Construction and Analysis of a ceRNA Network in Cardiac Fibroblast During Fibrosis Based on in vivo and in vitro Data

AimsActivation of cardiac fibroblasts (CF) is crucial to cardiac fibrosis. We constructed a cardiac fibroblast-related competing endogenous RNA (ceRNA) network. Potential functions related to fibrosis of “hub genes” in this ceRNA network were explored.Materials and MethodsThe Gene Expression Omnibus database was searched for eligible datasets. Differentially expressed messenger (m)RNA (DE-mRNA) and long non-coding (lnc)RNA (DE-lncRNA) were identified. microRNA was predicted and validated. A predicted ceRNA network was constructed and visualized by Cytoscape, and ceRNA crosstalk was validated. A Single Gene Set Enrichment Analysis (SGSEA) was done, and the Comparative Toxicogenomics Database (CTD) was employed to analyze the most closely associated pathways and diseases of DE-mRNA in the ceRNA network. The functions of DE-mRNA and DE-lncRNA in the ceRNA network were validated by small interfering (si)RNA depletion.ResultsThe GSE97358 and GSE116250 datasets (which described differentially expressed genes in human cardiac fibroblasts and failing ventricles, respectively) were used for analyses. Four-hundred-and-twenty DE-mRNA and 39 DE-lncRNA, and 369 DE-mRNA and 93 DE-lncRNA were identified, respectively, in the GSE97358 and GSE116250 datasets. Most of the genes were related to signal transduction, cytokine activity, and cell proliferation. Thirteen DE-mRNA with the same expression tendency were overlapped in the two datasets. Twenty-three candidate microRNAs were predicted and the expression of 11 were different. Only two DE-lncRNA were paired to any one of 11 microRNA. Finally, two mRNA [ADAM metallopeptidase domain 19, (ADAM19) and transforming growth factor beta induced, (TGFBI)], three microRNA (miR-9-5p, miR-124-3p, and miR-153-3p) and two lncRNA (LINC00511 and SNHG15) constituted our ceRNA network. siRNA against LINC00511 increased miR-124-3p and miR-9-5p expression, and decreased ADAM19 and TGFBI expression, whereas siRNA against SNHG15 increased miR-153-3p and decreased ADAM19 expression. ADAM19 and TGFBI were closely related to the TGF-β1 pathway and cardiac fibrosis, as shown by SGSEA and CTD, respectively. Depletion of two mRNA or two lncRNA could alleviate CF activation.ConclusionsThe CF-specific ceRNA network, including two lncRNA, three miRNA, and two mRNA, played a crucial role during cardiac fibrosis, which provided potential target genes in this field.

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Abstract 782: Fra2 Mediates Oxygen-induced TGFbeta-1 mRNA Expression In Adult Cardiac Fibroblasts: Significance In Myocardial Fibrosis Following Ischemia-reperfusion Injury

Circulation ◽

10.1161/circ.116.suppl_16.ii_150-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Sashwati Roy ◽

Savita Khanna ◽

Chandan K Sen

Keyword(s):

Mrna Expression ◽

Transforming Growth Factor Beta ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Ischemia Reperfusion Injury ◽

Cardiac Fibroblasts ◽

Ischemia Reperfusion ◽

Luciferase Reporter ◽

Mrna Levels

Background . Transforming growth factor beta-1 (TGFbeta-1) is a key cytokine implicated in the development of cardiac fibrosis following ischemia-reperfusion (IR) injury. The profibrotic effects of TGFbeta-1 are primarily attributable to the differentiation of cardiac fibroblasts (CF) to myofibroblasts. Previously, we have reported perceived hyperoxia (Circ Res 92:264 –71), sub-lethal reoxygenation shock during IR, induces differentiation of CF to myofibroblasts at the infarct site. The mechanisms underlying oxygen-sensitive induction of TGFbeta-1 mRNA remain to be characterized. Hypothesis . Fra2 mediates oxygen-induced TGFbeta-1 mRNA expression in adult cardiac fibroblasts. Methods. TGFbeta-1 mRNA expression in infarct tissue was investigated in an IR injury model. The left anterior descending coronary artery of mice was transiently occluded for 60 minutes followed by reperfusion to induce IR injury. Spatially resolved infarct and non-infarct tissues were collected at 0, 1, 3, 5, and 7 days post-IR using laser capture microdissection. TGFbeta-1 mRNA levels were measured using real-time PCR. To investigate the role of oxygen in the regulation of TGFbeta-1, we used our previously reported model of perceived hyperoxia where CF (from 5wks old mice) after isolation were cultured at 5%O 2 (physiological pO 2 ) followed by transferring them to 20%O 2 to induce hyperoxic insult. Results & Conclusions. In vivo, a significant increase (p<0.01; n=5) in TGFbeta-1 mRNA was observed at the infarct site already at day 1 post-IR. The levels continued to increase until day 7 post-IR. In vitro, exposure of CF to 20%O 2 hyperoxic insult induced TGFbeta-1 mRNA (p<0.001; n=4) and protein (p<0.01; n=4) expression. Using a TGFbeta-1 promoter-luciferase reporter and DNA binding assays, we collected first evidence that AP-1 and its component Fra2 as major mediators of oxygen-induced TGFbeta-1 expression. Exposure to 20%O 2 resulted in increased localization of Fra2 in nucleus. siRNA-dependent Fra-2 knock-down completely abrogated oxygen-induced TGFbeta1 expression. In conclusion, this study presents first evidence that Fra-2 is involved in inducible TGFbeta1 expression in CF. Fra2 was noted as being central in regulating oxygen-induced TGFbeta-1 expression.s

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Soluble St2 Induces Cardiac Fibroblast Activation and Collagen Synthesis via Neuropilin-1

Cells ◽

10.3390/cells9071667 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1667 ◽

Cited By ~ 1

Author(s):

Lara Matilla ◽

Vanessa Arrieta ◽

Eva Jover ◽

Amaia Garcia-Peña ◽

Ernesto Martinez-Martinez ◽

...

Keyword(s):

Collagen Synthesis ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Interleukin 1 ◽

Cardiac Fibroblast ◽

Pathogenic Role ◽

Fibroblast Activation ◽

Neuropilin 1 ◽

Human Cardiac Fibroblasts

Circulating levels of soluble interleukin 1 receptor-like 1 (sST2) are increased in heart failure and associated with poor outcome, likely because of the activation of inflammation and fibrosis. We investigated the pathogenic role of sST2 as an inductor of cardiac fibroblasts activation and collagen synthesis. The effects of sST2 on human cardiac fibroblasts was assessed using proteomics and immunodetection approaches to evidence the upregulation of neuropilin-1 (NRP-1), a regulator of the profibrotic transforming growth factor (TGF)-β1. In parallel, sST2 increased fibroblast activation, collagen and fibrosis mediators. Pharmacological inhibition of nuclear factor-kappa B (NF-κB) restored NRP-1 levels and blocked profibrotic effects induced by sST2. In NRP-1 knockdown cells, sST2 failed to induce fibroblast activation and collagen synthesis. Exogenous NRP-1 enhanced cardiac fibroblast activation and collagen synthesis via NF-κB. In a pressure overload rat model, sST2 was elevated in association with cardiac fibrosis and was positively correlated with NRP-1 expression. Our study shows that sST2 induces human cardiac fibroblasts activation, as well as the synthesis of collagen and profibrotic molecules. These effects are mediated by NRP-1. The blockade of NF-κB restored NRP-1 expression, improving the profibrotic status induced by sST2. These results show a new pathogenic role for sST2 and its mediator, NRP-1, as cardiac fibroblast activators contributing to cardiac fibrosis.

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MicroRNA-101a Inhibits Cardiac Fibrosis Induced by Hypoxia via Targeting TGFβRI on Cardiac Fibroblasts

Cellular Physiology and Biochemistry ◽

10.1159/000369689 ◽

2015 ◽

Vol 35 (1) ◽

pp. 213-226 ◽

Cited By ~ 49

Author(s):

Xin Zhao ◽

Kejing Wang ◽

Yuhua Liao ◽

Qiutang Zeng ◽

Yushu Li ◽

...

Keyword(s):

Signaling Pathway ◽

Transforming Growth Factor Beta ◽

Cardiac Remodeling ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Luciferase Reporter ◽

Migration Ability

Background/Aims: Hypoxia is a basic pathological challenge that is associated with numerous cardiovascular disorders including aberrant cardiac remodeling. Transforming growth factor beta (TGF-β) signaling pathway plays a pivotal role in mediating cardiac fibroblast (CF) function and cardiac fibrosis. Recent data suggested that microRNA-101a (miR-101a) exerted anti-fibrotic effects in post-infarct cardiac remodeling and improved cardiac function. This study aimed to investigate the potential relationship between hypoxia, miR-101a and TGF-β signaling pathway in CFs. Methods and Results: Two weeks following coronary artery occlusion in rats, the expression levels of both TGFβ1 and TGFβRI were increased, but the expression of miR-101a was decreased at the site of the infarct and along its border. Cultured rat neonatal CFs treated with hypoxia were characterized by the up-regulation of TGFβ1 and TGFβRI and the down-regulation of miR-101a. Delivery of miR-101a mimics significantly suppressed the expression of TGFβRI and p-Smad 3, CF differentiation and collagen content of CFs. These anti-fibrotic effects were abrogated by co-transfection with AMO-miR-101a, an antisense inhibitor of miR-101a. The repression of TGFβRI, a target of miR-101a, was validated by luciferase reporter assays targeting the 3'UTR of TGFβRI. Additionally, we found that overexpression of miR-101a reversed the improved migration ability of CFs and further reduced CF proliferation caused by hypoxia. Conclusion: Our study illustrates that miR-101a exerts anti-fibrotic effects by targeting TGFβRI, suggesting that miR-101a plays a multi-faceted role in modulating TGF-β signaling pathway and cardiac fibrosis.

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Exploring the Roles of Fecundity-related mRNAs and Long Non-coding RNAs in the Adrenal Glands of Small-tailed Han Sheep

10.21203/rs.2.15698/v3 ◽

2020 ◽

Author(s):

Qing Xia ◽

Qiuling Li ◽

Shangquan Gan ◽

Xiaofei Guo ◽

Xiaosheng Zhang ◽

...

Keyword(s):

Adrenal Gland ◽

Signaling Pathways ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Target Genes ◽

Transforming Growth Factor ◽

Differentially Expressed ◽

Mitogen Activated Protein Kinase ◽

Gene Expressions ◽

Non Coding Rnas

Abstract Background Long non-coding RNAs (lncRNAs) can play important roles in uterine and ovarian functions. However, little researches have been done on the role of lncRNAs in the adrenal gland of sheep. Herein, RNA sequencing was used to compare and analyze gene expressions in adrenal tissues between FecB ++ (WW) and FecB BB (MM) sheep in the follicular and luteal phases and key lncRNAs and genes associated with reproduction were identified. Results In MM sheep, 38 lncRNAs and 545 mRNAs were differentially expressed in the adrenal gland between the luteal and follicular phases; In WW sheep, 30 differentially expressed lncRNAs and 210 mRNAs were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that differentially expressed lncRNAs and their target genes are mainly involved in the circadian rhythm, the mitogen activated protein kinase, thyroid, ovarian steroidogenesis and transforming growth factor beta signaling pathways. Key lncRNAs can regulate reproduction by modulating genes involved in these signaling pathways and biological processes. Specifically, XLOC_254761 , XLOC_357966 , 105614839 and XLOC_212877 targeting CREB1 , PER3 , SMAD1 and TGFBR2 , respectively, appear to play key regulatory roles. Conclusion These results broaden our understanding of lncRNAs in adrenal gland of sheep and provide new insights into the molecular mechanisms underlying sheep reproduction.

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Exploring the Roles of Fecundity-related Long Non-coding RNAs and mRNAs in the Adrenal Glands of Small-tailed Han Sheep

10.21203/rs.2.15698/v4 ◽

2020 ◽

Author(s):

Qing Xia ◽

Qiuling Li ◽

Shangquan Gan ◽

Xiaofei Guo ◽

Xiaosheng Zhang ◽

...

Keyword(s):

Adrenal Gland ◽

Signaling Pathways ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Target Genes ◽

Transforming Growth Factor ◽

Differentially Expressed ◽

Mitogen Activated Protein Kinase ◽

Gene Expressions ◽

Non Coding Rnas

Abstract Background: Long non-coding RNAs (lncRNAs) can play important roles in uterine and ovarian functions. However, little researches have been done on the role of lncRNAs in the adrenal gland of sheep. Herein, RNA sequencing was used to compare and analyze gene expressions in adrenal tissues between follicular phases and luteal phases in FecBBB (MM) and FecB++ (WW) sheep, respectively, and differentially expressed lncRNAs and genes associated with reproduction were identified.Results: In MM sheep, 38 lncRNAs and 545 mRNAs were differentially expressed in the adrenal gland between the luteal and follicular phases; In WW sheep, 513 differentially expressed lncRNAs and 2481 mRNAs were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that differentially expressed lncRNAs and their target genes are mainly involved in the circadian rhythm, the mitogen activated protein kinase, thyroid, ovarian steroidogenesis and transforming growth factor beta signaling pathways. Differentially expressed lncRNAs can regulate reproduction by modulating genes involved in these signaling pathways and biological processes. Specifically, XLOC_254761, XLOC_357966, 105614839 and XLOC_212877 targeting CREB1, PER3, SMAD1 and TGFBR2, respectively, appear to play key regulatory roles. Conclusion: These results broaden our understanding of lncRNAs in adrenal gland of sheep and provide new insights into the molecular mechanisms underlying sheep reproduction.

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Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation

10.1101/563445 ◽

2019 ◽

Author(s):

Matthew S. Stratton ◽

Rushita A. Bagchi ◽

Rachel A. Hirsch ◽

Andrew S. Riching ◽

Marina B. Felisbino ◽

...

Keyword(s):

Rna Polymerase Ii ◽

Target Genes ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Cardiac Fibroblast ◽

Mitogen Activated Protein Kinase ◽

Fibroblast Activation ◽

Downstream Target ◽

Mitogen Activated Protein ◽

Clinical Models

AbstractSmall molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in pre-clinical models of heart failure (HF). However, the mechanisms by which BRD4 promotes pathological myocardial fibrosis remain unclear. Here, we demonstrate that BRD4 functions as an effector of TGF-β signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin (Postn)-positive cells that express high levels of extracellular matrix. BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the SERTA domain-containing protein 4 (Sertad4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 mitogen-activated protein kinase, and provide evidence of a novel function for Sertad4 in TGF-β-mediated cardiac fibroblast activation. These findings define BRD4 as a central regulator of the pro-fibrotic cell state of cardiac fibroblasts, and establish a signaling circuit for epigenetic reprogramming in HF.

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Function analysis of differentially expressed microRNAs in TGF-β1-induced cardiac fibroblasts differentiation

Bioscience Reports ◽

10.1042/bsr20182048 ◽

2019 ◽

Vol 39 (10) ◽

Author(s):

Suxuan Liu ◽

Wen Ke ◽

Yang Liu ◽

Zhenzhen Zhao ◽

Lina An ◽

...

Keyword(s):

Target Genes ◽

Cardiac Fibrosis ◽

Function Analysis ◽

Cardiac Fibroblasts ◽

Critical Role ◽

Differentially Expressed ◽

Small Rna Sequencing ◽

Altered Expression ◽

Differentially Expressed Mirnas ◽

Tgf Β1

Abstract Background: Cardiac fibroblasts differentiation plays a critical role in cardiac remodeling and failure, but the underlying molecular mechanisms are still poorly understood. MicroRNAs (miRNAs) had been identified as important regulators during cell differentiation. The aim of the present study was to screen the miRNAs involved in regulation of cardiac fibroblasts differentiation. Methods: The differentiation of rat cardiac fibroblasts into myofibroblasts was induced by transforming growth factor-β1 (TGF-β1). Small RNA sequencing was then applied to detect the differentially expressed miRNAs. Results: A total of 450 known miRNAs were detected, and 127 putative novel miRNAs were predicted by miRDeep2 analysis. DEGseq analysis and qRT-PCR confirmed that 24 known miRNAs were differentially expressed in TGF-β1-induced cardiac fibroblasts, including three up-regulated miRNAs and 21 down-regulated miRNAs. After miRNAs target genes prediction by miRanda algorithm, pathway analysis showed that these potential target genes were involved in Calcium signaling pathway, Type II diabetes mellitus, and Glutamatergic synapse pathway, etc. Meanwhile, seven putative miRNAs were also detected differentially expressed during TGF-β1-induced cardiac fibroblasts differentiation. Conclusions: These differentially expressed miRNAs might play critical roles in cardiac fibroblasts differentiation. Altered expression of miRNAs may yield new insights into the underlying mechanisms of cardiac fibrosis and provide novel mechanism-based therapeutic strategies for cardiac fibrosis.

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Role of sialidase Neu3 and ganglioside GM3 in cardiac fibroblasts activation

Biochemical Journal ◽

10.1042/bcj20200360 ◽

2020 ◽

Vol 477 (17) ◽

pp. 3401-3415

Author(s):

Andrea Ghiroldi ◽

Marco Piccoli ◽

Pasquale Creo ◽

Federica Cirillo ◽

Paola Rota ◽

...

Keyword(s):

Signaling Pathway ◽

Transforming Growth Factor Beta ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Tissue Injury ◽

Cardiac Fibroblasts ◽

Primary Cultures ◽

Cell Types ◽

Cell Content ◽

Ganglioside Gm3

Cardiac fibrosis is a key physiological response to cardiac tissue injury to protect the heart from wall rupture. However, its progression increases heart stiffness, eventually causing a decrease in heart contractility. Unfortunately, to date, no efficient antifibrotic therapies are available to the clinic. This is primarily due to the complexity of the process, which involves several cell types and signaling pathways. For instance, the transforming growth factor beta (TGF-β) signaling pathway has been recognized to be vital for myofibroblasts activation and fibrosis progression. In this context, complex sphingolipids, such as ganglioside GM3, have been shown to be directly involved in TGF-β receptor 1 (TGF-R1) activation. In this work, we report that an induced up-regulation of sialidase Neu3, a glycohydrolytic enzyme involved in ganglioside cell homeostasis, can significantly reduce cardiac fibrosis in primary cultures of human cardiac fibroblasts by inhibiting the TGF-β signaling pathway, ultimately decreasing collagen I deposition. These results support the notion that modulating ganglioside GM3 cell content could represent a novel therapeutic approach for cardiac fibrosis, warranting for further investigations.

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Exploring the Roles of Fecundity-related mRNAs and Long Non-coding RNAs in the Adrenal Glands of Small-tailed Han Sheep

10.21203/rs.2.15698/v1 ◽

2019 ◽

Author(s):

Qing Xia ◽

Qiuling Li ◽

Shangquan Gan ◽

Xiaofei Guo ◽

Xiaosheng Zhang ◽

...

Keyword(s):

Adrenal Gland ◽

Signaling Pathways ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Target Genes ◽

Transforming Growth Factor ◽

Differentially Expressed ◽

Mitogen Activated Protein Kinase ◽

Gene Expressions ◽

Non Coding Rnas

Abstract Background Long non-coding RNAs (lncRNAs) can play important roles in uterine and ovarian functions. However, little researches have been done on the role of lncRNAs in the adrenal gland of sheep. Herein, RNA sequencing was used to compare and analyze gene expressions in adrenal tissues between FecB ++ (WW) and FecB BB (MM) sheep in the follicular and luteal phases and key lncRNAs and genes associated with reproduction were identified.Results In MM sheep, 38 lncRNAs and 545 mRNAs were differentially expressed in the adrenal gland between the luteal and follicular phases; In WW sheep, 30 differentially expressed lncRNAs and 210 mRNAs were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that differentially expressed lncRNAs and their target genes are mainly involved in the circadian rhythm, the mitogen activated protein kinase, thyroid, ovarian steroidogenesis and transforming growth factor beta signaling pathways. Key lncRNAs can regulate reproduction by modulating genes involved in these signaling pathways and biological processes. Specifically, XLOC_254761 , XLOC_357966 , 105614839 and XLOC_212877 targeting CREB1 , PER3 , SMAD1 and TGFBR2 , respectively, appear to play key regulatory roles.Conclusion These results broaden our understanding of lncRNAs in adrenal gland of sheep and provide new insights into the molecular mechanisms underlying sheep reproduction.

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Infarct Collagen Topography Regulates Fibroblast Fate via p38-Yes-Associated Protein Transcriptional Enhanced Associate Domain Signals

Circulation Research ◽

10.1161/circresaha.119.316162 ◽

2020 ◽

Vol 127 (10) ◽

pp. 1306-1322

Author(s):

Darrian Bugg ◽

Ross Bretherton ◽

Peter Kim ◽

Emily Olszewski ◽

Abigail Nagle ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Phenotypic Diversity ◽

Cardiac Fibroblasts ◽

Focal Adhesions ◽

Cardiac Fibroblast ◽

Stress Fibers ◽

Mouse Heart ◽

Myofibroblast Differentiation ◽

Collagen Organization

Rationale: Myocardial infarction causes spatial variation in collagen organization and phenotypic diversity in fibroblasts, which regulate the heart’s ECM (extracellular matrix). The relationship between collagen structure and fibroblast phenotype is poorly understood but could provide insights regarding the mechanistic basis for myofibroblast heterogeneity in the injured heart. Objective: To investigate the role of collagen organization in cardiac fibroblast fate determination. Methods and Results: Biomimetic topographies were nanofabricated to recapitulate differential collagen organization in the infarcted mouse heart. Here, adult cardiac fibroblasts were freshly isolated and cultured on ECM topographical mimetics for 72 hours. Aligned mimetics caused cardiac fibroblasts to elongate while randomly organized topographies induced circular morphology similar to the disparate myofibroblast morphologies measured in vivo. Alignment cues also induced myofibroblast differentiation, as >60% of fibroblasts formed αSMA (α-smooth muscle actin) stress fibers and expressed myofibroblast-specific ECM genes like Postn (periostin). By contrast, random organization caused 38% of cardiac fibroblasts to express αSMA albeit with downregulated myofibroblast-specific ECM genes. Coupling topographical cues with the profibrotic agonist, TGFβ (transforming growth factor beta), additively upregulated myofibroblast-specific ECM genes independent of topography, but only fibroblasts on flat and randomly oriented mimetics had increased percentages of fibroblasts with αSMA stress fibers. Increased tension sensation at focal adhesions induced myofibroblast differentiation on aligned mimetics. These signals were transduced by p38-YAP (yes-associated protein)-TEAD (transcriptional enhanced associate domain) interactions, in which both p38 and YAP-TEAD (yes-associated protein transcriptional enhanced associate domain) binding were required for myofibroblast differentiation. By contrast, randomly oriented mimetics did not change focal adhesion tension sensation or enrich for p38-YAP-TEAD interactions, which explains the topography-dependent diversity in fibroblast phenotypes observed here. Conclusions: Spatial variations in collagen organization regulate cardiac fibroblast phenotype through mechanical activation of p38-YAP-TEAD signaling, which likely contribute to myofibroblast heterogeneity in the infarcted myocardium.

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