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PubMed: 24760868

Title
Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers.
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
34
Issue
None
Pages
6084-97
Date
2014-04-23
Authors
Arnal I | Borel E | Buisson A | De Seranno S | Elie A | Frandemiche ML | Lanté F | Rush T

Evidence 57f4e3caa0
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For this, we treated our primary cortical neurons with jasplakinolide (1 M), a compound that promotes actin polymerization (Lazaro- Dieguez et al., 2008), or with a latrunculin A (at 500 nM), a compound that depolymerizes F-actin into soluble globular actin (Gactin; Coue´ et al., 1987; Fig. 5C). After jasplakinolide application, we observed a large increase in synaptic EGFP-tau fluorescence

a(CHEBI:"latrunculin A") increases bp(GO:"actin filament depolymerization") View Subject | View Object

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a(MESH:jasplakinolide) increases p(HGNC:MAPT) View Subject | View Object

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a(MESH:jasplakinolide) increases bp(GO:"actin filament polymerization") View Subject | View Object

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Evidence 241e90c217
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Latrunculin treatment produced rapid actin depolymerization and the corresponding disappearance of LifeAct-RFP fluorescence in every spine studied; no synaptic EGFP-tau fluorescence was observed (data not shown).

a(CHEBI:"latrunculin A") increases bp(GO:"actin filament depolymerization") View Subject | View Object

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a(CHEBI:"latrunculin A") decreases p(HGNC:MAPT) View Subject | View Object

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Evidence a7e3a6f63d
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Abetao exposure induced a translocation of tau into the PSD fraction (***p  0.0002, 2-tailed Student’s t test; control 20.12  1228 vs Abetao 29.74  1.748, N  12 independent culture). There was also an increase of PSD-95 (***p0.0006, 2-tailed Student’s t test; control 19.10  2.557 vs Abetao 33.3  2153, N  9 independent culture), GluA1 (**p  0.0078, 2-tailed Student’s t test; control 18.841.930 vs Abetao 26.221.475,N9 independent culture) and fyn (**p  0.0041, 2-tailed Student’s t test; control 19.42  1.337 vs Abetao 29.67  2.181, N  6 independent cultures; Fig. 6D).

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT, loc(MESH:"Post-Synaptic Density")) View Subject | View Object

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a(HBP:"amyloid-beta oligomers") increases p(HGNC:DLG4) View Subject | View Object

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a(HBP:"amyloid-beta oligomers") increases p(HGNC:GRIA1) View Subject | View Object

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a(HBP:"amyloid-beta oligomers") increases p(HGNC:FYN) View Subject | View Object

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Evidence dfacb4228c
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After Abetao treatment, synaptic activation did not trigger any increase in synaptic markers and in fact decreased synaptic actin (***p  0.0009, 2-tailed Student’s t test; Abetao 29.64  1.495, Abetao Bic/4-AP 18.56 2.030, N  7 independent cultures; Fig. 7C), PSD-95 (***p0.0007, 2-tailed Student’s t test; Abetao 33.37  2.153, Abetao Bic/4-AP 19.25 2.550, N  7 independent cultures) and tau levels (**p0.0014, 2-tailed Student’s t test; Abetao 29.74 1.748, Abetao Bic/4-AP 20.68 1.751, N  12 independent cultures).

a(HBP:"amyloid-beta oligomers") decreases p(HGNC:MAPT, loc(GO:synapse)) View Subject | View Object

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a(HBP:"amyloid-beta oligomers") decreases p(HGNC:DLG4, loc(GO:synapse)) View Subject | View Object

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a(HBP:"amyloid-beta oligomers") decreases a(MESH:Actins, loc(GO:synapse)) View Subject | View Object

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Evidence 54a2e756c7
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When we investigated Abetao-driven tau translocation to the synapse, we did not see any change in half-life recovery (4.729 s) from those measured with synaptic activation. However, the plateau value was drastically modified (71.20%), illustrating that, whereas Abetao induced tau translocation and subsequently its interaction with actin filament, the resulting synaptic tau is less stable.

a(HBP:"amyloid-beta oligomers") increases tloc(p(HGNC:MAPT)) View Subject | View Object

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a(HBP:"amyloid-beta oligomers") increases complex(complex(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

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a(HBP:"amyloid-beta oligomers") decreases complex(a(MESH:"Dendritic Spines"), p(HGNC:MAPT)) View Subject | View Object

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Evidence 621518bd31
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Preceded by 15 min Abetao treatment, synaptic activation disrupted LifeAct-RFP fluorescence, suggesting an alteration of F-actin organization and no additional EGFPtau recruitment at the synapse.

a(HBP:"amyloid-beta oligomers") decreases bp(GO:"actin filament polymerization") View Subject | View Object

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Evidence ad5f341577
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Finally, we performed a phalloidin precipitation assay after a 15 min Abetao treatment on our neuron culture (Fig. 8A) and observed that tau/F-actin content was increased (**,*p 0.05 relative to control, #p  0.05 relative to Abetao, 1-way ANOVA; control 15.45  1.529, Abetao 32.90  3.181, Abetao Bic/ 4-AP 20.182671 for actin; control 16.342.618, Abetao 31.77 1.952, Abetao Bic/4-AP 17.704.080 for tau,N5 independent cultures Fig. 8B). A subsequent synaptic activation did alter tau interaction with F-actin.

a(HBP:"amyloid-beta oligomers") increases complex(complex(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

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Neurons
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bp(GO:"long-term synaptic potentiation") association complex(complex(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

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Neurons
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complex(complex(GO:"filamentous actin"), p(HGNC:MAPT)) association bp(GO:"long-term synaptic potentiation") View Subject | View Object

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Evidence 1e85c869d6
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Thr-205 phosphorylated tau was only increased under synaptic activation in the PSD fraction (control 24.57  0.9754 vs Bic/4-AP 38.90  1.936; Fig. 9E), whereas it was decreased after Abetao treatment (control 24.57  0.9754 vs Abeta 13.64  2.416). Synaptic activation after Abetao exposure did not produce any significant Thr-205 phosphorylation of tau (Abeta Bic/4-AP 22.892.796 vs Bic/ 4-AP 38.90  1.93 vs Abeta 13.642.50).

a(HBP:"amyloid-beta oligomers") decreases p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

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bp(GO:"long-term synaptic potentiation") increases p(HGNC:MAPT, pmod(Ph, Thr, 205)) View Subject | View Object

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Evidence dae62df55b
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Conversely, only Abetao exposure promoted significant tau phosphorylation on Ser 404 (**p0.05, 1-way ANOVA; control 15.672.418 vs Abetao 32.65  3.76 vs Bic/4-AP 26.75  1.17 vs Abetao Bic/4-AP 24.97  4.48, N  4). These results revealed that, although synaptic activation or Abetao promote tau translocation to PSD fractions, the synaptic tau displays a different phosphorylation profile that may be responsible for the conditional tau properties observed.

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

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Post-Synaptic Density
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a(HBP:"amyloid-beta oligomers") regulates p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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Post-Synaptic Density
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act(p(HGNC:MAPT)) association p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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Post-Synaptic Density
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p(HGNC:MAPT, pmod(Ph)) association act(p(HGNC:MAPT)) View Subject | View Object

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Post-Synaptic Density
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Evidence bb8c91a9bf
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We observed that synaptic activation promoted EGFP-Tau T205A translocation to the spine but FRAP experiments revealed a shorter tau turnover time in the spine (Fig. 9B), whereas Abetao driven translocation to the spine was no longer observable in EGFP-Tau S404A-transfected neurons (Fig. 9F,G). These experiments highlight the pivotal role of these phosphorylations in tau translocation features to the spine.

a(HBP:"amyloid-beta oligomers") causesNoChange p(HGNC:MAPT, var("p.S404A"), loc(MESH:"Dendritic Spines")) View Subject | View Object

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bp(GO:"long-term synaptic potentiation") increases p(HGNC:MAPT, var("p.T205A"), loc(MESH:"Dendritic Spines")) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph, Ser, 404)) increases p(HGNC:MAPT, loc(MESH:"Dendritic Spines")) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph, Thr, 205)) increases p(HGNC:MAPT, loc(MESH:"Dendritic Spines")) View Subject | View Object

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Evidence d6e4210b5d
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The recovery curves indicated 3 pools of tau: a mobile, unbleached fraction comprising 9.72  1.03%, a dynamic fraction at 47.08  3.06%, and a stable, unrecoverable fraction at 42.75  2.78%. This stable fraction suggests that a large portion of tau is anchored in the spine.

a(MESH:"Dendritic Spines") association tloc(p(HGNC:MAPT)) View Subject | View Object

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a(MESH:"Dendritic Spines") association p(HGNC:MAPT) View Subject | View Object

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a(MESH:"Dendritic Spines") association complex(a(MESH:"Dendritic Spines"), p(HGNC:MAPT)) View Subject | View Object

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complex(a(MESH:"Dendritic Spines"), p(HGNC:MAPT)) association a(MESH:"Dendritic Spines") View Subject | View Object

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tloc(p(HGNC:MAPT)) association a(MESH:"Dendritic Spines") View Subject | View Object

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p(HGNC:MAPT) association a(MESH:"Dendritic Spines") View Subject | View Object

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Evidence e1972a1b66
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We analyzed actin and tau in the PSD-enriched fraction from primary cortical neurons treated with jasplakinolide (Fig. 5E). We observed that increased neuronal F-actin content promotes concurrent tau enrichment (*p0.0150, 2-tailed Student’s t test; control 17.49  0.7755 vs jasplakinolide 27.02  2719, N  4 independent cultures; Fig. 5F). GLUA1, the membrane trafficking of which is known to be actin dependent, was increased (*p 0.0279, 2-tailed Student’s t test; control 16.91  1015 vs jasplakinolide 31.00  4.778, N  4 independent cultures). The amount of Fyn in the PSD was decreased (*p  0.0265, 2-tailed Student’s t test; control 27.25 5.003 vs jasplakinolide 11.71  1.786, N  4 independent cultures).

a(MESH:jasplakinolide) increases bp(GO:"actin filament polymerization") View Subject | View Object

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a(MESH:jasplakinolide) increases p(HGNC:GRIA1) View Subject | View Object

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a(MESH:jasplakinolide) decreases p(HGNC:FYN) View Subject | View Object

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bp(GO:"actin filament polymerization") increases complex(GO:"filamentous actin") View Subject | View Object

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complex(GO:"filamentous actin") increases p(HGNC:MAPT) View Subject | View Object

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Evidence 2e5bea0545
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Therefore, during a long-lasting synaptic activation, we observed an increase in tau, fyn, actin, GluA1, and PSD-95 content in the PSD-positive fraction, which is consistent with the characteristic features of synaptic plasticity (Ehlers, 2003).

bp(GO:"long-term synaptic potentiation") positiveCorrelation p(HGNC:MAPT, loc(GO:synapse)) View Subject | View Object

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bp(GO:"long-term synaptic potentiation") positiveCorrelation p(MESH:Actins, loc(GO:synapse)) View Subject | View Object

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bp(GO:"long-term synaptic potentiation") positiveCorrelation p(HGNC:FYN, loc(GO:synapse)) View Subject | View Object

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bp(GO:"long-term synaptic potentiation") positiveCorrelation p(HGNC:GRIA1, loc(GO:synapse)) View Subject | View Object

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bp(GO:"long-term synaptic potentiation") positiveCorrelation p(HGNC:DLG4, loc(GO:synapse)) View Subject | View Object

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p(HGNC:MAPT, loc(GO:synapse)) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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p(HGNC:DLG4, loc(GO:synapse)) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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p(HGNC:FYN, loc(GO:synapse)) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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p(HGNC:GRIA1, loc(GO:synapse)) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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p(MESH:Actins, loc(GO:synapse)) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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Evidence 6b32f2f21d
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These results suggest that tau translocates from the dendritic shaft to the synapse during activation and probably takes part in the activity-driven synaptic reorganization that underlies synaptic plasticity

bp(GO:"long-term synaptic potentiation") positiveCorrelation tloc(p(HGNC:MAPT), fromLoc(GO:"dendritic shaft"), toLoc(GO:synapse)) View Subject | View Object

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bp(MESH:"Neuronal Plasticity") association tloc(p(HGNC:MAPT), fromLoc(GO:"dendritic shaft"), toLoc(GO:synapse)) View Subject | View Object

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tloc(p(HGNC:MAPT), fromLoc(GO:"dendritic shaft"), toLoc(GO:synapse)) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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tloc(p(HGNC:MAPT), fromLoc(GO:"dendritic shaft"), toLoc(GO:synapse)) association bp(MESH:"Neuronal Plasticity") View Subject | View Object

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Evidence 1345960006
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We observed a similar LTPinduced increase in tau content within the PSD-enriched fraction from CA1 synaptosomes (29.86 +-4.86 to 70.15 +- 4.86, **p = 0.0011; Fig. 3B). As expected, actin and GluA1 were also increased, strengthening the idea that tau is involved in synaptic reorganization processes necessary for synaptic plasticity

bp(GO:"long-term synaptic potentiation") positiveCorrelation p(HGNC:MAPT) View Subject | View Object

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bp(GO:"long-term synaptic potentiation") positiveCorrelation p(MESH:Actins) View Subject | View Object

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bp(GO:"long-term synaptic potentiation") positiveCorrelation p(HGNC:GRIA1) View Subject | View Object

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p(HGNC:MAPT) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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p(HGNC:MAPT) regulates bp(MESH:"Neuronal Plasticity") View Subject | View Object

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p(HGNC:GRIA1) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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p(MESH:Actins) positiveCorrelation bp(GO:"long-term synaptic potentiation") View Subject | View Object

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Evidence 7634ef1cf1
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These results show that the amount of tau collected is proportional to neuronal F-actin content, suggesting a close link between F-actin and tau.

complex(GO:"filamentous actin") association p(HGNC:MAPT) View Subject | View Object

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p(HGNC:MAPT) association complex(GO:"filamentous actin") View Subject | View Object

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Evidence 4c3233be5c
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Together, these results suggest that tau translocation to the synapse depends on the F-actin stabilization that promotes their interaction.

complex(GO:"filamentous actin") increases p(HGNC:MAPT, loc(GO:synapse)) View Subject | View Object

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Evidence d140376b6b
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Although tau alone were observed only in the supernatant in both experimental conditions, ruling out a nonspecific coaggregation, we found that tau coprecipitated with the pellet obtained from high- and low-speed centrifugation, illustrating its direct interaction with both F-actin (Fig. 4A) and actin bundles (Fig. 4B).

p(HGNC:MAPT) increases complex(complex(GO:"filamentous actin"), p(HGNC:MAPT)) View Subject | View Object

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p(HGNC:MAPT) increases complex(complex(GO:"actin filament bundle"), p(HGNC:MAPT)) View Subject | View Object

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