scholarly journals Mitogen-activated Protein Kinase Kinase Antagonized Fas-associated Death Domain Protein–mediated Apoptosis by Induced FLICE-inhibitory Protein Expression

1998 ◽  
Vol 188 (10) ◽  
pp. 1795-1802 ◽  
Author(s):  
Jung-Hua Yeh ◽  
Shu-Ching Hsu ◽  
Shou-Hwa Han ◽  
Ming-Zong Lai
Keyword(s):  
Cell Death ◽  
Map Kinase ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
General Mechanism ◽  
Death Domain ◽  
Con A ◽  
Inhibitory Protein ◽  
Mitogen Activated Protein

Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3– induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.

Functional Role of p38 Mitogen Activated Protein Kinase in Platelet Activation induced by a Thromboxane A2 Analogue and by 8-iso-prostaglandin F2 α

2002 ◽  
Vol 87 (05) ◽  
pp. 888-898 ◽  
Author(s):  
Stefania Gaino ◽  
Valeria Zuliani ◽  
Rosa Tommasoli ◽  
Donatella Benati ◽  
Riccardo Ortolani ◽  
...  
Keyword(s):  
Map Kinase ◽  
Platelet Activation ◽  
Tyrosine Kinases ◽  
Actin Polymerization ◽  
Shape Change ◽  
Specific Inhibitor ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Kinase Phosphorylation

SummaryWe investigated similarities in the signaling pathways elicited by the F2 isoprostane 8-iso-PGF2α and by low doses of U46619 to induce platelet activation. Both 0.01-0.1 µmol/L U46619 and 0.01-1 µmol/L 8-isoPGF2α triggered shape change and filopodia extension, as well as adhesion to immobilized fibrinogen of washed platelets. At these doses the two platelet agonists failed to trigger secretion and aggregation, which were however induced by higher doses of U46619 (0.1-1 µmol/L). SB203580 (1-10 µmol/L), a specific inhibitor of the p38 mitogen activated protein (MAP) kinase blunted platelet shape change and adhesion induced by 0.05-1 µmol/L 8-iso-PGF2α and by 0.01 µmol/L U46619. These platelet responses were also inhibited by 20 µmol/L cytochalasin D, an inhibitor of actin polymerization, and 50 µmol/L piceatannol, an inhibitor of the Syk tyrosine kinases. Both 8-iso-PGF2α and U46619-induced p38 MAP kinase phosphorylation in suspended platelets and this was inhibited by piceatannol, indicating that Syk activation occurs upstream p38 MAP kinase phosphorylation. These findings suggest that the signaling pathway triggered by both 8-iso-PGF2α and low concentrations of U46619 to induce platelet adhesion and shape change implicates Syk, the p38 MAP kinase, and actin polymerization.

scholarly journals MAP Kinase OsMEK2 and OsMPK1 Signaling for Ferroptotic Cell Death in Rice-Magnaporthe oryzae Interactions

2020 ◽  
Author(s):  
Sarmina Dangol ◽  
Raksha Singh ◽  
Khoa Nam Nguyen ◽  
Yafei Chen ◽  
Juan Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Map Kinase ◽  
Signaling Pathways ◽  
Magnaporthe Oryzae ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Microbial Pathogens ◽  
Blast Disease ◽  
Related Cell ◽  
Mitogen Activated Protein

ABSTRACTMitogen-activated protein kinase (MAPK) signaling is required for plant cell death responses to invading microbial pathogens. Ferric ions and reactive oxygen species (ROS) accumulate in rice (Oryza sativa) tissues undergoing cell death during Magnaporthe oryzae infection. Here, we report that rice MAP kinase (OsMEK2 and OsMPK1) signaling cascades are involved in iron- and ROS-dependent ferroptotic cell death responses of rice to M. oryzae infection. OsMEK2 interacted with OsMPK1 in the cytoplasm, and OsMPK1 moved from the cytoplasm into the nucleus to bind to the OsWRKY90 transcription factor. OsMEK2 expression may trigger OsMPK1-OsWRKY90 signaling pathways in the nucleus. Avirulent M. oryzae infection in ΔOsmek2 mutant rice did not trigger iron and ROS accumulation and lipid peroxidation, and also downregulated OsMPK1, OsWRKY90, OsRbohB, and OsPR-1b expression. However, OsMEK2 overexpression induced ROS-and iron-dependent cell death in rice during M. oryzae infection. The downstream MAP kinase (OsMPK1) overexpression induced ROS- and iron-dependent ferroptotic cell death in the compatible rice-M. oryzae interaction. These data suggest that the OsMEK2-OsMPK1-OsWRKY90 signaling cascade is involved in the ferroptotic cell death in rice. The small-molecule inducer erastin triggered iron- and lipid ROS-dependent, but OsMEK2-independent, ferroptotic cell death in ΔOsmek2 mutant plants during M. oryzae infection. Disease-related cell death was lipid ROS-dependent and iron-independent in the ΔOsmek2 mutant plants. These combined results suggest that OsMEK2 and OsMPK1 expression positively regulates iron- and ROS-dependent ferroptotic cell death via OsMEK2-OsMPK1-OsWRKY90 signaling pathways, and blast disease (susceptibility)-related cell death was ROS-dependent but iron-independent in rice-M. oryzae interactions.

scholarly journals Sprouty-4 negatively regulates cell spreading by inhibiting the kinase activity of testicular protein kinase

2005 ◽  
Vol 387 (3) ◽  
pp. 627-637 ◽  
Author(s):  
Yoshikazu TSUMURA ◽  
Jiro TOSHIMA ◽  
Onno C. LEEKSMA ◽  
Kazumasa OHASHI ◽  
Kensaku MIZUNO
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Inhibitory Activity ◽  
Kinase Activity ◽  
Cultured Cells ◽  
Critical Role ◽  
Cell Spreading ◽  
Inhibitory Effect ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

TESK1 (testicular protein kinase 1) is a serine/threonine kinase that phosphorylates cofilin and plays a critical role in integrin-mediated actin cytoskeletal reorganization and cell spreading. We previously showed that TESK1 interacts with Sprouty-4 (referred to as Spry4), an inhibitor of growth factor-induced Ras/MAP (mitogen-activated protein) kinase signalling, but the functional role of this interaction has remained unknown. In the present study, we show that Spry4 inhibits the kinase activity of TESK1 by binding to it through the C-terminal cysteine-rich region. Expression of Spry4 in cultured cells suppressed integrin-mediated cell spreading, and TESK1 reversed the inhibitory effect of Spry4 on cell spreading. Furthermore, Spry4 suppressed integrin- and TESK1-mediated cofilin phosphorylation during the spreading of cells on laminin. These findings suggest that Spry4 suppresses cell spreading by inhibiting the kinase activity of TESK1. Although tyrosine phosphorylation is required for the inhibitory activity of Spry4 on a Ras/MAP kinase pathway, mutation of the corresponding tyrosine residue (Tyr-75 in human Spry4) to an alanine had no apparent effect on its inhibitory actions on TESK1 activity and cell spreading, which suggests a novel cellular function of Spry to regulate the actin cytoskeleton, independent of its inhibitory activity on the Ras/MAP kinase signalling.

scholarly journals Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis

2002 ◽  
Vol 368 (3) ◽  
pp. 705-720 ◽  
Author(s):  
Koichi SAEKI ◽  
Norihiko KOBAYASHI ◽  
Yuko INAZAWA ◽  
Hong ZHANG ◽  
Hideki NISHITOH ◽  
...  
Keyword(s):  
Cell Death ◽  
Map Kinase ◽  
Map Kinases ◽  
Specific Inhibitor ◽  
P38 Map Kinase ◽  
Dominant Negative ◽  
Chemically Induced ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis

We investigated intracellular signalling pathways for apoptosis induced by epigallocatechin-3-gallate (EGCG) as compared with those induced by a toxic chemical substance (etoposide, VP16) or the death receptor ligand [tumour necrosis factor (TNF)]. EGCG as well as VP16 and TNF induced activation of two apoptosis-regulating mitogen-activated protein (MAP) kinases, namely c-Jun N-terminal kinase (JNK) and p38 MAP kinase, in both human leukaemic U937 and OCI-AML1a cells. In U937 cells, the apoptosis and activation of caspases-3 and −9 induced by EGCG but not VP16 and TNF were inhibited with SB203580, a specific inhibitor of p38, while those induced by EGCG and VP16 but not TNF were inhibited with SB202190, a rather broad inhibitor of JNK and p38. In contrast, the EGCG-induced apoptosis in OCI-AML1a cells was resistant to SB203580 but not to SB202190. Unlike TNF, EGCG did not induce the activation of nuclear factor-κB but rather induced the primary activation of caspase-9. N-Acetyl-l-cysteine (NAC) almost completely abolished apoptosis induced by EGCG under conditions in which the apoptosis induced by VP16 or TNF was not affected. The JNK/p38 activation by EGCG was also potently inhibited by NAC, whereas those by VP16 and TNF were either not or only minimally affected by NAC. In addition, dithiothreitol also suppressed both apoptosis and JNK/p38 activation by EGCG, and EGCG-induced activation of MAP kinase kinase (MKK) 3/6, MKK4 and apoptosis-regulating kinase 1 (ASK1) was suppressed by NAC. Dominant negative ASK1, MKK6, MKK4 and JNK1 potently inhibited EGCG-induced cell death. EGCG induced an intracellular increase in reactive oxygen species and GSSG, both of which were also inhibited by NAC, and the decreased synthesis of glutathione rendered the cell susceptible to EGCG-induced apoptosis. Taken together these results strongly suggest that EGCG executed apoptotic cell death via an ASK1, MKK and JNK/p38 cascade which is triggered by NAC-sensitive intracellular oxidative events in a manner distinct from chemically induced or receptor-mediated apoptosis.

scholarly journals 3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways.

1996 ◽  
Vol 16 (12) ◽  
pp. 6687-6697 ◽  
Author(s):  
S Ludwig ◽  
K Engel ◽  
A Hoffmeyer ◽  
G Sithanandam ◽  
B Neufeld ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Stress Responses ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Cascades ◽  
Mitogen Activated Protein ◽  
Stimulation Of

Recently we have identified a mitogen-activated protein kinase (MAPK)-activated protein kinase, named 3pK (G. Sithanandam, F. Latif, U. Smola, R. A. Bernal, F.-M. Duh, H. Li, I. Kuzmin, V. Wixler, L. Geil, S. Shresta, P. A. Lloyd, S. Bader, Y. Sekido, K. D. Tartof, V. I. Kashuba, E. R. Zabarovsky, M. Dean, G. Klein, B. Zbar, M. I. Lerman, J. D. Minna, U. R. Rapp, and A. Allikmets, Mol. Cell. Biol. 16:868-876, 1996). In vitro characterization of the kinase revealed that 3pK is activated by ERK. It was further shown that 3pK is phosphorylated in vivo after stimulation of cells with serum. However, the in vivo relevance of this observation in terms of involvement of the Raf/MEK/ERK cascade has not been established. Here we show that 3pK is activated in vivo by the growth inducers serum and tetradecanoyl phorbol acetate in promyelocytic HL60 cells and transiently transfected embryonic kidney 293 cells. Activation of 3pK was Raf dependent and was mediated by the Raf/MEK/ERK kinase cascade. 3pK was also shown to be activated after stress stimulation of cells. In vitro studies with recombinant proteins demonstrate that in addition to ERK, members of other subgroups of the MAPK family, namely, p38RK and Jun-N-terminal kinases/stress-activated protein kinases, were also able to phosphorylate and activate 3pK. Cotransfection experiments as well as the use of a specific inhibitor of p38RK showed that these in vitro upstream activators also function in vivo, identifying 3pK as the first kinase to be activated through all three MAPK cascades. Thus, 3pK is a novel convergence point of different MAPK pathways and could function as an integrative element of signaling in both mitogen and stress responses.

Importance of glucose-6-phosphate dehydrogenase activity in cell death

1999 ◽  
Vol 276 (5) ◽  
pp. C1121-C1131 ◽  
Author(s):  
Wang-Ni Tian ◽  
Leigh D. Braunstein ◽  
Kira Apse ◽  
Jiongdong Pang ◽  
Mark Rose ◽  
...  
Keyword(s):  
Cell Death ◽  
Redox Potential ◽  
Critical Role ◽  
Pentose Phosphate ◽  
Serum Deprivation ◽  
Mitogen Activated Protein Kinase ◽  
Protein Thiols ◽  
Mitogen Activated Protein ◽  
Kinase Phosphorylation ◽  
Glucose 6 Phosphate Dehydrogenase

The intracellular redox potential plays an important role in cell survival. The principal intracellular reductant NADPH is mainly produced by the pentose phosphate pathway by glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme, and by 6-phosphogluconate dehydrogenase. Considering the importance of NADPH, we hypothesized that G6PDH plays a critical role in cell death. Our results show that 1) G6PDH inhibitors potentiated H2O2-induced cell death; 2) overexpression of G6PDH increased resistance to H2O2-induced cell death; 3) serum deprivation, a stimulator of cell death, was associated with decreased G6PDH activity and resulted in elevated reactive oxygen species (ROS); 4) additions of substrates for G6PDH to serum-deprived cells almost completely abrogated the serum deprivation-induced rise in ROS; 5) consequences of G6PDH inhibition included a significant increase in apoptosis, loss of protein thiols, and degradation of G6PDH; and 6) G6PDH inhibition caused changes in mitogen-activated protein kinase phosphorylation that were similar to the changes seen with H2O2. We conclude that G6PDH plays a critical role in cell death by affecting the redox potential.

scholarly journals Requirement for phosphoinositide 3-OH kinase in growth hormone signalling to the mitogen-activated protein kinase and p70s6k pathways

1996 ◽  
Vol 315 (2) ◽  
pp. 517-522 ◽  
Author(s):  
Elaine KILGOUR ◽  
Ivan GOUT ◽  
Neil G. ANDERSON
Keyword(s):  
Growth Hormone ◽  
Map Kinase ◽  
Map Kinases ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Subunit ◽  
Glutathione S Transferase ◽  
Map Kinase Cascade ◽  
Mitogen Activated Protein ◽  
Kinase Cascade

Pituitary growth hormone (GH) co-ordinately stimulates three distinct signalling pathways in 3T3-F442A preadipocytes, the STAT (signal transducer and activator of transcription) pathway, the mitogen-activated protein (MAP) kinase cascade and p70s6k. The mechanisms linking the GH receptor to these signals have not been fully identified. In this study we have examined the role of phosphoinositide 3-OH kinase (PI 3-kinase). Pretreatment of cells with wortmannin, a specific inhibitor of PI 3-kinase, prevented the activation of p70s6k and partially inhibited the activation of p42 and p44 MAP kinases by GH. In contrast, wortmannin failed to appreciably affect the GH-stimulated tyrosyl phosphorylation of JAK-2 or STAT-1. GH transiently increased the activity of PI 3-kinase recovered in anti-phosphotyrosine immunoprecipitates. In addition, several tyrosyl-phosphorylated proteins were specifically adsorbed from lysates of cells exposed to GH by a glutathione S-transferase fusion protein containing the 85 kDa regulatory subunit of PI 3-kinase. GH also induced an increase in the PI 3-kinase activity associated with both JAK-2 and insulin receptor substrate-1 (IRS-1) immunoprecipitates. These results establish PI 3-kinase as an important mediator of GH signalling to the MAP kinase and p70s6k pathways and suggest that PI 3-kinase is activated by a mechanism involving JAK-2 and IRS-1.

scholarly journals Both rapamycin-sensitive and -insensitive pathways are involved in the phosphorylation of the initiation factor-4E-binding protein (4E-BP1) in response to insulin in rat epididymal fat-cells

1996 ◽  
Vol 316 (2) ◽  
pp. 447-453 ◽  
Author(s):  
Tricia A. DIGGLE ◽  
S. Kelly MOULE ◽  
Matthew B. AVISON ◽  
Andrea FLYNN ◽  
Emily J. FOULSTONE ◽  
...  
Keyword(s):  
Map Kinase ◽  
Time Course ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Fat Cells ◽  
Epididymal Fat ◽  
Mitogen Activated Protein ◽  
Phosphorylation Event

There is mounting evidence that in fat and other insulin-sensitive cells activation of protein synthesis may involve the dissociation of a protein (4E-BP1) from eukaryotic initiation factor (eIF)-4E thus allowing formation of the eIF-4F complex. This study compares the effects of insulin and epidermal growth factor (EGF) on the phosphorylation of 4E-BP1 in fat-cells (followed by gel-shift assays and incorporation of 32P) and on its association with eIF-4E. Several lines of evidence suggest that mitogen-activated protein kinase (MAP kinase) is not involved in these effects of insulin. Insulin causes much more extensive phosphorylation and dissociation of 4E-BP1 from eIF-4E than EGF, although EGF activates MAP kinase to a much greater extent than insulin. Moreover, MAP kinase does not phosphorylate 4E-BP1 when it is complexed with eIF-4E. In contrast, insulin activates the 40S ribosomal protein S6 kinase (p70S6K) 18-fold compared with a 2-fold activation by EGF, and the time course of this activation is similar to the phosphorylation and dissociation of 4E-BP1. Rapamycin, a specific inhibitor of the activation of this latter kinase, inhibits dissociation of 4E-BP1 from eIF-4E in cells incubated with insulin but reveals a phosphorylated form of 4E-BP1 which remains bound to eIF-4E. It is concluded that in rat epididymal fat-cells, the effects of insulin on 4E-BP1 involves multiple phosphorylation events. One phosphorylation event is rapamycin-insensitive, occurs only on bound 4E-BP1 and does not initiate dissociation. The second event does result in dissociation and is blocked by rapamycin, suggesting that the p70S6K signalling pathway is involved: p70S6K itself is probably not involved directly as this kinase does not phosphorylate 4E-BP1 in vitro.

scholarly journals The Coiled-Coil and Leucine-Rich Repeat Domain of the Potyvirus Resistance Protein Pvr4 Has a Distinct Role in Signaling and Pathogen Recognition

2018 ◽  
Vol 31 (9) ◽  
pp. 906-913 ◽  
Author(s):  
Saet-Byul Kim ◽  
Hye-Young Lee ◽  
Eun-Hye Choi ◽  
Eunsook Park ◽  
Ji-Hyun Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Coiled Coil ◽  
Mitogen Activated Protein Kinase ◽  
Protein Signaling ◽  
Death Domain ◽  
Leucine Rich Repeat ◽  
Domain Swap ◽  
Mitogen Activated Protein ◽  
And Function ◽  
Lrr Domain

The pepper Pvr4 protein encoding coiled-coil (CC) nucleotide-binding (NB) leucine-rich repeat (LRR) (NLR) confer hypersensitive response (HR) to potyviruses, including Pepper mottle virus (PepMoV), by recognizing the viral avirulence protein NIb. To figure out the Pvr4-mediated HR mechanism, we analyzed signaling component genes and structure-function relationships of Pvr4, using chimeras and deletion mutants in Nicotiana benthamiana. Molecular chaperone components including HSP90, SGT1, and RAR1 were required, while plant hormones and mitogen-activated protein kinase signaling components had little effect on Pvr4-NIb-mediated HR cell death. Domain swap analyses indicated that the LRR domain of Pvr4 determines recognition of PepMoV-NIb. Our deletion analysis further revealed that the CC domain or CC-NBARC domain alone can trigger autoactive cell death in N. benthamiana. However, the fragments having only an LRR domain could suppress CC-NBARC domain-induced cell death in trans. Further, C-terminal truncation analysis of Pvr4 revealed that a minimum three of five LRR exons showing high similarity was essential for Pvr4 function. The LRR domain may maintain Pvr4 in an inactive state in the absence of NIb. These results provide further insight into the structure and function of NLR protein signaling in plants.

scholarly journals Mitogen-Activated Protein Kinase OsMEK2 and OsMPK1 Signaling Is Required for Ferroptotic Cell Death in Rice–Magnaporthe oryzae Interactions

2021 ◽  
Vol 12 ◽  
Author(s):  
Sarmina Dangol ◽  
Nam Khoa Nguyen ◽  
Raksha Singh ◽  
Yafei Chen ◽  
Juan Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Map Kinase ◽  
Small Molecule ◽  
Magnaporthe Oryzae ◽  
Disease Susceptibility ◽  
Mitogen Activated Protein Kinase ◽  
Knock Out ◽  
Related Cell ◽  
Mitogen Activated Protein

Mitogen-activated protein kinase (MAPK) signaling is required for plant cell death responses to invading microbial pathogens. Iron- and reactive oxygen species (ROS)-dependent ferroptotic cell death occurs in rice (Oryza sativa) during an incompatible rice–Magnaporthe oryzae interaction. Here, we show that rice MAP kinase (OsMEK2 and OsMPK1) signaling cascades are involved in iron- and ROS-dependent ferroptotic cell death responses of rice to M. oryzae infection using OsMEK2 knock-out mutant and OsMEK2 and OsMPK1 overexpression rice plants. The OsMPK1:GFP and OsWRKY90:GFP transcription factor were localized to the nuclei, suggesting that OsMPK1 in the cytoplasm moves into the nuclei to interact with the WRKY90. M. oryzae infection in ΔOsmek2 knock-out plants did not trigger iron and ROS accumulation and lipid peroxidation, and also downregulated OsMPK1, OsWRKY90, OsRbohB, and OsPR-1b expression. However, 35S:OsMEK2 overexpression induced ROS- and iron-dependent cell death in rice. The downstream MAP kinase (OsMPK1) overexpression induced ROS- and iron-dependent ferroptotic cell death response to virulent M. oryzae infection. The small-molecule ferroptosis inhibitor ferrostatin-1 suppressed iron- and ROS-dependent ferroptotic cell death in 35S:OsMPK1 overexpression plants. However, the small-molecule inducer erastin triggered iron- and lipid ROS-dependent, but OsMEK2-independent, ferroptotic cell death during M. oryzae infection. Disease (susceptibility)-related cell death was lipid ROS-dependent, but iron-independent in the ΔOsmek2 knock-out mutant during the late M. oryzae infection stage. These combined results suggest that OsMEK2 and OsMPK1 expression positively regulates iron- and ROS-dependent ferroptotic cell death, and blast disease (susceptibility)-related cell death was ROS-dependent but iron-independent in rice–M. oryzae interactions.

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