scholarly journals Protective effects of sodium butyrate on rotavirus inducing endoplasmic reticulum stress-mediated apoptosis via PERK-eIF2α signaling pathway in IPEC-J2 cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ye Zhao ◽  
Ningming Hu ◽  
Qin Jiang ◽  
Li Zhu ◽  
Ming Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protective Effect ◽  
Er Stress ◽  
Signaling Pathway ◽  
Sodium Butyrate ◽  
Cell Apoptosis ◽  
Specific Inhibitor ◽  
Initiation Factor ◽  
Intestinal Damage ◽  
Protective Effects

Abstract Background Rotavirus (RV) is a major pathogen that causes severe gastroenteritis in infants and young animals. Endoplasmic reticulum (ER) stress and subsequent apoptosis play pivotal role in virus infection. However, the protective mechanisms of intestinal damage caused by RV are poorly defined, especially the molecular pathways related to enterocytes apoptosis. Thus, the aim of this study was to investigate the protective effect and mechanism of sodium butyrate (SB) on RV-induced apoptosis of IPEC-J2 cells. Results The RV infection led to significant cell apoptosis, increased the expression levels of ER stress (ERS) markers, phosphorylated protein kinase-like ER kinase (PERK), eukaryotic initiation factor 2 alpha (eIF2α), caspase9, and caspase3. Blocking PERK pathway using specific inhibitor GSK subsequently reversed RV-induced cell apoptosis. The SB treatment significantly inhibited RV-induced ERS by decreasing the expression of glucose regulated protein 78 (GRP78), PERK, and eIF2α. In addition, SB treatment restrained the ERS-mediated apoptotic pathway, as indicated by downregulation of C/EBP homologous protein (CHOP) mRNA level, as well as decreased cleaved caspase9 and caspase3 protein levels. Furthermore, siRNA-induced GPR109a knockdown significantly suppressed the protective effect of SB on RV-induced cell apoptosis. Conclusions These results indicate that SB exerts protective effects against RV-induced cell apoptosis through inhibiting ERS mediated apoptosis by regulating PERK-eIF2α signaling pathway via GPR109a, which provide new ideas for the prevention and control of RV.

scholarly journals Protective Effects of Sodium Butyrate on Rotavirus Inducing Endoplasmic Reticulum Stress-Mediated Apoptosis Via PERK-eIF2α Signaling Pathway in IPEC-J2 Cells

2020 ◽  
Author(s):  
Ye Zhao ◽  
Ningming Hu ◽  
Qin Jiang ◽  
Li Zhu ◽  
Ming Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protective Effect ◽  
Er Stress ◽  
Signaling Pathway ◽  
Sodium Butyrate ◽  
Cell Apoptosis ◽  
Initiation Factor ◽  
Intestinal Damage ◽  
Dependent Manner ◽  
Protective Effects

Abstract Background: Rotavirus (RV) is an important pathogens that causes severe gastroenteritis in infants and young animals. Endoplasmic reticulum (ER) stress and subsequent apoptosis played pivotal role in virus infection. However, the protective mechanisms of intestinal damage caused by RV are poorly defined, especially the molecular pathways related to enterocytes apoptosis. Thus, the aim of this study was to investigate the protective effect and mechanism of sodium butyrate (SB) on RV-induced apoptosis of IPEC-J2 cells. Results: The RV infection led to significant cell apoptosis, increased the expression levels of ER stress (ERS) markers, phosphorylated protein kinase-like ER kinase (PERK), phosphorylated eukaryotic initiation factor 2 alpha (eIF2α), caspase9, and caspase3. Blocking PERK pathway using specific inhibitor GSK subsequently reversed RV-induced cell apoptosis. The SB treatment significantly inhibited RV-induced ERS by decreasing the expression of glucose regulated protein 78 (GRP78), PERK, and eIF2α. In addition, SB treatment restrained the ERS-mediated apoptotic pathway, as indicated by downregulation of C/EBP homologous protein (CHOP), as well as decreased cleaved caspase 9 and 3. Furthermore, siRNA-induced GPR109a knockdown significantly suppressed the protective effect of SB on RV-induced cell apoptosis. Conclusion: Taken together, these findings revealed that SB exerts protective effects against RV-induced cell apoptosis through inhibiting ERS mediated apoptosis via PERK-eIF2α signaling pathway in a GPR109a-dependent manner, which provide new ideas for the prevention and control of RV.

scholarly journals Tunicamycin-Induced Endoplasmic Reticulum Stress Promotes Breast Cancer Cell MDA-MB-231 Apoptosis through Inhibiting Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Zhongsheng You ◽  
Linkang He ◽  
Nianlong Yan
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Triple Negative ◽  
Basic Mechanism ◽  
Chemotherapy Treatment ◽  
Related Proteins

Triple negative breast cancer (TNBC) has significantly threatened human health. Many aspects of TNBC are closely related to Wnt/β-catenin pathway, and cell apoptosis induced by endoplasmic reticulum stress (ER stress) in TNBC may act as a potential target of non-chemotherapy treatment. However, how ER stress interacts with this pathway in TNBC has not yet been understood. Here, the tunicamycin and LiCl have been applied to MDA-MB-231. The related proteins’ expression was measured by western blotting. Moreover, acridine orange/ethidium bromide (AO/EB) staining was applied to test the apoptosis degree of the cells, and cell viability was tested by MTT experiment. Then, we found the ER stress and apoptosis degree of MDA-MB-231 were induced after treatment with tunicamycin. Besides, tunicamycin dose dependently inhibited both Wnt/β-catenin pathway and cells viability. Licl, an activator of Wnt/β-catenin signaling pathway, could significantly inhibit cell apoptosis. In conclusion, our study found that the activation of ER stress could promote the MDA-MB-231 apoptosis by repressing Wnt/β-catenin pathway, which provides some promising prospects and basic mechanism to the further research.

A novel secretagogin/ATF4 pathway is involved in oxidized LDL-induced endoplasmic reticulum stress and islet β-cell apoptosis

2020 ◽  
Author(s):  
Li Wu ◽  
Yuncheng Lv ◽  
Ying Lv ◽  
Sunmin Xiang ◽  
Zhibo Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Initiation Factor ◽  
Β Cells ◽  
Β Cell ◽  
Immunoprecipitation Assay ◽  
Min6 Cells ◽  
Stress Markers

Abstract Excessive accumulation of cholesterol in β cells initiates endoplasmic reticulum (ER) stress and associated apoptosis. We have reported that excessive uptake of cholesterol by MIN6 cells decreases the expression of secretagogin (SCGN) and then attenuates insulin secretion. Here, we aimed to determine whether cholesterol-induced SCGN decrease is involved in the modulation of ER stress and apoptosis in pancreatic β cells. In this study, MIN6 cells were treated with oxidized low-density lipoprotein (ox-LDL) for 24 h, and then intracellular lipid droplets and cell apoptosis were quantified, and SCGN and ER stress markers were identified by western blot analysis. Furthermore, small interfer RNA (siRNA)-mediated SCGN knockdown and recombinant plasmid-mediated SCGN restoration experiments were performed to confirm the role of SCGN in ER stress and associated cell apoptosis. Finally, the interaction of SCGN with ATF4 was computationally predicted and then validated by a co-immunoprecipitation assay. We found that ox-LDL treatment increased the levels of ER stress markers, such as phosphorylated protein kinase-like endoplasmic reticulum kinase, phosphorylated eukaryotic initiation factor 2 alpha, activating transcription factor 4 (ATF4), and transcription factor CCAAT-enhancer-binding protein homologous protein, and promoted MIN6 cell apoptosis; in addition, the expression of SCGN was downregulated. siRNA-mediated SCGN knockdown exacerbated β-cell ER stress by increasing ATF4 expression. Pretreatment of MIN6 cells with the recombinant SCGN partly antagonized ox-LDL-induced ER stress and apoptosis. Furthermore, a co-immunoprecipitation assay revealed an interaction between SCGN and ATF4 in MIN6 cells. Taken together, these results demonstrated that pancreatic β-cell apoptosis induced by ox-LDL treatment can be attributed, in part, to an SCGN/ATF4-dependent ER stress response.

scholarly journals Protective Effect of Enalapril against Methionine-Enriched Diet-Induced Hypertension: Role of Endoplasmic Reticulum and Oxidative Stress

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Yanfen Zhou ◽  
Lianyou Zhao ◽  
Zhimin Zhang ◽  
Xuanhao Lu
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Protective Effect ◽  
Er Stress ◽  
Pathological Condition ◽  
Initiation Factor ◽  
Activating Transcription Factor 3 ◽  
Tbars Level ◽  
Induced Hypertension ◽  
And Oxidative Stress

In the present study, we investigated the effect of methionine-enriched diet (MED) on blood pressure in rats and examined the protective effect of enalapril, a widely used angiotensin converting enzyme inhibitors (ACEi) class antihypertensive drug. The results showed that MED induced significant increase of SBP and Ang II-induced contractile response in aortae of rats. MED significantly increased plasma levels of homocysteine (Hcy) and ACE. In addition, MED increased the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2 (eIF2α) and expression of activating transcription factor 3 (ATF3) and ATF6 in aortae of rats, indicating the occurrence of endoplasmic reticulum (ER) stress. Moreover, MED resulted in oxidative stress as evidenced by significant increase of TBARS level and decrease of superoxide dismutase and catalase activities. Administration of enalapril could effectively inhibit these pathological changes induced by MED in rats. These results demonstrated that ACE-mediated ER stress and oxidative stress played an important role in high Hcy-induced hypertension and MED may exert a positive loop between the activation of ACE and accumulation of Hcy, aggravating the pathological condition of hypertension. The data provide novel insights into the mechanism of high Hcy-associated hypertension and the therapeutic efficiency of enalapril.

scholarly journals Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Feng Liao ◽  
Yang Zheng ◽  
Junyan Cai ◽  
Jinghui Fan ◽  
Jing Wang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Receptor Antagonist ◽  
Acetylcholine Receptor ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia ◽  
Protective Effects ◽  
Muscarinic Acetylcholine

Abstract Catestatin (CST) is a catecholamine secretion inhibiting peptide as non-competitive inhibitor of nicotinic acetylcholine receptor. CST play a protective role in cardiac ischemia/reperfusion (I/R) but the molecular mechanism remains unclear. Cardiomyocytes endogenously produced CST and its expression was reduced after I/R. CST pretreatment decreased apoptosis especially endoplasmic reticulum (ER) stress response during I/R. The protection of CST was confirmed in H9c2 cardiomyoblasts under Anoxia/reoxygenation (A/R). In contrast, siRNA-mediated knockdown of CST exaggerated ER stress induced apoptosis. The protective effects of CST were blocked by extracellular signal-regulated kinases 1/2 (ERK1/2) inhibitor PD90895 and phosphoinositide 3-kinase (PI3 K) inhibitor wortmannin. CST also increased ERK1/2 and protein kinase B (Akt) phosphorylation and which was blocked by atropine and selective type 2 muscarinic acetylcholine (M2) receptor, but not type 1 muscarinic acetylcholine (M1) receptor antagonist. Receptor binding assay revealed that CST competitively bound to the M2 receptor with a 50% inhibitory concentration of 25.7 nM. Accordingly, CST inhibited cellular cAMP stimulated by isoproterenol or forskolin and which was blocked by selective M2 receptor antagonist. Our findings revealed that CST binds to M2 receptor, then activates ERK1/2 and PI3 K/Akt pathway to inhibit ER stress-induced cell apoptosis resulting in attenuation cardiac I/R injury.

scholarly journals Endoplasmic Reticulum Stress Cooperates in Silica Nanoparticles-Induced Macrophage Apoptosis via Activation of CHOP-Mediated Apoptotic Signaling Pathway

2019 ◽  
Vol 20 (23) ◽  
pp. 5846 ◽  
Author(s):  
Fenglei Chen ◽  
Jiaqi Jin ◽  
Jiahui Hu ◽  
Yujing Wang ◽  
Zhiyu Ma ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Raw 264.7 ◽  
Apoptotic Signaling ◽  
Macrophage Cells ◽  
Raw 264.7 Macrophage ◽  
Raw 264.7 Macrophage Cells

While silica nanoparticles (SiNPs) have wide applications, they inevitably increase atmospheric particulate matter and human exposure to this nanomaterial. Numerous studies have focused on how to disclose SiNP toxicity and on understanding its toxic mechanisms. However, there are few studies in the literature reporting the interaction between endoplasmic reticulum (ER) stress and SiNP exposure, and the corresponding detailed mechanisms have not been clearly determined. In this study, CCK-8 and flow cytometry assays demonstrated that SiNPs gradually decreased cell viability and increased cell apoptosis in RAW 264.7 macrophage cells in dose- and time-dependent manners. Western blot analysis showed that SiNPs significantly activated ER stress by upregulating GRP78, CHOP, and ERO1α expression. Meanwhile, western blot analysis also showed that SiNPs activated the mitochondrial-mediated apoptotic signaling pathway by upregulating BAD and Caspase-3, and downregulating the BCL-2/BAX ratio. Moreover, 4-phenylbutyrate (4-PBA), an ER stress inhibitor, significantly decreased GRP78, CHOP, and ERO1α expression, and inhibited cell apoptosis in RAW 264.7 macrophage cells. Furthermore, overexpression of CHOP significantly enhanced cell apoptosis, while knockdown of CHOP significantly protected RAW 264.7 macrophage cells from apoptosis induced by SiNPs. We found that the CHOP-ERO1α-caspase-dependent apoptotic signaling pathway was activated by upregulating the downstream target protein ERO1α and caspase-dependent mitochondrial-mediated apoptotic signaling pathway by upregulating Caspase-3 and downregulating the ratio of BCL-2/BAX. In summary, ER stress participated in cell apoptosis induced by SiNPs and CHOP regulated SiNP-induced cell apoptosis, at least partly, via activation of the CHOP-ERO1α-caspase apoptotic signaling pathway in RAW 264.7 macrophage cells.

scholarly journals NEFA Promotes Autophagosome Formation through Modulating PERK Signaling Pathway in Bovine Hepatocytes

Animals ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 3400
Author(s):  
Yan Huang ◽  
Chenxu Zhao ◽  
Yaoquan Liu ◽  
Yezi Kong ◽  
Panpan Tan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Metabolic Stress ◽  
Perinatal Period ◽  
High Plasma ◽  
Negative Energy ◽  
Initiation Factor ◽  
Sequestosome 1

During the perinatal period, the abnormally high plasma non-esterified fatty acids (NEFA) concentration caused by the negative energy balance (NEB) can impose a significant metabolic stress on the liver of dairy cows. Endoplasmic reticulum (ER) stress is an important adaptive response that can serve to maintain cell homeostasis in the event of stress. The protein kinase R-like endoplasmic reticulum kinase (PERK) pathway is the most rapidly activated cascade when ER stress occurs in cells and has an important impact on the regulation of hepatic lipid metabolism and autophagy modulation. However, it is unknown whether NEFA can affect autophagy through modulating the PERK pathway, under NEB conditions. In this study, we provide evidence that NEFA treatment markedly increased lipid accumulation, the phosphorylation level of PERK and eukaryotic initiation factor 2α (eIF2α), and the expression of glucose-regulated protein 78 (Grp78), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). More importantly, NEFA treatment can cause a substantial increase in the protein levels of autophagy-related gene 7 (ATG7), Beclin-1 (BECN1), sequestosome-1 (p62), and microtubule-associated protein 1 light chain 3 (LC3)-II, and in the number of autophagosomes in primary bovine hepatocytes. The addition of GSK2656157 (PERK phosphorylation inhibitor) can significantly inhibit the effect of NEFA on autophagy and can further increase lipid accumulation. Overall, our results indicate that NEFA could promote autophagy via the PERK pathway in bovine hepatocytes. These findings provide novel evidence about the potential role of the PERK signaling pathway in maintaining bovine hepatocyte homeostasis.

scholarly journals Dihydromyricetin alleviates endothelial inflammatory response through IRE1α/NF-κB signaling pathway in sepsis

2021 ◽  
Author(s):  
Xifeng Wang ◽  
Xiaomin Xu ◽  
Yu peng Yang ◽  
Xin Xin ◽  
Zekang Li ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Inflammatory Response ◽  
Er Stress ◽  
Signaling Pathway ◽  
Umbilical Vein ◽  
Cecal Ligation ◽  
Protective Effects ◽  
Necrosis Factor Alpha

IntroductionThe high mortality of sepsis is closely related to disorder of coagulation induced by endothelial inflammatory response. Our aim is to investigate the protective effects of Dihydromyricetin (DHM) on endothelial cells in sepsis and the endoplasmic reticulum (ER) stress mechanism.Material and methodsIn vivo, we conducted an animal study for which fifty male Wistar rats were randomly and equally divided into five groups: sham group, cecal ligation and puncture (CLP) group and three CLP+ DHM (50, 100, 150 mg/kg) groups, the DHM was orally administered 2 h after CLP for 3 days (once per day). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with DHM (50μmol) for 24 h after stimulation by lipopolysaccharide (LPS). In the inhibition groups, reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC, 3 mmol) and endoplasmic reticulum (ER) stress inhibitor (STF-083010, 10 μmol) were incubated prior to LPS.ResultsOur results indicated that DHM (150 mg/kg) alleviated the histopathological injury of endothelium, decreased the release of inflammatory cytokines and adhesion molecules such as interleukin-1β (IL-1β), interleukin-6 (IL-6) , tumor necrosis factor alpha (TNF-α), vascular cell adhesion molecule 1 (VCAM-1) and endothelin-1 (ET-1), and inhibited the production of ROS production. In addition, we found that DHM ameliorated ER damage, significantly decreased the protein expressions of IRE1α/NF-κB signaling pathway.ConclusionsDHM treatment alleviated inflammatory response of endothelial cells in sepsis through the IRE1α/NF-κB signaling pathway triggered by oxidative stress. This study provided experimental rationale for the treatment of DHM on therapy of sepsis.

Protective effect of hydrogen against ischemia-reperfusion induced spinal nerve cell apoptosis

2021 ◽  
Author(s):  
Yanqing Sun ◽  
Wei Shi ◽  
Bo Yuan ◽  
Zhiwei Wang ◽  
Shengyuan Zhou ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protective Effect ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Pc12 Cells ◽  
Pc12 Cell ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Ischemia Reperfusion ◽  
Caspase 12

Abstract Background: This study aims to explore the protective effect of hydrogen against oxygen-glucose-serum deprivation/restoration (OGSD/R)-induced PC12 cell apoptosis in vitro and the possible underlying mechanism. Methods: A normal control (NC) group was set where PC12 cells were cultured normal, while a positive control (PC) group, where PC12 cells were exposed to OGSD 12h/R1h without intervention, and a hydrogen intervention (HI) group, where PC12 cells were exposed to OGSD 12h/R1h plus HI, were conducted at the same time. At OGSD 12h/R 1h, cells were DAPI stained to detect viability and changes in the expression of apoptosis-associated proteins caspase-3, caspase-12 and CHOP/GADD153, and the endoplasmic reticulum-related signaling pathway protein PERK-eIF2α-ATF4. At the same time, the effect of HI was observed. Results: The result revealed that compared with NC group, cell apoptosis was more severe and cell viability was reduced significantly in PC group, while cell apoptosis was ameliorated and cell viability was increased significantly in HI as compared with PC group. In addition, the content of caspase-3 and caspase-12 in HI group was decreased significantly as compared with that in PC group. During this process, the endoplasmic reticulum-related signaling pathway protein PERK-eIF2α-ATF4 was activated. In HI group, the expression of this protein was decreased and cell viability was increased significantly as compared with those in PC group. Conclusions: Hydrogen was able to inhibit OGSD/R-induced PC12 cell apoptosis and exert a protective effect against ischemia-repurfusion injury (IRI) to nerve cells, probably through inhibiting the endoplasmic reticulum-related signaling pathway protein.

Inhibition of PERK-dependent pro-adaptive signaling pathway as a promising approach for cancer treatment

2017 ◽  
Vol 89 (3) ◽  
pp. 7-10 ◽  
Author(s):  
Wioletta Rozpędek ◽  
Dariusz Pytel ◽  
Łukasz Dziki ◽  
Alicja Nowak ◽  
Adam Dziki ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Small Molecule ◽  
Colorectal Adenocarcinoma ◽  
Initiation Factor ◽  
Human Neuroblastoma ◽  
Ht 29

Endoplasmic Reticulum (ER) is an organelle that is vital for cell growth and maintenance of homeostasis. Recent studies have reported that numerous human diseases, including cancer, are strictly connected to disruption of ER homeostasis. In order to counteract adverse intracellular conditions, cancer cells induce protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-dependent, pro-adaptive unfolded protein response (UPR) signaling branches. If ER stress is severe or prolonged, pro-adaptive signaling networks are insufficient, resulting in apoptotic cell death of cancer cells. The main aim: of the study was to evaluate the biological activity of a small-molecule PERK inhibitor GSK2606414 in two cancer cell lines - human neuroblastoma (SH-SY5Y) and human colorectal adenocarcinoma (HT-29) cell lines. We analyzed the level of phosphorylation of the eukaryotic initiation factor 2 (eIF2), which is the main substrate of PERK and a subsequent activator of UPR, which under long-term ER stress may evoke apoptotic death of cancer cells. Material and methods: In the study, we utilized commercially available cell lines of human colorectal adenocarcinoma HT-29 and human neuroblastoma SH-SY5Y. Cells were exposed to the tested PERK-dependent signaling inhibitor GSK2606414 in suitable culture media with addition of thapsigargin (500 nM) to induce ER stress. To identify the protein, Western blot with specific antibodies was used. Detection of immune complexes was performed using chemiluminescence. Results: We found a complete inhibition of p-eIF2α expression due to the GSK2606414 inhibitor in both cell lines, SH-SY5Y and HT-29. Conclusions: Currently available cancer treatments are insufficient and cause various side effects. It has been assumed that utilization of small-molecule inhibitors of the PERK-dependent signaling pathway, like GSK2606414, may switch the pro-adaptive branch of UPR to its pro-apoptotic branch. It is believed that the tested inhibitor GSK2606414 may become a promising treatment for many cancer types.

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