translational profiles of Synechocystis sp. PCC 6803 under various environmental culture coditions and genetic backgrounds. Moreover, CyanoOmicsDB includes 23 689 gene transcriptional start sites, 94 644 identified peptides, and 16 778 post-translation modification sites obtained from transcriptomes or proteomes of several model cyanobacteria. Compared with other existing cyanobacterial databases, CyanoOmicsDB comprises more datasets and more comprehensive functional information. CyanoOmicsDB will provide researchers in this field with a convenient way to retrieve functional information on cyanobacterial genes.

The leading cause of cancer deaths is lung cancer, non-small cell lung cancer (NSCLC), the most common type of lung cancers, remains a difficult cancer to treat and cure. It is urgent to develop new products to treat NSCLS. Gracillin, extracted from Reineckia carnea, Dioscorea villosa, and other medicinal plants, has anti-tumor potential with toxic effect on a variety of tumor cells such as NSCLC. However, the anti-NSCLC mechanism of gracillin is not completely clear. In this study, A549 cells and athymic nude mice were used as models to evaluate the anti-NSCLC effects of gracillin. The antiproliferative activity of gracillin on A549 cells was conducted by CCK-8, and obvious autophagy was observed in gracillin-treated A549 through transmission electron microscopy. Furthermore, the expressions of Beclin-1, LC3-II, and WIPI1 were upregulated, while the expression of p62 was downregulated in gracillin-treated A549. The further mechanism study found that the mTOR signaling pathway was significantly inhibited by gracillin. Accordingly, the PI3K/Akt pathway positively regulating mTOR was inhibited, and AMPK negatively regulating mTOR was activated. Meanwhile, LC3-II transformation was found to be significantly reduced after WIPI1 was silenced in A549 cells but increased after gracillin treatment. It also proves that WIPI is involved in the process of gracillin regulating A549 autophagy. At last, the anti-tumor growth activity of gracillin in vivo was validated in A549-bearing athymic nude mice. In conclusion, gracillin has anti-NSCLC activity by inducing autophagy. The mechanism maybe that gracillin inhibited the mTOR signaling pathway. Gracillin has the potential to be a candidate product for the treatment of NSCLC in the future.

Loin muscle area (LMA) is an important meat production trait and plays a key role in determining carcass leanness. Genome-wide association study (GWAS) and RNA sequencing (RNA-seq) analysis were used to identify candidate LMA genes in Beijing Black pigs, a popular breed among consumers in northern China. Ten single nucleotide polymorphisms (SNPs) in sus scrofa chromosome (SSC) 9 were significantly associated with LMA. These SNPs were mapped to a 2.90 Mb (84.94-87.84 Mb) region. A total of 11 annotated genes were mapped on this region, namely MEOX2, CRPPA, SOSTDC1, LRRC72, ANKMY2, BZW2, TSPAN13, AGR2, AHR, SNX13, and HDAC9. In addition, RNA-seq analysis was performed between the high- and low-LMA groups, and 329 differentially expressed genes (DEGs) were identified. Further, Kyoto Encyclopedia of Genes and Genomes analysis based on DEGs revealed that the JAK/STAT signaling pathway and oxytocin signaling pathway may be responsible for LMA. Both GWAS and RNA-seq analysis identified the HDAC9 gene, indicating that it may be an important candidate gene affecting LMA in Beijing Black pigs. The findings provide valuable molecular insights into the mechanisms that influence LMA content in pigs, which can be utilized in targeted approaches to enhance meat quality and commercial profitability.

Taste receptor T1R1-T1R3 can be activated by binding to several natural ligands, e.g., l-glutamate and 5'-ribonucleotides etc., thereby stimulating the umami taste. The molecular mechanism of umami recognition at atomic details, however, remains elusive. Here, using homology modeling, molecular docking and molecular dynamics (MD) simulations, we investigate the effects of five natural umami ligands on the structural dynamics of T1R1-T1R3. Our work identifies the key residues that are directly involved in recognizing the binding ligands. In addition, two adjacent binding sites in T1R1 are determined for substrate binding, and depending on the molecular size and chemical properties of the incoming ligand, one or both binding sites can be occupied. More interestingly, the ligand binding can modulate the pocket size, which is likely correlated with the closing and opening motions of T1R1. We then classify these five ligands into two groups according to their different binding effects on T1R1, which likely associate with the distinct umami signals stimulated by various ligands. This work warrants new experimental assays to further validate the theoretical model and provides guidance to design more effective umami ligands.

The expression of CYP4Z1 and the pseudogene CYP4Z2P has been shown to be specifically increased in breast cancer by our group and others. Additionally, we previously revealed the roles of the competitive endogenous RNA (ceRNA) network mediated by these genes (ceRNET_CC) in breast cancer angiogenesis, apoptosis, and tamoxifen resistance. However, the roles of ceRNET_CC in regulating the stemness of breast cancer cells and the mechanisms through which ceRNET_CC is regulated remain unclear.

Periodontal tissue damage, accompanied by the degradation and destruction of periodontal tissue collagen, is one of the most clinically common complications and difficulty self-repair in patients with diabetes. Human periodontal ligament stem cells (PDLSC) are the undifferentiated mesenchymal cells that persist in the periodontal ligament after development of periodontal tissue and the ability of PDLSC osteogenic differentiation is responsible for repairing periodontal tissue defects. However, the reasons of high glucose environment in diabetic patients inhibiting PDLSC to repair periodontal tissues are unclear. To address these issues, we propose exposing PDLSC to high-sugar mimics the diabetic environment and investigating the activity of osteogenic differentiation and adipogenic differentiation of PDLSC. At the cellular level, high glucose can promote the adipogenic differentiation and inhibit osteogenic differentiation to decrease the self-repair ability of PDLSC in periodontal tissues. Mechanistically at the molecular level, these effects are elicited via regulating the mRNA and protein expression of C/EBPβ, PPAR-γ.

Cell wall polysaccharide biosynthesis enzymes play important roles in plant growth, development and stress responses. The functions of cell wall polysaccharide synthesis enzymes in plant growth and development have been well studied. In contrast, their roles in plant responses to environmental stress are poorly understood. Previous studies have demonstrated that the rice cell wall cellulose synthase-like D4 protein (OsCSLD4) is involved in cell wall polysaccharide synthesis and is important for rice growth and development. This study demonstrated that the OsCSLD4 function-disrupted mutant nd1 was sensitive to salt stress, but insensitive to abscisic acid (ABA). The expression of some ABA synthesis and response genes was repressed in nd1 under both normal and salt stress conditions. Exogenous ABA can restore nd1-impaired salt stress tolerance. Moreover, overexpression of OsCSLD4 can enhance rice ABA synthesis gene expression, increase ABA content and improve rice salt tolerance, thus implying that OsCSLD4-regulated rice salt stress tolerance is mediated by ABA synthesis. Additionally, nd1 decreased rice tolerance to osmotic stress, but not ion toxic tolerance. The results from the transcriptome analysis showed that more osmotic stress-responsive genes were impaired in nd1 than salt stress-responsive genes, thus indicating that OsCSLD4 is involved in rice salt stress response through an ABA-induced osmotic response pathway. Intriguingly, the disruption of OsCSLD4 function decreased grain width and weight, while overexpression of OsCSLD4 increased grain width and weight. Taken together, this study demonstrates a novel plant salt stress adaptation mechanism by which crops can coordinate salt stress tolerance and yield.