scholarly journals Transcriptomic Analysis Exploring the Molecular Mechanisms of Hanchuan Zupa Granules in Alleviating Asthma in Rat

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Hailong Yin ◽  
Yanbo Fan ◽  
Dandan Mu ◽  
Fei Song ◽  
Fang Tian ◽  
...  
Keyword(s):  
Protein Expression ◽  
Wall Thickness ◽  
Molecular Mechanisms ◽  
Group Discussion ◽  
Expression Patterns ◽  
Muscle Layer ◽  
Sprague Dawley ◽  
Hub Genes ◽  
Activated T Cells ◽  
Asthma Model

Context. Hanchuan Zupa granule (HCZP), as a Chinese traditional medicine, is used to treat asthma. Objective. To investigate the molecular mechanisms of HCZP treatment of asthma. Materials and Methods. Thirty Sprague Dawley (SD) rats were divided into normal, asthma, and HCZP groups (n = 10). The asthma model was sensitized by 1 mg ovalbumin (OVA)/aluminum hydroxide Al(OH)3mixture and then challenged with 1% aerosolized OVA for four weeks. Rats in the HCZP group received 10.08 g/kg/d HCZP for four weeks during OVA challenge. Then, lung tissues of rats in each group were collected for RNA sequencing. Moreover, the expression level of some core genes was detected by using western blotting and immunohistochemistry. Results. Inflammatory cell infiltration and pathological damage of the lungs improved in the HCZP group. Compared with the asthma group (0.049 ± 0.002 mm2/mm; 0.036 ± 0.006 mm2/mm; and 0.014 ± 0.001 mm2/mm), total wall thickness (0.042 ± 0.001 mm2/mm), inner wall thickness (0.013 ± 0.001 mm2/mm), and smooth muscle layer thickness (0.012 ± 0.001 mm2/mm) significantly decreased in the HCZP group. Bioinformatics analysis showed that hub genes such as bradykinin receptor B2 (Bdkrb2) and CD4 molecule (Cd4) had different expression patterns between model and HCZP groups. Two transcription factors, forkhead box Q1 (Foxq1) and nuclear factor of activated T cells 2 (Nfatc2), served important regulatory roles in asthma. Compared with the model group, Bdkrb2 protein expression increased and Nfatc2 protein expression decreased in the HCZP group. Discussion and Conclusion. HCZP could alleviate asthma via regulating the expression of several hub genes, which might serve as therapeutic targets for asthma. However, the mechanism of these genes will be studied in the future.

scholarly journals PGC-1α Participates in the Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiomyocytes

2018 ◽  
Vol 50 (5) ◽  
pp. 1891-1902 ◽  
Author(s):  
Shuo Gu ◽  
Hong Hua ◽  
Xinqi Guo ◽  
Zhanfeng Jia ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Protein Expression ◽  
Protein Level ◽  
Hypobaric Hypoxia ◽  
Molecular Mechanisms ◽  
Ventricular Myocytes ◽  
Ischemia Reperfusion ◽  
Sprague Dawley ◽  
Knock Down ◽  
Intermittent Hypobaric Hypoxia

Background/Aims: Myocardial ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injury is always characterized by Ca2+ overload, energy metabolism disorder and necrocytosis of cardiomyocytes. We showed previously that chronic intermittent hypobaric hypoxia (CIHH) improves cardiac function during I/R through improving cardiac glucose metabolism. However, the underlying cellular and molecular mechanisms of CIHH treatment improving energy metabolism in cardiomyocytes are still unclear. In this study, we determined whether and how CIHH protects cardiomyocytes from Ca2+ overload and necrocytosis through energy regulating pathway. Methods: Adult male Sprague-Dawley rats were randomly divided into two groups: control (CON) and CIHH group. CIHH rats received a hypobaric hypoxia simulating 5,000-m altitude for 28 days, 6 hours each day, in hypobaric chamber. Rat ventricular myocytes were obtained by enzymatic dissociation. The intracellular calcium concentration ([Ca2+]i) and cTnI protein expression were used to evaluate the degree of cardiomyocytes injury during and after H/R. The mRNA and protein expressions involved in cardiac energy metabolism were determined using quantitative PCR and Western blot techniques. PGC-1α siRNA adenovirus transfection was used to knock down PGC-1α gene expression of cardiomyocytes to determine the effect of PGC-1α in the energy regulating pathway. Results: H/R increased [Ca2+]i and cTnI protein expression in cardiomyocytes. CIHH treatment decreased [Ca2+]i (p< 0.01) and cTnI protein expression (p< 0.01) in cardiomyocytes after H/R. Both mRNA and protein expression of PGC-1α increased after CIHH treatment, which was reversed by PGC-1α siRNA adenovirus transfection. Furthermore, CIHH treatment increased the expression of HIF-1α, AMPK and p-AMPK in cardiomyocytes, and pretreatment with AMPK inhibitor dorsomorphin abolished the enhancement of PGC-1α protein expression in cardiomyocytes by CIHH (p< 0.01). In addition, PGC-1α knock down also abolished the increased protein level of GLUT4 (p< 0.01) and decreased the protein level of CPT-1b (p< 0.05) in cardiomyocytes by CIHH treatment. Conclusion: CIHH treatment could reduce the calcium overload and H/R injury in cardiomyocytes by up-regulating the expression of PGC-1α and regulating the energy metabolism of glucose and lipid. The HIF-1α-AMPK signaling pathway might be involved in the process.

scholarly journals Isoform-Selective NFAT Inhibitor: Potential Usefulness and Development

2021 ◽  
Vol 22 (5) ◽  
pp. 2725
Author(s):  
Noriko Kitamura ◽  
Osamu Kaminuma
Keyword(s):  
T Cells ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Family Members ◽  
Activated T Cells ◽  
Structural Abnormalities ◽  
Structural Differences ◽  
Almost All

Nuclear factor of activated T cells (NFAT), which is the pharmacological target of immunosuppressants cyclosporine and tacrolimus, has been shown to play an important role not only in T cells (immune system), from which their name is derived, but also in many biological events. Therefore, functional and/or structural abnormalities of NFAT are linked to the pathogenesis of diseases in various organs. The NFAT protein family consists of five isoforms, and each isoform performs diverse functions and has unique expression patterns in the target tissues. This diversity has made it difficult to obtain ideal pharmacological output for immunosuppressants that inhibit the activity of almost all NFAT family members, causing serious and wide-ranging side effects. Moreover, it remains unclear whether isoform-selective NFAT regulation can be achieved by targeting the structural differences among NFAT isoforms and whether this strategy can lead to the development of better drugs than the existing ones. This review summarizes the role of the NFAT family members in biological events, including the development of various diseases, as well as the usefulness of and problems associated with NFAT-targeting therapies, including those dependent on current immunosuppressants. Finally, we propose a novel therapeutic strategy based on the molecular mechanisms that enable selective regulation of specific NFAT isoforms.

scholarly journals NFAT3/c4-mediated excitotoxicity in hippocampal apoptosis during radiation-induced brain injury

2017 ◽  
Vol 58 (6) ◽  
pp. 827-833 ◽  
Author(s):  
Meiling Xu ◽  
Qiuhong Fan ◽  
Junjun Zhang ◽  
Yanfang Chen ◽  
Ruizhe Xu ◽  
...  
Keyword(s):  
Brain Injury ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Cranial Irradiation ◽  
Metastatic Carcinoma ◽  
Sprague Dawley ◽  
Whole Brain Irradiation ◽  
Activated T Cells ◽  
Radiation Induced ◽  
Hippocampal Apoptosis

Abstract Whole brain irradiation (WBI) has become an indispensible tool in the treatment of head and neck cancer, and it has greatly improved patient survival rate and total survival time. In addition, prophylactic cranial irradiation (PCI) has dramatically decreased the incidence of brain metastatic carcinoma. However, WBI may induce temporary functional deficits or even progressive, irreversible cognitive dysfunction that compromises the quality of life for survivors. Unfortunately, the exact molecular mechanisms for cognitive damage remain elusive, and no treatment or preventative measures are available for use in the clinic. In the present study, the nuclear factor of activated T cells isoform 4 (NFAT3/c4) was found to play a vital role in excitotoxic hippocampus cell apoptosis induced by radiation. Sprague–Dawley (SD) rats received 20 Gy WBI, after which we detected NFAT3/c4-mediated excitotoxicity. We found that radiation caused hippocampus excitotoxicity, resulting from overactivation of the N-methyl-D-aspartate receptor (NMDAR) and always accompanied by subsequent elevation of the intracellular calcium level and activation of calcineurin (CaN). P-NFAT3/c4 was the principal downstream target of CaN, including regulation of its nuclear translocation as well as transcriptional activities. Radiation recruited NMDAR/NFAT3/c4 activation and subsequent Bax induction in hippocampus cells. Once treated with the NFAT3/c4 inhibitor 11R-VIVIT peptide pre-irradiation, hippocampal proliferation and neuron survival (dentate gyrus cells in particular) were protected from radiation-induced injury, resulting in inhibition of the apoptosis marker Bax. Our principal aim was to illuminate the role of NFAT3/c4-mediated excitotoxicity in hippocampal apoptosis during radiation-induced brain injury. This study is the first time that radiation-induced activation of NFAT3/c4 has been recorded, and our results suggest that NFAT3/c4 may be a novel target for prevention and treatment of radiation-induced brain injury.

scholarly journals Identification of potential biomarkers and candidate small molecule drugs in glioblastoma

2020 ◽  
Author(s):  
Wei-cheng Lu ◽  
Hui Xie ◽  
Ce Yuan ◽  
Jin-jiang Li ◽  
Zhao-yang Li ◽  
...  
Keyword(s):  
Protein Expression ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Integrated Analysis ◽  
Hub Genes ◽  
Expression Levels ◽  
Small Molecule Drugs ◽  
Key Genes

Abstract Background and aims:Glioblastoma (GBM) is a common and aggressive primary brain tumor, and the prognosis for GBM patients remains poor. This study aimed to identify the key genes associated with the development of GBM and provide new diagnostic and therapies for GBM. Methods:Three microarray datasets (GSE111260, GSE103227, and GSE104267) were selected from Gene Expression Omnibus (GEO) database for integrated analysis. The differential expressed genes (DEGs) between GBM and normal tissues were identified. Then, prognosis-related DEGs were screened by survival analysis, followed by functional enrichment analysis. The protein-protein interaction (PPI) network was constructed to explore the hub genes associated with GBM. The mRNA and protein expression levels of hub genes were respectively validated in silico using The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) databases. Subsequently, the small molecule drugs of GBM were predicted by using Connectivity Map (CMAP) database. Results:A total of 78 prognosis-related DEGs were identified, of which10 hub genes with higher degree were obtained by PPI analysis. The mRNA expression and protein expression levels of CETN2, MKI67, ARL13B, and SETDB1 were overexpressed in GBM tissues, while the expression levels of CALN1, ELAVL3, ADCY3, SYN2, SLC12A5, and SOD1 were down-regulated in GBM tissues. Additionally, these genes were significantly associated with the prognosis of GBM. We eventually predicted the 10 most vital small molecule drugs, which potentially imitate or reverse GBM carcinogenic status. Cycloserine and 11-deoxy-16,16-dimethylprostaglandin E2 might be considered as potential therapeutic drugs of GBM. Conclusions:Our study provided 10 key genes for diagnosis, prognosis, and therapy for GBM. These findings might contribute to a better comprehension of molecular mechanisms of GBM development, and provide new perspective for further GBM research. However, specific regulatory mechanism of these genes needed further elaboration.

scholarly journals Genetics Responses to Hypoxia and Reoxygenation Stress in Larimichthys crocea Revealed via Transcriptome Analysis and Weighted Gene Co-Expression Network

Animals ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 3021
Author(s):  
Yibo Zhang ◽  
Jie Ding ◽  
Cheng Liu ◽  
Shengyu Luo ◽  
Xinming Gao ◽  
...  
Keyword(s):  
Gene Network ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Enrichment Analysis ◽  
Hypoxia Tolerance ◽  
Large Yellow Croaker ◽  
Larimichthys Crocea ◽  
Hub Genes ◽  
Gsk 3Β ◽  
Different Tissues

The large yellow croaker (Larimichthys crocea) is an important marine economic fish in China; however, its intolerance to hypoxia causes widespread mortality. To understand the molecular mechanisms underlying hypoxia tolerance in L. crocea, the transcriptome gene expression profiling of three different tissues (blood, gills, and liver) of L. crocea exposed to hypoxia and reoxygenation stress were performed. In parallel, the gene relationships were investigated based on weighted gene co-expression network analysis (WGCNA). Accordingly, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that several pathways (e.g., energy metabolism, signal transduction, oxygen transport, and osmotic regulation) may be involved in the response of L. crocea to hypoxia and reoxygenation stress. In addition, also, four key modules (darkorange, magenta, saddlebrown, and darkolivegreen) that were highly relevant to the samples were identified by WGCNA. Furthermore, some hub genes within the association module, including RPS16, EDRF1, KCNK5, SNAT2, PFKL, GSK-3β, and PIK3CD, were found. This is the first study to report the co-expression patterns of a gene network after hypoxia stress in marine fish. The results provide new clues for further research on the molecular mechanisms underlying hypoxia tolerance in L. crocea.

scholarly journals Bile Ductal Transcriptome Identifies Key Pathways and Hub Genes in Clonorchis sinensis-Infected Sprague-Dawley Rats

2020 ◽  
Vol 58 (5) ◽  
pp. 513-525
Author(s):  
Won Gi Yoo ◽  
Jung-Mi Kang ◽  
Huong Giang Lê ◽  
Jhang Ho Pak ◽  
Sung-Jong Hong ◽  
...  
Keyword(s):  
Bile Ducts ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Clonorchis Sinensis ◽  
Gene Expression Profiles ◽  
Predictive Biomarkers ◽  
Gene Interaction ◽  
Sprague Dawley ◽  
Hub Genes ◽  
Protein Protein Interaction

Clonorchis sinensis is a food-borne trematode that infects more than 15 million people. The liver fluke causes clonorchiasis and chronical cholangitis, and promotes cholangiocarcinoma. The underlying molecular pathogenesis occurring in the bile duct by the infection is little known. In this study, transcriptome profile in the bile ducts infected with C. sinensis were analyzed using microarray methods. Differentially expressed genes (DEGs) were 1,563 and 1,457 at 2 and 4 weeks after infection. Majority of the DEGs were temporally dysregulated at 2 weeks, but 519 DEGs showed monotonically changing expression patterns that formed seven distinct expression profiles. Protein-protein interaction (PPI) analysis of the DEG products revealed 5 sub-networks and 10 key hub proteins while weighted co-expression network analysis (WGCNA)-derived gene-gene interaction exhibited 16 co-expression modules and 13 key hub genes. The DEGs were significantly enriched in 16 Kyoto Encyclopedia of Genes and Genomes pathways, which were related to original systems, cellular process, environmental information processing, and human diseases. This study uncovered a global picture of gene expression profiles in the bile ducts infected with C. sinensis, and provided a set of potent predictive biomarkers for early diagnosis of clonorchiasis.

scholarly journals Identification of Hub Genes Correlated With Poor Prognosis for Patients With Uterine Corpus Endometrial Carcinoma by Integrated Bioinformatics Analysis and Experimental Validation

2021 ◽  
Vol 11 ◽  
Author(s):  
Yi Yuan ◽  
Zhengzheng Chen ◽  
Xushan Cai ◽  
Shengxiang He ◽  
Dong Li ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Female Genital Tract ◽  
Therapeutic Targets ◽  
Public Health Problem ◽  
The Cancer Genome Atlas ◽  
Major Public Health Problem ◽  
Hub Genes ◽  
Uterine Corpus

Uterine Corpus Endometrial Carcinoma (UCEC) is one of the most common malignancies of the female genital tract and there remains a major public health problem. Although significant progress has been made in explaining the progression of UCEC, it is still warranted that molecular mechanisms underlying the tumorigenesis of UCEC are to be elucidated. The aim of the current study was to investigate key modules and hub genes related to UCEC pathogenesis, and to explore potential biomarkers and therapeutic targets for UCEC. The RNA-seq dataset and corresponding clinical information for UCEC patients were obtained from the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were screened between 23 paired UCEC tissues and adjacent non-cancerous tissues. Subsequently, the co-expression network of DEGs was determined via weighted gene co-expression network analysis (WGCNA). The Blue and Brown modules were identified to be significantly positively associated with neoplasm histologic grade. The highly connected genes of the two modules were then investigated as potential key factors related to tumor differentiation. Additionally, a protein-protein interaction (PPI) network for all genes in the two modules was constructed to obtain key modules and nodes. 10 genes were identified by both WGCNA and PPI analyses, and it was shown by Kaplan-Meier curve analysis that 6 out of the 10 genes were significantly negatively related to the 5-year overall survival (OS) in patients (AURKA, BUB1, CDCA8, DLGAP5, KIF2C, TPX2). Besides, according to the DEGs from the two modules, lncRNA-miRNA-mRNA and lncRNA-TF-mRNA networks were constructed to explore the molecular mechanism of UCEC-related lncRNAs. 3 lncRNAs were identified as being significantly negatively related to the 5-year OS (AC015849.16, DUXAP8 and DGCR5), with higher expression in UCEC tissues compared to non-tumor tissues. Finally, quantitative Real-time PCR was applied to validate the expression patterns of hub genes. Cell proliferation and colony formation assays, as well as cell cycle distribution and apoptosis analysis, were performed to test the effects of representative hub genes. Altogether, this study not only promotes our understanding of the molecular mechanisms for the pathogenesis of UCEC but also identifies several promising biomarkers in UCEC development, providing potential therapeutic targets for UCEC.

Exogenous liposomal IGF-I cDNA gene transfer leads to endogenous cellular and physiological responses in an acute wound

2004 ◽  
Vol 286 (5) ◽  
pp. R958-R966 ◽  
Author(s):  
Marc G. Jeschke ◽  
Thomas Schubert ◽  
Dagmar Klein
Keyword(s):  
Gene Transfer ◽  
Protein Expression ◽  
Molecular Mechanisms ◽  
Physiological Responses ◽  
Cellular Responses ◽  
Sprague Dawley ◽  
Igf I ◽  
Acute Wound ◽  
Epidermal Regeneration ◽  
Lac Z

The purpose of the present study was to examine whether exogenous liposomal cDNA gene transfer is recognized by the cell and causes endogenous cellular and physiological responses. When administered as a protein, IGF-I is known to cause adverse side effects due to lack of cellular responses. Therefore, we used IGF-I cDNA as a vector to study cellular and physiological effects after liposomal administration to wounded skin. Sprague-Dawley rats were given a scald burn to inflict an acute wound and were divided into two groups to receive weekly subcutaneous injections of liposomes plus the Lac-Z gene (0.2 μg vehicle) or liposomes plus the IGF-I cDNA (2.2 μg) and Lac Z gene (0.22 μg). Transfection was confirmed by histochemical assays for β-galactosidase. Planimetry, immunological assays, and histological and immunohistochemical techniques were used to determine molecular mechanisms after gene transfer, protein expression, and dermal and epidermal regeneration. IGF-I cDNA transfer increased IGF-I protein expression and caused concomitant cellular responses by increasing IGF binding protein (IGFBP)-3 and decreasing IGFBP-1. IGF-I cDNA gene transfer increased keratinocyte growth factor expression and exerted promitogenic antiapoptotic effects on basal keratinocytes, thus improving epidermal regeneration. IGF-I cDNA improved dermal regeneration by an increased collagen deposition and morphology. IGF-I cDNA increased VEGF concentrations and thus neovascularization. Exogenous-administered IGF-I cDNA is recognized by the cell and leads to similar intracellular responses as the endogenous gene. Liposomal IGF-I gene transfer further leads to improved dermal and epidermal regeneration by interacting with other growth factors.

scholarly journals Hub microRNAs and genes in the development of atrial fibrillation identified by weighted gene co-expression network analysis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Qiang Qu ◽  
Jin-Yu Sun ◽  
Zhen-Ye Zhang ◽  
Yue Su ◽  
Shan-Shan Li ◽  
...  
Keyword(s):  
Network Analysis ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Patterns ◽  
Mirna Gene ◽  
Differentially Expressed ◽  
Integrated Analysis ◽  
Interaction Patterns ◽  
Hub Genes ◽  
Key Genes

AbstractCo-expression network may contribute to better understanding molecular interaction patterns underlying cellular processes. To explore microRNAs (miRNAs) expression patterns correlated with AF, we performed weighted gene co-expression network analysis (WGCNA) based on the dataset GSE28954. Thereafter, we predicted target genes using experimentally verified databases (ENOCRI, miRTarBase, and Tarbase), and overlapped genes with differentially expressed genes (DEGs) from GSE79768 were identified as key genes. Integrated analysis of association between hub miRNAs and key genes was conducted to screen hub genes. In general, we identified 3 differentially expressed miRNAs (DEMs) and 320 DEGs, predominantly enriched in inflammation-related functional items. Two significant modules (red and blue) and hub miRNAs (hsa-miR-146b-5p and hsa-miR-378a-5p), which highly correlated with AF-related phenotype, were detected by WGCNA. By overlapping the DEGs and predicted target genes, 38 genes were screened out. Finally, 9 genes (i.e. ATP13A3, BMP2, CXCL1, GABPA, LIF, MAP3K8, NPY1R, S100A12, SLC16A2) located at the core region in the miRNA-gene interaction network were identified as hub genes. In conclusion, our study identified 2 hub miRNAs and 9 hub genes, which may improve the understanding of molecular mechanisms and help to reveal potential therapeutic targets against AF.

scholarly journals Development of Biomarker Signatures Associated with Anoikis to Predict Prognosis in Endometrial Carcinoma Patients

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Shan Chen ◽  
Jiamin Gu ◽  
Qinfen Zhang ◽  
Yan Hu ◽  
Yu Ge
Keyword(s):  
Clinical Outcome ◽  
Endometrial Carcinoma ◽  
Molecular Mechanisms ◽  
Immune Status ◽  
Expression Patterns ◽  
Immune Dysfunction ◽  
Survival Outcome ◽  
Biological Pathways ◽  
Hub Genes ◽  
Regression Methods

Purpose. To generate a signature based on anoikis-related genes (ARGs) for endometrial carcinoma (EC) patients and elucidate the molecular mechanisms in EC. Methods. On the basis of TCGA-UCEC dataset, we identified specific anoikis-related genes (ARGs) in EC. Cox-relative regression methods were used to generate an anoikis-related signature (ARS). The possible biological pathways of ARS-related genes were analyzed by GSEA. The clinical potency and immune status of ARS were analyzed by CIBERSORT method, ssGSEA algorithm, Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Moreover, the expression patterns of ARS genes were verified by HPA database. Results. Seven anoikis genes (CDKN2A, E2F1, ENDOG, EZH2, HMGA1, PLK1, and SLC2A1) were determined to develop a prognostic ARS. Both genes of ARS were closely bound up with the prognosis of EC patients. The ARS could accurately classify EC cases with different clinical outcome and mirror the specific immune status of EC. We observed that ARS-high patients could not benefit from immunotherapy. Finally, all the hub genes of ARS were proved to be upregulated in EC tissues by immunohistology. Conclusion. ARS can be used to stratify the risk and forecast the survival outcome of EC patients and provide prominent reference for individualized treatment in EC.

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