scholarly journals MyD88 and Trif Signaling Play Distinct Roles in Cardiac Dysfunction and Mortality during Endotoxin Shock and Polymicrobial Sepsis

2011 ◽  
Vol 115 (3) ◽  
pp. 555-567 ◽  
Author(s):  
Yan Feng ◽  
Lin Zou ◽  
Ming Zhang ◽  
Yan Li ◽  
Chan Chen ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Critical Role ◽  
Endotoxin Shock ◽  
Left Ventricular ◽  
Polymicrobial Sepsis ◽  
Wild Type ◽  
Endotoxin Challenge ◽  
Cardiac Depression ◽  
Cecum Ligation ◽  
Myeloid Differentiation Factor

Background Toll-like receptors (TLRs) such as TLR2, TLR4, and TLR9 contribute to the pathogenesis of polymicrobial sepsis. These TLRs signal via the common myeloid differentiation factor 88 (MyD88)-dependent pathways. TLR4 also signals through MyD88-independent but TIR domain-containing adaptor inducing interferon-β-mediated transcription factor (Trif)-dependent pathway. The role of the two signaling pathways in cardiac dysfunction during polymicrobial sepsis and endotoxin shock is unknown. Methods Sepsis was generated by cecum ligation and puncture. Mice were divided into sham and cecum ligation and puncture groups or subjected to saline or endotoxin. Left ventricular function was assessed in a Langendorff apparatus or by echocardiography. Cytokines were examined using a multiplex immunoassay. Neutrophil migratory and phagocytic functions were assessed using flow cytometry. Results In comparison with wild-type mice, MyD88(-/-) but not Trif(-/-) mice had markedly improved cardiac function and survival after cecum ligation and puncture. In comparison, both MyD88(-/-) and Trif(-/-) mice were protected from cardiac depression and mortality during endotoxin shock. Septic MyD88(-/-) but not Trif(-/-) mice had diminished cytokine production in serum and in peritoneal space in comparison with wild-type mice after cecum ligation and puncture. In contrast, both MyD88(-/-) and Trif(-/-) mice had attenuated serum cytokines in comparison with wild-type mice after endotoxin challenge. Neither MyD88(-/-) nor Trif(-/-) signaling had any effect on neutrophil phagocytic function or bacterial clearance at 24 h of polymicrobial sepsis. Conclusions These studies establish that MyD88 but not Trif signaling plays a critical role in mediating cardiac dysfunction, systemic inflammation, and mortality during polymicrobial sepsis. Both MyD88 and Trif are essential for cardiac depression and mortality during endotoxin shock.

scholarly journals Role of Cardiac- and Myeloid-MyD88 Signaling in Endotoxin Shock

2014 ◽  
Vol 121 (6) ◽  
pp. 1258-1269 ◽  
Author(s):  
Yan Feng ◽  
Lin Zou ◽  
Chan Chen ◽  
Dan Li ◽  
Wei Chao
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Endotoxin Shock ◽  
Endotoxin Challenge ◽  
Cardiac Inflammation ◽  
Gene And Protein Expression ◽  
Myd88 Signaling ◽  
Myeloid Differentiation Factor ◽  
Oxide Synthase

Abstract Background: Myeloid differentiation factor 88 (MyD88) is an adaptor molecule critical for host innate immunity. Studies have shown that signaling via MyD88 contributes to cytokine storm, cardiac dysfunction, and high mortality during endotoxin shock. However, the specific contribution of MyD88 signaling of immune and cardiac origins to endotoxin shock remains unknown. Methods: Tissue-specific MyD88 deletion models: Cre-recombinase transgenic mice with α-myosin heavy chain (α-MHC) or lysozyme M promoters were cross-bred with MyD88-loxP (MyD88fl/fl) mice, respectively, to generate cardiomyocyte- (α-MHC-MyD88−/−) or myeloid-specific (Lyz-MyD88−/−) MyD88 deletion models and their respective MyD88fl/fl littermates. Endotoxin shock model: Mice were subjected to 15 mg/kg lipopolysaccharide (intraperitoneal injection). Cardiac function was measured by echocardiography and cytokines by multiplex assay and quantitative reverse transcription-polymerase chain reaction. Results: α-MHC-MyD88−/− mice had 61 and 87% reduction in MyD88 gene and protein expression in cardiomyocytes, respectively, whereas Lyz-MyD88−/− had 73 and 67% decrease, respectively, in macrophages (n = 3 per group). After lipopolysaccharide treatment, the two groups of MyD88fl/fl littermates had 46% (n = 10) and 60% (n = 15) of mortality, respectively. Both α-MHC-MyD88−/− and Lyz-MyD88−/− mice had markedly improved survival. Compared with the MyD88fl/fl littermates, Lyz-MyD88−/− mice had warmer body temperature, attenuated systemic and cardiac inflammatory cytokine production, and significantly improved cardiac function, whereas α-MHC-MyD88−/− mice had decreased myocardial inducible nitric oxide synthase induction and modestly preserved cardiac function. Conclusions: Both cardiomyocyte- and myeloid-MyD88 signaling play a role in cardiac dysfunction and mortality during endotoxin shock. Myeloid-MyD88 signaling plays a predominant role in systemic and cardiac inflammation after endotoxin challenge.

Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH

2002 ◽  
Vol 282 (2) ◽  
pp. H726-H733 ◽  
Author(s):  
Nina B. Radford ◽  
Bang Wan ◽  
Angela Richman ◽  
Lidia S. Szczepaniak ◽  
Jia-Ling Li ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Cardiac Dysfunction ◽  
Mechanical Performance ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Stroke Work ◽  
Wild Type ◽  
Oxidase Subunit ◽  
End Diastolic Volume

Cytochrome -c oxidase subunit VIaH (COXVIaH) has been implicated in the modulation of COX activity. A gene-targeting strategy was undertaken to generate mice that lacked COXVIaH to determine its role in regulation of oxidative energy production and mechanical performance in cardiac muscle. Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered assembly of the holoenzyme COX. However, total myocardial ATP was not significantly different in wild-type and mutant mice. Myocardial performance was examined using the isolated working heart preparation. As left atrial filling pressure increased, hearts from mutant mice were unable to generate equivalent stroke work compared with hearts from wild-type mice. Direct measurement of left ventricular end-diastolic volume using magnetic resonance imaging revealed that cardiac dysfunction was a consequence of impaired ventricular filling or diastolic dysfunction. These findings suggest that a genetic deficiency of COXVIaH has a measurable impact on myocardial diastolic performance despite the presence of normal cellular ATP levels.

Abstract P050: Novel Mechanism of Ser-496 ERK5 Phosphorylation and Association with p90RSK Is Critical for Regulating C Terminus of Hsc70-Interacting Protein (CHIP) Ubiquitin E3 Ligase Activity in Diabetes-Mediated Exacerbation of Cardiomyocyte Apoptosis and Left Ventricular Dysfunction After Myocardial Infarction

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Nhat-Tu Le ◽  
Yuichiro Takei ◽  
Chang-Hoon Woo ◽  
Tetsuro Shishido ◽  
Yan Lu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Active Form ◽  
E3 Ligase ◽  
Left Ventricular ◽  
Ang Ii ◽  
Lv Dysfunction ◽  
On Chip

Rationale: Cardiac dysfunction is accelerated in DM patients after MI. Previously, we reported the critical role of ERK5 and CHIP association on CHIP Ub E3 ligase activity, which inhibits inducible cAMP early repressor (ICER)-mediated apoptosis and left ventricle (LV) dysfunction after MI in DM (DM + MI). Yet the regulatory mechanism of ERK5-CHIP has not been established. Objective: Since we found that p90RSK activation was increased in DM heart, we investigated whether p90RSK activation may inhibit ERK5-mediated CHIP activation, and subsequent ICER induction and apoptosis. Methods and Results: The inhibition of p90RSK activation prevented the reduction of ERK5-CHIP binding, CHIP activity, as well as ICER induction and cardiac apoptosis both in vitro after angiotensin II (ang II) stimulation and in vivo after DM + MI. p90RSK and CHIP share a same binding site with ERK5 C-terminal domain (aa571–807), and overexpression of both p90RSK and ERK5 (aa571–807) fragment, but not kinase dead mutant of p90RSK, inhibited ERK5-CHIP association, suggesting the critical role of p90RSK activation on ERK5-CHIP interaction, and competitive nature of p90RSK and CHIP against ERK5 association. Furthermore. LC-MS/MS analysis identified ERK5-S496 as being directly phosphorylated by p90RSK, and ERK5 S496A mutant significantly impaired ang II-mediated inhibition of CHIP Ub ligase activity, suggesting the critical role of Ser-496 phoaphorylation of ERK5 on CHIP activity. Therefore, p90RSK activation is critical for both p90RSK-ERK5 association as well as ERK5-Ser496 phosphorylation, and following disruption of ERK5-CHIP interaction and subsequent inhibition of CHIP Ub ligase activity. The reduction of CHIP Ub ligase activity and LV dysfunction were accelerated both in cardio-specific ERK5 knock out and wild type p90RSK transgenic mice (WT-p90RSK-Tg). Furthermore, double transgenic mice of WT-p90RSK and constitutively active form of MEK5α (specific ERK5 activator) inhibited single WT-p90RSK-Tg-medaited reduction of CHIP Ub ligase activity, LV dysfunction, and improved mortality after MI. Conclusions: These data strongly suggested that p90RSK activation accelerated cardiac dysfunction and apoptosis after DM + MI via inhibiting ERK5-CHIP module.

scholarly journals Toll-like receptor 2 plays a critical role in cardiac dysfunction during polymicrobial sepsis*

2010 ◽  
Vol 38 (5) ◽  
pp. 1335-1342 ◽  
Author(s):  
Lin Zou ◽  
Yan Feng ◽  
Yu-Jung Chen ◽  
Rui Si ◽  
Shiqian Shen ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Critical Role ◽  
Polymicrobial Sepsis ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2

scholarly journals Circadian mutant mice with obesity and metabolic syndrome are resilient to cardiovascular disease

2020 ◽  
Vol 319 (5) ◽  
pp. H1097-H1111
Author(s):  
Cristine J. Reitz ◽  
Faisal J. Alibhai ◽  
Bruna Gazzi de Lima-Seolin ◽  
Ashley Nemec-Bakk ◽  
Neelam Khaper ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Metabolic Syndrome ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Metabolic Dysfunction ◽  
Wild Type ◽  
High Fat

We examined whether obesity and metabolic syndrome underlie the development of cardiac dysfunction in circadian mutant ClockΔ19/Δ19 mice. Surprisingly, we demonstrate that although ClockΔ19/Δ19 mice develop metabolic dysfunction, they are protected from cardiac hypertrophy, left ventricular remodeling, and diastolic dysfunction, in contrast to wild-type controls, even when challenged with a chronic high-fat diet. These findings shed new light on the circadian regulation of oxidative stress pathways that can mediate resilience to cardiovascular disease.

Abstract 12624: Blockade of Exosome Secretion Attenuates Inflammatory Cytokines, Mitigates Cardiac Dysfunction, and Reduces Mortality in Polymicrobial Sepsis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Xiaohong Wang ◽  
Dongze Qin ◽  
Kobina Essandoh ◽  
Wei Huang ◽  
Liwang Yang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Contractile Function ◽  
Cecal Ligation ◽  
Left Ventricular ◽  
Polymicrobial Sepsis ◽  
Raw 264.7 Cells ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Tnf Α

Introduction: Exosomes, a group of nano-vesicles secreted from living cells, are documented to increase in the circulation and are believed to promote cardiac dysfunction in sepsis patients and animal models. However, whether inhibition of exosome release could exert a cardio-protective effect in polymicrobial sepsis remains unexplored. Methods and Results: C57BL/6 mice (male, 8-week old) were pre-treated with GW4869 (dissolved in DMSO, injection i.p. at a dose of 2.5μg/g body weight), a known inhibitor of exosome secretion. Same volume of DMSO was used as controls. One hour later, cecal ligation and puncture (CLP) surgery was performed to induce polymicrobial sepsis. We found that the concentration of serum exosomes, measured by membrane markers CD63 and CD81with detection ELISA kits, was increased by 3.5-fold in DMSO-CLP mice, but no increase was detected in GW4869-CLP mice or in sham operated mice (n=4-6, p<0.01). Myocardial contractile function, assessed at 12h post-CLP using a SONOS-7500 echocardiography system, revealed that pre-injection of GW4869 significantly attenuated CLP-associated cardiac dysfunction, evidenced by an improved left ventricular ejection fraction (LVEF) and minor axis fractional shortening (LVFS), compared to DMSO controls (n=8-10, p<0.01). Myeloperoxidase (MPO) activity, a marker of myocardial inflammation, measured with a [[Unable to Display Character: &#64258;]]uorometric assay kit, also showed a significant reduction in GW4869-pre-treated mice, compared to DMSO-controls (n=5, p<0.01). Similarly, serum levels of inflammatory cytokines TNF-α and IL-1β triggered by CLP were reduced by 72% and 61%, respectively in GW4869-treated mice, compared with controls (n=6). Furthermore, we observed that 67% (n=9) of the DMSO controls, but only 20% in GW4869-treated mice (n=10) had died by 48h post-CLP. In vitro study confirmed that GW4869 limited the production of TNF-α and IL-1β in RAW 264.7 cells (a mouse macrophage cell line) challenged with endotoxin (LPS, 1μg/ml, 24 h). Conclusions: Together, this study indicates that blockade of exosome secretion could attenuate the inflammatory cytokine response as well as the consequent cardiac dysfunction and mortality in polymicrobial sepsis. Thus, our study may provide a new approach to the treatment of sepsis.

Abstract 132: The First Mouse Mutants of a Novel Epigenetic Modifier, Rearranged L-Myc Fusion, Display Defects in Heart Development

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Lauren M Bourke ◽  
Sarah Harten ◽  
Vandhana Bharti ◽  
Harry Oey ◽  
Nadia Whitelaw ◽  
...  
Keyword(s):  
Heart Development ◽  
Critical Role ◽  
Interventricular Septum ◽  
Notch Pathway ◽  
Regulatory Elements ◽  
Left Ventricular ◽  
Wild Type ◽  
Ventricular Noncompaction ◽  
Mouse Mutants ◽  
Epigenetic Modifier

Rearranged L-Myc Fusion, Rlf, was recently identified as a novel epigenetic modifier from a mouse N-ethyl-N-nitrosourea mutagenesis screen. The mice used in this study carry a multi-copy green fluorescent protein (GFP) transgene linked to an erythroid specific α-globin promoter that is sensitive to epigenetic silencing. Three independent mouse lines with mutations in Rlf were each found to have a decrease in GFP expression, suggesting Rlf acts an epigenetic modifier. Our study is the first to reveal a role for Rlf in epigenetics. Preliminary phenotyping has found loss of Rlf results in perinatal lethality. Late gestation homozygous null Rlf mutants were found to weigh significantly less than their heterozygous or wild type littermates. Histological analysis of mid gestation embryos has identified a potential heart defect in homozygous mutants. Rlf mutants display a thin compact layer, an overabundance of trabeculae and a fenestrated interventricular septum. The Rlf mutant phenotype is reminiscent of ventricular noncompaction defects observed in humans, such as left ventricular noncompaction cardiomyopathy. RNA-seq analysis of mid gestation Rlf wild type and null hearts, prior to the observation of a cardiac defect, was undertaken to determine which pathways may be regulated by Rlf in the heart. More genes were observed to be significantly down-regulated in Rlf mutant hearts compared to wild types. Pathway analysis of differentially expressed genes showed genes involved in cell-cell adhesion, cell signalling, glycosylation and the Notch pathway were dysregulated. These findings indicate that Rlf may play a critical role in cardiac development. Whole genome bisulphite sequencing of different embryonic tissue/stages has shown loss of Rlf results in an increase in methylation at a large number of distinct loci across the genome. Many of which were found to overlap sites reported to be putative regulatory elements, and histone marks associated with active or poised regulatory elements in the heart. Our data suggest Rlf plays a key role in regulating gene expression pathways during heart development. These are the first mouse mutants available to study how Rlf functions as an epigenetic modifier and the phenotypic consequences of Rlf inactivation.

scholarly journals Syndecan-4 Deficiency Leads to High Mortality of Lipopolysaccharide-injected Mice

2001 ◽  
Vol 276 (50) ◽  
pp. 47483-47488 ◽  
Author(s):  
Kazuhiro Ishiguro ◽  
Kenji Kadomatsu ◽  
Tetsuhito Kojima ◽  
Hisako Muramatsu ◽  
Mitsunori Iwase ◽  
...  
Keyword(s):  
Growth Factor ◽  
High Mortality ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Endotoxin Shock ◽  
Left Ventricular ◽  
Wild Type ◽  
In The Wild ◽  
Deficient Mice ◽  
Fractional Shortening

Syndecan-4 is a transmembrane heparan sulfate proteoglycan belonging to the syndecan family. Following intraperitoneal injection of lipopolysaccharide (LPS), syndecan-4-deficient mice exhibited high mortality compared with wild-type controls. Severe endotoxin shock was observed in the deficient mice: systolic blood pressure and left ventricular fractional shortening were lower in the deficient mice than in the wild-type controls 9 h after LPS injection. Although histological examinations revealed no apparent differences between two groups, the plasma level of interleukin (IL)-1β was higher in the deficient mice than in the wild-type controls 9 h after LPS injection. Consistent with the regulatory roles of syndecan-4, its expression in monocytes and endothelial cells of microvasculature increased in the wild-type mice after LPS administration. Although IL-1β was produced to the same extent by macrophages from syndecan-4-deficient and wild-type mice after LPS stimulation, inhibition of its production by transforming growth factor-β1 was impaired in the syndecan-4-deficient macrophages. These results indicate that syndecan-4 could be involved in prevention of endotoxin shock, at least partly through the inhibitory action of transforming growth factor-β1 on IL-1β production.

scholarly journals Toll-like Receptor 4 Is Essential to Preserving Cardiac Function and Survival in Low-grade Polymicrobial Sepsis

2014 ◽  
Vol 121 (6) ◽  
pp. 1270-1280 ◽  
Author(s):  
Ming Zhang ◽  
Lin Zou ◽  
Yan Feng ◽  
Yu-Jung Chen ◽  
Qichang Zhou ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Polymicrobial Sepsis ◽  
Low Grade ◽  
Oxygen Species ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Cecum Ligation

Abstract Background: Toll-like receptor 4 (TLR4), the receptor for endotoxin, mediates hyperinflammatory response and contributes to high mortality during both endotoxin shock and severe sepsis. However, little is known about the role of TLR4 in the pathogenesis of low-grade polymicrobial sepsis, which is often associated with immunosuppression. Methods: Low-grade polymicrobial sepsis was generated by cecum ligation and puncture. Mortality was monitored in wild- type (C57BL/10ScSn) and TLR4def (C57BL/10ScCr) mice. Ex vivo heart and individual cardiomyocyte function were assessed in Langendorff (Hugo Sachs Elektronik; Harvard Apparatus, Holliston, MA) and IonOptix systems (IonOptix, Milton, MA), respectively. Serum chemistry was tested for liver and kidney injury. Cytokines were examined using a multiplex immunoassay. Neutrophil migratory and phagocytic functions were assessed using flow cytometry. Reactive oxygen species were measured using redox-sensitive dichlorodihydrofluorescein dye. Results: Following cecum ligation and puncture, wild-type mice developed bacterial peritonitis with mild cardiac dysfunction (n = 3 in sham and n = 8 in cecum ligation and puncture) and a mortality of 23% within 14 days (n = 22). In comparison, septic TLR4def mice had deleterious cardiac dysfunction (n = 6 in sham and n = 10 in cecum ligation and puncture), kidney and liver injury (n = 7), and much higher mortality at 81% (n = 21). The deleterious effects observed in septic TLR4def mice were associated with increased local and systemic cytokine response, reduced neutrophil migratory and phagocytic function, increased reactive oxygen species generation in leukocytes, and impaired bacterial clearance. Conclusion: TLR4 plays an essential role in host defense against low-grade polymicrobial sepsis by mediating neutrophil migratory/phagocytic functions, attenuating inflammation, reducing reactive oxygen species generation, and enhanced bacterial clearance.

Abstract WMP77: SUMO1 Plays an Important Role in Cardiac Dysfunction After Intracerebral Hemorrhage in Aged Mice

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Wei Li ◽  
Michael Chopp ◽  
Poornima Venkat ◽  
Zhili Chen ◽  
Alex Zacharek ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Cardiac Dysfunction ◽  
Calcium Binding ◽  
Contractile Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Wild Type ◽  
Neuroprotective Effects ◽  
Ventricular Ejection Fraction ◽  
Aged Mice

Background: The conjugation of the small ubiquitin-like modifier1 (SUMO1) plays an important role in numerous biological processes, including DNA repair and signal transduction. SUMO1 also reduces cardiac oxidative stress and hypertrophy as well as induces neuroprotective effects. Intracerebral hemorrhage (ICH) induces cardiac deficit in the absence of primary cardiac diseases in young adult wild type mice. In this study, we tested the hypothesis that SUMO1 plays a key role in regulating brain-heart interaction after ICH, and SUMO1 deficit leads to worse brain and heart deficit after ICH in aged mice. Methods: Aged (16-20 months) female Sumo1-deficient (SUMO1-/-) mice or wild-type (SUMO1+/+) mice were subjected to ICH by injecting collagenase IV into the basal ganglia. Cardiac function was measured by echocardiography before ICH induction and at 7 days after ICH. Modified neurological severity (mNSS) ,foot-fault and adhesive removal tests were performed at 1, 3, 6 days after ICH to investigate neurological function. Cognitive functional tests (odor and novel objective tests) were performed before sacrificing the mice at 10 days after ICH, and then histological and immunohistochemically staining were used to evaluate the mechanisms. Results: Compared to SUMO1+/+ mice, SUMO1-/- mice did not exhibit significant cardiac deficit before ICH in aged mice. Compared to SUMO1+/+ICH mice, SUMO1-/-ICH mice exhibit significantly (p<0.05) increased: 1) brain hemorrhage volume and induced worse neurological and cognitive deficits, 2) cardiac dysfunction identified by decreased cardiac contractile function measured by left ventricular ejection fraction (LVEF) and fractional shortening (FS); 3) cardiac hypertrophy and fibrosis; 4) ionized calcium binding adaptor molecule (IBA1) positive macrophages/microglia and CD45 positive leukocyte infiltration into both heart and brain tissue. Conclusions: Aged SUMO1 deficient mice subjected to ICH not only exhibit increased neurological and cognitive functional deficit, but also significantly increased cardiac dysfunction and inflammatory cell infiltration into heart. These data suggest that SUMO1 plays an important role in brain-heart interaction and SUMO1 impacts brain-cardiac dysfunction after ICH.

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