scholarly journals Silencing of lipocalin-2 and its receptor improved cardiomyocytes viability via decreasing iron uptake, mitochondrial fission, mitophagy and apoptosis under iron overload condition

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Kumfu ◽  
S.C Chattipakorn ◽  
N Chattipakorn
Keyword(s):  
Calcium Channels ◽  
Iron Overload ◽  
Cell Viability ◽  
Iron Uptake ◽  
Mitochondrial Fission ◽  
Iron Accumulation ◽  
Funding Source ◽  
Lipocalin 2 ◽  
Intracellular Iron ◽  
Beneficial Effects

Abstract Background Iron overload cardiomyopathy is a common cause of death in iron overload patients. L-type calcium channels (LTCC) and T-type calcium channels (TTCC) have been shown to play important roles for iron uptake into the heart under iron overload condition. Recently, cardiomyocytes which exposed to lipocalin-2 (LCN-2) have been shown to increase apoptosis due to excessive intracellular iron accumulation. However, the mechanistic roles of LCN-2 and LCN-2 receptor (LCN-2R) as iron transporters in cardiomyocytes under iron overload condition have never been investigated. Purpose We hypothesized that the LCN-2 and LCN-2R are alternate iron uptake pathways into cardiomyocytes under iron overload condition. Methods H9c2 cardiomyocytes were treated with either LCN-2 siRNA or LCN-2R siRNA for 72 hr or LTCC blocker (verapamil), TTCC blocker (TTA-P2), or iron chelator deferiprone (DFP) for 1 hr. After treatment, cells were exposed to ferric ammonium citrate (FAC, Fe3+) or FAC + 1mM ascorbic acid (Fe2+) at 200 μM for 48 hr. Intracellular iron level, cell viability, mitochondrial dynamics, mitophagy and apoptosis were determined. Results Both Fe2+ and Fe3+ treated groups showed significantly increased intracellular iron uptake, decreased cell viability, increased mitochondrial fission, mitophagy and apoptotic protein expression in cardiomyocytes. Under Fe2+ overload condition, treatments with LTCC blocker, TTCC blocker, and DFP could significantly decrease intracellular iron accumulation and increase cell viability via decreasing mitochondrial fission, mitophagy and cleaved caspase-3 (Figure), whereas both LCN-2 and LCN-2R siRNA treatment had no beneficial effects on these parameters. Under Fe3+ overload condition, treatment with LCN-2 siRNA, LCN-2R siRNA, and DFP showed beneficial effects on those parameters, whereas neither LTCC nor TTCC blocker provided these benefits (Figure 1). Conclusion Silencing of LCN-2 and LCN-2R increased cardiomyocyte viability via decreasing iron uptake, mitochondrial fission, mitophagy and apoptosis under Fe3+ iron overload condition. Meanwhile, treatment with calcium channel blockers improved cardiomyocytes viability via decreasing iron uptake, mitochondrial fission, mitophagy and apoptosis under Fe2+ iron overload condition. All of these findings suggested that LTCC and TTCC played important roles for Fe2+ uptake, whereas LCN-2 and LCN-2R were essential for Fe3+ uptake into the cardiomyocytes under iron overload conditions. Figure 1. Cell viability and apoptosis Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Thailand Research Fund and NSTDA Research Chair Grant (NC)

scholarly journals Dopamine Is a Siderophore-Like Iron Chelator That PromotesSalmonella entericaSerovar Typhimurium Virulence in Mice

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Stefanie Dichtl ◽  
Egon Demetz ◽  
David Haschka ◽  
Piotr Tymoszuk ◽  
Verena Petzer ◽  
...  
Keyword(s):  
Bacterial Growth ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Acquisition ◽  
Lipocalin 2 ◽  
Intracellular Iron ◽  
Content Type ◽  
Hepcidin Expression

ABSTRACTWe have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course ofSalmonellainfections. Dopamine was found to promote the growth ofSalmonellaboth in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected withSalmonella entericaserovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth.Salmonellalacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria.IMPORTANCEHere we show that dopamine increases bacterial iron incorporation and promotesSalmonellaTyphimurium growth bothin vitroandin vivo. These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.

scholarly journals Lipocalin-2 Induces Cardiomyocyte Apoptosis by Increasing Intracellular Iron Accumulation

2011 ◽  
Vol 287 (7) ◽  
pp. 4808-4817 ◽  
Author(s):  
Guoxiong Xu ◽  
JinHee Ahn ◽  
SoYoung Chang ◽  
Megumi Eguchi ◽  
Arnaud Ogier ◽  
...  
Keyword(s):  
Cardiomyocyte Apoptosis ◽  
Iron Accumulation ◽  
Lipocalin 2 ◽  
Intracellular Iron

scholarly journals Metal-Ion Transporter SLC39A14 Is Required for Cardiac Iron Loading in the Hjv Mouse Model of Iron Overload

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 758-758
Author(s):  
Qingli Liu ◽  
Corbin Azucenas ◽  
Bryan Mackenzie ◽  
Mitchell Knutson
Keyword(s):  
Calcium Channels ◽  
Iron Overload ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Knockout Mice ◽  
Iron Uptake ◽  
Nonheme Iron ◽  
Channel Blockers ◽  
Iron Loading ◽  
Cardiac Iron

Abstract Although iron overload-related cardiomyopathy is a leading cause of morbidity and mortality in iron-overload disorders (e.g., thalassemia major and hemochromatosis), the molecular mechanisms that mediate cardiac iron uptake and accumulation are incompletely understood. Previous studies using Slc39a14 knockout mice have revealed that SLC39A14 is required for the uptake of non-transferrin-bound iron (NTBI) by the liver and pancreas and is essential for iron loading of hepatocytes and pancreatic acinar cells. To investigate the requirement for SLC39A14 in cardiac iron accumulation, we generated cardiomyocyte-specific Slc39a14 knockout (Slc39a14 hrt/hrt) mice and crossed them with iron-loading hemojuvelin (Hjv) knockout mice to generate Hjv -/-;Slc39a14 hrt/hrt animals. At 12 and 24 weeks of age, cardiac nonheme iron levels were ~340% higher in Hjv -/- mice than in controls. By contrast, cardiac nonheme iron levels in Hjv -/-;Slc39a14 hrt/hrt mice at these ages were only ~60% higher than those than in controls, and ~65% less than those in Hjv -/- mice. Moreover, cardiac nonheme iron levels in Hjv -/-;Slc39a14 +/hrt (heterozygous conditional Slc39a14 knockout) mice were between those of Hjv -/- and Hjv -/-;Slc39a14 hrt/hrt mice, suggesting a gene-dosage effect of Slc39a14 on cardiac iron accumulation. A role for voltage-dependent calcium channels in mediating the uptake of NTBI into cardiomyocytes has been proposed based on observations of the effects of L-type calcium-channel blockers on iron uptake and accumulation in vitro and in vivo. We considered the possibility that these observations could be explained if SLC39A14 were reactive with calcium-channel blockers. To test this hypothesis, we examined the effects of blockers on the activity of SLC39A14 by using radiotracer assays in RNA-injected Xenopus oocytes expressing mouse SLC39A14. We found that 100 µM amlodipine (Amld), nifedipine, and nicardipine each afforded modest inhibition of SLC39A14-mediated 55Fe 2+. Inhibition of iron transport by Amld was dose-dependent, EC 50 = 167 µM ± (SEM) 30 µM. Our findings implicate SLC39A14 in mediating cardiomyocyte NTBI uptake in the mouse and raise doubts about the relative importance of calcium channels as a mechanism by which NTBI gains entry to the heart. Disclosures No relevant conflicts of interest to declare.

scholarly journals A32 EMPAGLIFOZIN IMPROVES GASTROINTESTINAL INFLAMMATION IN A MOUSE MODEL OF COLITIS

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 213-215
Author(s):  
K Madsen ◽  
H Dang ◽  
N Hotte ◽  
V Mocanu ◽  
M Ferdaoussi ◽  
...  
Keyword(s):  
Animal Model ◽  
Sglt2 Inhibitor ◽  
Direct Effects ◽  
Lipocalin 2 ◽  
Wild Type ◽  
Gut Inflammation ◽  
Beneficial Effects ◽  
Histological Score ◽  
Cytokine Levels ◽  
Gastrointestinal Inflammation

Abstract Background Empagliflozin (EMPA) is a highly selective sodium glucose cotransporter-2 (SGLT2) inhibitor and is increasingly being utilized as an antihyperglycemic agent in the management of type 2 diabetes. Interestingly, it has been demonstrated in human trials that EMPA treatment exerts potent cardioprotective effects by reducing cardiac inflammation independently of glycemic control. Further, EMPA has also been shown to suppress LPS-induced renal and systemic inflammation in an animal model. Based on these findings, we hypothesized that EMPA treatment may also be effective in reducing gut inflammation. Aims The aim of this study was to examine the effects of treatment with EMPA on gastrointestinal inflammation in an animal model of inflammatory bowel disease and to determine mechanistic insights regarding its direct effects on gut cytokine secretion. Methods Adult male and female IL-10-/- mice with established colitis were treated with a daily gavage of EMPA (10mg/kg; n=10) or vehicle (n=10) for 14 days. Disease activity was assessed by measurement of mouse weight, colonic weight and length, histological score, cytokine levels in colonic homogenate and lipocalin-2 levels in stool. To examine for possible direct effects of EMPA, colonic explants from wild-type (n=8) and IL-10-/- (n=8) mice were incubated with increasing doses of EMPA (0.1–5 µM) ± LPS (10µg/ml) for 2 hours and tissue levels of IL-1β and TNFα protein measured by ELISA. Results After 14 days EMPA treated IL-10-/- mice had a significant improvement in colonic inflammation as evidenced by decreased colonic weight to length ratio (p=0.019), decreased fecal lipocalin-2 (p=0.03), as well as decreased enterocyte injury (p=0.01), decreased lamina propria neutrophils (p=0.01) and decreased total histological score (p=0.006). EMPA treated mice also maintained their weight over the 14 days while untreated mice continued to lose weight (p=0.04). There were no significant differences in colonic homogenate levels of TNFα, IL-1β, or IL-6 or in blood glucose levels between EMPA-treated mice and controls. In addition, EMPA did not suppress levels of basal or LPS-induced TNFα and IL-1β in colonic explants from either wild-type or IL-10-/- mice suggesting that the beneficial effects in IL-10-/- mice were not due to direct effects of EMPA on colonic TNFα or IL-1β cytokine levels. Conclusions EMPA treatment dramatically improved histologic and fecal inflammatory markers and maintained body weight in adult IL-10-/- mice with established colitis. These findings suggest further investigations into the effects of EMPA in treating gut inflammation are warranted. Funding Agencies CAG, CIHR

scholarly journals The beneficial effects of physical preoperative and postoperative training for the cognitive function in cardiosurgical patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
O Trubnikova ◽  
I Tarasova ◽  
E Moskin ◽  
Y Argunova ◽  
D Kupriyanova ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Cognitive Function ◽  
Physical Training ◽  
Training Group ◽  
Aerobic Exercise Training ◽  
Funding Source ◽  
Beneficial Effects ◽  
Preoperative Training ◽  
Cabg Patients ◽  
Cycling Training

Abstract Background and aim The cardiac surgery patients have an increased risk of postoperative cognitive dysfunction (POCD). The positive healing effects of physical exercise was demonstrated early in patients with cognitive impairment. The aim of the study was to evaluate the effect of physical preoperative and postoperative training for the cognitive function in patients undergoing on-pump coronary artery bypass grafting (CABG). Methods We analyzed the neurophysiological data from 125 male coronary artery disease (CAD) patients who participated in two sub-studies: the patients with a short preoperative course of treadmill training (n=33) and with postoperative aerobic exercise training (n=92). The study of preoperative physical training included CABG-candidates, which were divided into 2 groups: with (n=17) and without training (n=16). The preoperative physical training consisted of a 5–7 day course of intensive training on a treadmill. The study with postoperative aerobic exercise training enrolled CAD patients, undergoing on-pump CABG, which were divided into 2 groups: with supervised cycling training (n=39) and without training (n=53). Three-week trainings course began on the 14-th day after CABG. The patients with and without preoperative and postoperative physical training were comparable in terms of preoperative characteristics and intraoperative parameters. The patients were underwent the neuropsychological and EEG examination to assess postoperative changes in neurophysiological performance. Results The patients with preoperative treadmill training had the POCD incidence at 7–10 days after GABG in 44% cases vs. 74% - in the group without training. The relative risk of POCD developing in the patients with preoperative training was: OR=0.24, 95% CI: 0.07–0.81, Z=2.297, p=0.02. Additionally, the patients with preoperative training demonstrated a lower power in the theta (4–6 Hz) and beta1 (13–20 Hz) frequency ranges 7–10 days after CABG. The patients with postoperative cycling training also demonstrated better cognitive function at 1 month after CABG compared to the patients without training. The incidence of POCD was 21% in the cycling training group vs. 44% – in the group without training. The relative risk of POCD developing was: OR=0.23, 95% CI: 0.09–0.60, Z=3.041, p=0.0024. Also, it was found that the postoperative cycling training group showed a lower percentage theta power increase at 1 month after CABG. Conclusion Both the short preoperative and three-week postoperative physical training course can produce beneficial effects on the postoperative neurophysiological status in CABG patients. The engagement of physical training in the rehabilitation program of CABG patients can improve cognitive functioning after cardiac surgery. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): RFBR and Kemerovskaya region

scholarly journals Bacterial effector targeting of a plant iron sensor facilitates iron acquisition and pathogen colonization

2021 ◽  
Author(s):  
Yingying Xing ◽  
Ning Xu ◽  
Deepak D Bhandari ◽  
Dmitry Lapin ◽  
Xinhua Sun ◽  
...  
Keyword(s):  
Pseudomonas Syringae ◽  
Iron Uptake ◽  
Iron Acquisition ◽  
Iron Accumulation ◽  
Regulatory Proteins ◽  
Mineral Nutrient ◽  
Effector Protein ◽  
Iron Regulatory Proteins ◽  
Protein Levels ◽  
Pathogen Colonization

Abstract Acquisition of nutrients from different species is necessary for pathogen colonization. Iron is an essential mineral nutrient for nearly all organisms, but little is known about how pathogens manipulate plant hosts to acquire iron. Here, we report that AvrRps4, an effector protein delivered by Pseudomonas syringae bacteria to plants, interacts with and targets the plant iron sensor protein BRUTUS (BTS) to facilitate iron uptake and pathogen proliferation in Arabidopsis thaliana. Infection of rps4 and eds1 by P. syringae pv. tomato (Pst) DC3000 expressing AvrRps4 resulted in iron accumulation, especially in the plant apoplast. AvrRps4 alleviates BTS-mediated degradation of bHLH115 and ILR3(IAA-Leucine resistant 3), two iron regulatory proteins. In addition, BTS is important for accumulating immune proteins Enhanced Disease Susceptibility1 (EDS1) at both the transcriptional and protein levels upon Pst (avrRps4) infections. Our findings suggest that AvrRps4 targets BTS to facilitate iron accumulation and BTS contributes to RPS4/EDS1-mediated immune responses.

Evaluation effects of Quercetin on streptozotocin-treated RINm5F pancreatic β-cells in vitro

2021 ◽  
Vol 16 ◽  
Author(s):  
Maryam Mazraesefidi ◽  
Maryam Mohammad Sadeghipour ◽  
Hossein Khorramdelazad ◽  
Mahdi Mahmoodi ◽  
Alireza Khoshdel ◽  
...  
Keyword(s):  
Cell Viability ◽  
Insulin Content ◽  
Β Cells ◽  
Simultaneous Treatment ◽  
Beneficial Effects ◽  
Naturally Occurring ◽  
Low Toxicity ◽  
Pre Treatment ◽  
Glucose Stimulated Insulin Secretion

Background and objectives: Quercetin is a naturally occurring phenolic compound abundantly present in plants as a secondary metabolite. The purpose of this study was to investigate the effect of quercetin on improving RINm5F β-insulinemia cell viability, glucose-stimulated insulin secretion (GSIS), and cell insulin content in the presence or absence of streptozotocin (STZ). Methods: This experimental study was conducted on RINm5F β-insulinemia cell line. The cell viability was evaluated by MTT assay. The necrosis was confirmed by flowcytometry and insulin ELISA kit was used to measure the GSIS level and cell insulin content. It should be noted that for testing of cells by 50μM of quercetin, simultaneous treatment and pre-treatment of quercetin were performed in the presence of STZ (20mM). Results: The quercetin was able to improve the viability of RINm5F cells in the presence of STZ and to increase the GSIS level and cell insulin content under STZ and glucotoxic conditions Conclusion: The quercetin seems to have beneficial effects on β-cells, especially the synthesis and secretion of insulin. In addition to the therapeutic effect, given the low toxicity of this flavonoid and the results of this study, the quercetin as a preventive agent may play an important role in maintaining the health of β-cells in people at risk of diabetes.

scholarly journals Myocardial Iron Overload in an Experimental Model of Sudden Unexpected Death in Epilepsy

2021 ◽  
Vol 12 ◽  
Author(s):  
Enes Akyuz ◽  
Zuleyha Doganyigit ◽  
Ece Eroglu ◽  
Franco Moscovicz ◽  
Amalia Merelli ◽  
...  
Keyword(s):  
Iron Overload ◽  
Cardiac Arrhythmia ◽  
Refractory Epilepsy ◽  
Experimental Models ◽  
Sudden Unexpected Death ◽  
Iron Accumulation ◽  
Hypoxic Stress ◽  
Unexpected Death ◽  
Transfusion Therapy ◽  
Iron Overload Cardiomyopathy

Uncontrolled repetitive generalized tonic-clonic seizures (GTCS) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). GTCS can be observed in models such as Pentylenetetrazole kindling (PTZ-K) or pilocarpine-induced Status Epilepticus (SE-P), which share similar alterations in cardiac function, with a high risk of SUDEP. Terminal cardiac arrhythmia in SUDEP can develop as a result of a high rate of hypoxic stress-induced by convulsions with excessive sympathetic overstimulation that triggers a neurocardiogenic injury, recently defined as “Epileptic Heart” and characterized by heart rhythm disturbances, such as bradycardia and lengthening of the QT interval. Recently, an iron overload-dependent form of non-apoptotic cell death called ferroptosis was described at the brain level in both the PTZ-K and SE-P experimental models. However, seizure-related cardiac ferroptosis has not yet been reported. Iron overload cardiomyopathy (IOC) results from the accumulation of iron in the myocardium, with high production of reactive oxygen species (ROS), lipid peroxidation, and accumulation of hemosiderin as the final biomarker related to cardiomyocyte ferroptosis. Iron overload cardiomyopathy is the leading cause of death in patients with iron overload secondary to chronic blood transfusion therapy; it is also described in hereditary hemochromatosis. GTCS, through repeated hypoxic stress, can increase ROS production in the heart and cause cardiomyocyte ferroptosis. We hypothesized that iron accumulation in the “Epileptic Heart” could be associated with a terminal cardiac arrhythmia described in the IOC and the development of state-potentially in the development of SUDEP. Using the aforementioned PTZ-K and SE-P experimental models, after SUDEP-related repetitive GTCS, we observed an increase in the cardiac expression of hypoxic inducible factor 1α, indicating hypoxic-ischemic damage, and both necrotic cells and hemorrhagic areas were related to the possible hemosiderin production in the PTZ-K model. Furthermore, we demonstrated for the first time an accumulation of hemosiderin in the heart in the SE-P model. These results suggest that uncontrolled recurrent seizures, as described in refractory epilepsy, can give rise to high hypoxic stress in the heart, thus inducing hemosiderin accumulation as in IOC, and can act as an underlying hidden mechanism contributing to the development of a terminal cardiac arrhythmia in SUDEP. Because iron accumulation in tissues can be detected by non-invasive imaging methods, cardiac iron overload in refractory epilepsy patients could be treated with chelation therapy to reduce the risk of SUDEP.

scholarly journals Noninvasive assessment of iron overload by magnetic resonance imaging

2020 ◽  
Vol 19 (3) ◽  
pp. 158-163
Author(s):  
E. E. Nazarova ◽  
D. A. Kupriyanov ◽  
G. A. Novichkova ◽  
G. V. Tereshchenko
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Iron Concentration ◽  
The Body ◽  
Iron Accumulation ◽  
Resonance Imaging

The assessment of iron accumulation in the body is important for the diagnosis of iron overload syndrome or planning and monitoring of the chelation therapy. Excessive iron accumulation in the organs leads to their toxic damage and dysfunction. Until recently iron estimation was performed either directly by liver iron concentration and/or indirectly by measuring of serum ferritin level. However, noninvasive iron assessment by Magnetic resonance imaging (MRI) is more accurate method unlike liver biopsy or serum ferritin level test. In this article, we demonstrate the outlines of non-invasive diagnostics of iron accumulation by MRI and its specifications.

scholarly journals Nucleolin Rescues TDP-43 Toxicity in Yeast and Human Cell Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Caterina Peggion ◽  
Maria Lina Massimino ◽  
Roberto Stella ◽  
Raissa Bortolotto ◽  
Jessica Agostini ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cell Viability ◽  
Human Cell ◽  
Neurodegenerative Disorders ◽  
Nuclear Protein ◽  
Human Cells ◽  
Cell Models ◽  
Nuclear Retention ◽  
Beneficial Effects ◽  
Lateral Sclerosis

TDP-43 is a nuclear protein involved in pivotal processes, extensively studied for its implication in neurodegenerative disorders. TDP-43 cytosolic inclusions are a common neuropathologic hallmark in amyotrophic lateral sclerosis (ALS) and related diseases, and it is now established that TDP-43 misfolding and aggregation play a key role in their etiopathology. TDP-43 neurotoxic mechanisms are not yet clarified, but the identification of proteins able to modulate TDP-43-mediated damage may be promising therapeutic targets for TDP-43 proteinopathies. Here we show by the use of refined yeast models that the nucleolar protein nucleolin (NCL) acts as a potent suppressor of TDP-43 toxicity, restoring cell viability. We provide evidence that NCL co-expression is able to alleviate TDP-43-induced damage also in human cells, further supporting its beneficial effects in a more consistent pathophysiological context. Presented data suggest that NCL could promote TDP-43 nuclear retention, reducing the formation of toxic cytosolic TDP-43 inclusions.

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