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  • Cell Research
    are known to regulate apoptosis Activation of caspase 9 the initial caspase in the mitochondrial apoptotic cascade is closely associated with ROS but it is unclear whether ROS regulate caspase 9 via direct oxidative modification The present study aims to elucidate the molecular mechanisms by which ROS mediate caspase 9 activation Our results show that the cellular oxidative state facilitates caspase 9 activation Hydrogen peroxide treatment causes the activation of caspase 9 and apoptosis and promotes an interaction between caspase 9 and apoptotic protease activating factor 1 Apaf 1 via disulfide formation In addition in an in vitro mitochondria free system the thiol oxidant diamide promotes auto cleavage of caspase 9 and the caspase 9 Apaf 1 interaction by facilitating the formation of disulfide linked complexes Finally a point mutation at C403 of caspase 9 impairs both H 2 O 2 promoted caspase 9 activation and interaction with Apaf 1 through the abolition of disulfide formation The association between cytochrome c and the C403S mutant is significantly weaker than that between cytochrome c and wild type caspase 9 indicating that oxidative modification of caspase 9 contributes to apoptosome formation under oxidative stress Taken together oxidative modification of caspase 9 by ROS can mediate its interaction with Apaf 1 and can thus promote its auto cleavage and activation This mechanism may facilitate apoptosome formation and caspase 9 activation under oxidative stress Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin dependent kinase 1 activation Hai Jiang 1 2 Jianchun Wu 1 Chen He 1 Wending Yang 1 Honglin Li 1 Cell Research 2009 19 458 468 doi 10 1038 cr 2009 14 published online 17 February 2009 Full Text PDF Cyclin dependent kinase 1 Cdk1 cyclin B1 complex is the driving force for mitotic entry and its activation is tightly regulated by the G2 M checkpoint We originally reported that a novel protein C53 also known as Cdk5rap3 and LZAP potentiates DNA damage induced cell death by modulating the G2 M checkpoint More recently Wang et al 2007 found that C53 LZAP may function as a tumor suppressor by way of inhibiting NF B signaling We report here the identification of C53 protein as a novel regulator of Cdk1 activation We found that knockdown of C53 protein causes delayed Cdk1 activation and mitotic entry During DNA damage response activation of checkpoint kinase 1 and 2 Chk1 and Chk2 is partially inhibited by C53 overexpression Intriguingly we found that C53 interacts with Chk1 and antagonizes its function Moreover a portion of C53 protein is localized at the centrosome and centrosome targeting C53 potently promotes local Cdk1 activation Taken together our results strongly suggest that C53 is a novel negative regulator of checkpoint response By counteracting Chk1 C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell cycle progression and DNA damage response Repression of PKR mediates palmitate induced apoptosis in HepG2 cells through regulation of Bcl 2 Xuerui Yang 1 2 and Christina Chan 1 2 Cell Research 2009 19

    Original URL path: http://www.cell-research.com/artsmore.asp?id=51 (2016-02-14)
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  • Cell Research
    interest in skeletal muscle regeneration is associated with the opening of new therapeutic strategies for muscle injury after trauma as well as several muscular degenerative pathologies including dystrophies muscular atrophy and cachexia Studies focused on the ability of extracellular factors to promote myogenesis are therefore highly promising We now report that an adipocyte derived factor globular adiponectin gAd is able to induce muscle gene expression and cell differentiation gAd besides its well known ability to regulate several metabolic functions in muscle including glucose uptake and consumption and fatty acid catabolism is able to block cell cycle entry of myoblasts to induce the expression of specific skeletal muscle markers such as myosin heavy chain or caveolin 3 as well as to provoke cell fusion into multinucleated syncytia and finally muscle fibre formation gAd exerts its pro differentiative activity through redox dependent activation of p38 Akt and 5 AMP activated protein kinase pathways Interestingly differentiating myoblasts are autocrine for adiponectin and the mimicking of pro inflammatory settings or exposure to oxidative stress strongly increases the production of the hormone from differentiating cells These data suggest a novel function of adiponectin directly coordinating the myogenic differentiation program and serving an autocrine function during skeletal myogenesis NECK LEAF 1 a GATA type transcription factor modulates organogenesis by regulating the expression of multiple regulatory genes during reproductive development in rice Liping Wang 1 3 Hengfu Yin 1 Qian Qian 2 Jun Yang 1 Chaofeng Huang 1 Xiaohe Hu 1 and Da Luo 1 Cell Research 2009 19 598 611 doi 10 1038 cr 2009 36 published online 31 March 2009 Full Text PDF In the monocot rice species Oryza sativa L one of the most striking morphological processes during reproductive development is the concurrence of panicle development with the sequential elongation of upper internodes UPIs To elucidate the underlying molecular mechanisms we cloned the rice gene NECK LEAF 1 NL1 which when mutated results in delays in flowering time smaller panicles with overgrown bracts and abnormal UPI elongation patterns The NL1 gene encodes a GATA type transcription factor with a single zinc finger domain and its transcripts are detected predominantly in the bract primordia which normally degenerate in the wild type plants Overexpression of NL1 in transgenic plants often gives rise to severe growth retardation less vegetative phytomers and smaller leaves suggesting that NL1 plays an important role in organ differentiation A novel mutant allele of PLASTOCHRON1 PLA1 a gene known to play a key role in regulating leaf initiation was identified in this study Genetic analysis demonstrated an interaction between nl1 and pla1 with NL1 acting upstream of PLA1 The expression level and spatial pattern of PLA1 were found to be altered in the nl1 mutant Furthermore the expression of two regulators of flowering Hd3a and OsMADS1 was also affected in the nl1 mutant On the basis of these findings we propose that NL1 is an intrinsic factor that modulates and coordinates organogenesis through regulating the expression of PLA1 and other regulatory genes during

    Original URL path: http://www.cell-research.com/artsmore.asp?id=50 (2016-02-14)
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  • Cell Research
    evaluated AKT phosphorylation in major insulin responsive tissues the liver muscle and fat We found that Pten loss in the pancreas causes the elevation of AKT signaling in the liver The phosphorylation of AKT and its downstream substrate GSK3β was increased in the liver of PPKO mice while PTEN level was decreased without detectable excision of Pten allele in the liver of PPKO mice Proteomics analysis revealed dramatically decreased level of 78 kDa glucose regulated protein GRP78 in the liver of PPKO mice which may also contribute to the lower blood glucose level of PPKO mice fed with HFD Together our findings reveal a novel response in the liver to pancreatic defect in metabolic regulation adding a new dimension to understanding diabetes resistance Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator activated receptor γ Xiaoqi Li 1 Xuanming Yang 1 Youli Xu 1 Xuejun Jiang 2 Xin Li 3 Fajun Nan 3 and Hong Tang 1 Cell Research 2009 19 720 732 doi 10 1038 cr 2009 53 published online 5 May 2009 Full Text PDF Peroxisome proliferator activated receptors PPAR belong to the nuclear hormone receptor superfamily of ligand dependent transcription factors Recent results have shown that agonists of PPARγ such as troglitazone TGZ can inhibit cell proliferation and promote cell differentiation independent of PPARγ In the present study we provide evidence that TGZ may bind directly to EGFR and trigger its signaling and internalization independent of PPARγ Detailed studies revealed that prolonged incubation with TGZ effectively attenuated EGFR signaling by targeting the receptor to the endo lysosomal degradation machinery Although the extracellular signal regulated kinase signaling pathway was transiently activated by TGZ in EGFR overexpressing cancer cells inhibition of EGF induced Akt phosphorylation most likely accounted for the growth arrest of tumor cells caused by TGZ at pharmacologically achievable concentrations Therefore we have provided a new line of evidence indicating that TGZ inhibits cell proliferation by promoting EGFR degradation and attenuating Akt phosphorylation CIN85 associates with endosomal membrane and binds phosphatidic acid Jing Zhang Xiudan Zheng Xiao Yang and Kan Liao Cell Research 2009 19 733 746 doi 10 1038 cr 2009 51 published online 5 May 2009 Full Text PDF CIN85 Cbl interacting protein of 85 kDa is an important molecule involved in receptor tyrosine kinase endocytosis Here we report that through its positively charged C terminus CIN85 associates with a fusogenic lipid phosphatidic acid Its coiled coil domain plays an important role in mediating this protein lipid interaction Deletion of the coiled coil domain results in loss of membrane association and reduced interaction with c cbl finally causing the blockage of epidermal growth factor receptor downregulation In addition a significant portion of CIN85 is located on the endosomal compartment and is related to endocytic cargo sorting characterized by CIN85 s localization on the E class compartment and EGF degradation blockage in CIN85 knockdown cells Taken together our results suggest that CIN85 may function as a scaffold molecule in

    Original URL path: http://www.cell-research.com/artsmore.asp?id=49 (2016-02-14)
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  • Cell Research
    and polarization Our results reveal that LGN is cortically polarized in mouse oocytes and is critical for meiotic spindle organization Ten1p promotes the telomeric DNA binding activity of Cdc13p implication for its function in telomere length regulation Wei Qian 1 2 Jianyong Wang 1 Na Na Jin 2 Xiao Hong Fu 1 Yi Chien Lin 3 Jing Jer Lin 3 and Jin Qiu Zhou 1 Cell Research 2009 19 849 863 doi 10 1038 cr 2009 67 published online 16 June 2009 Full Text PDF In Saccharomyces cerevisiae the essential gene CDC13 encodes a telomeric single stranded DNA binding protein that interacts with Stn1p and Ten1p genetically and physically and is required for telomere end protection and telomere length control The molecular mechanism by which Ten1 participates in telomere length regulation and chromosome end protection remains elusive In this work we observed a weak interaction of Cdc13p and Ten1p in a gel filtration analysis using purified recombinant Cdc13p and Ten1p Ten1p itself exhibits a weak DNA binding activity but enhances the telomeric TG 1 3 DNA binding ability of Cdc13p Cdc13p is co immunoprecipitated with Ten1p In the mutant ten1 55 or ten1 66 cells the impaired interaction between Ten1p and Cdc13p results in much longer telomeres as well as a decreased association of Cdc13p with telomeric DNA Consistently the Ten1 55 and Ten1 66 mutant proteins fail to stimulate the telomeric DNA binding activity of Cdc13p in vitro These results suggest that Ten1p enhances the telomeric DNA binding activity of Cdc13p to negatively regulate telomere length Membrane steroid binding protein 1 MSBP1 negatively regulates brassinosteroid signaling by enhancing the endocytosis of BAK1 Li Song 1 Qiu Ming Shi 1 Xiao Hua Yang 1 2 Zhi Hong Xu 1 and Hong Wei Xue 1 Cell Research 2009 19 864 876 doi 10 1038 cr 2009 66 published online 16 June 2009 Full Text PDF Brassinosteroids BRs are perceived by transmembrane receptors and play vital roles in plant growth and development as well as cell in responses to environmental stimuli The transmembrane receptor BRI1 can directly bind to brassinolide BL and BAK1 interacts with BRI1 to enhance the BRI1 mediated BR signaling Our previous studies indicated that a membrane steroid binding protein 1 MSBP1 could bind to BL in vitro and is negatively involved in BR signaling To further elucidate the underlying mechanism we here show that MSBP1 specifically interacts with the extracellular domain of BAK1 in vivo in a BL independent manner Suppressed cell expansion and BR responses by increased expression of MSBP1 can be recovered by overexpressing BAK1 or its intracellular kinase domain suggesting that MSBP1 may suppress BR signaling through interacting with BAK1 Subcellular localization studies revealed that both MSBP1 and BAK1 are localized to plasma membrane and endocytic vesicles and MSBP1 accelerates BAK1 endocytosis which results in suppressed BR signaling by shifting the equilibrium of BAK1 toward endosomes Indeed enhanced MSBP1 expression reduces the interaction between BRI1 and BAK1 in vivo demonstrating that MSBP1 acts as a

    Original URL path: http://www.cell-research.com/artsmore.asp?id=48 (2016-02-14)
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  • Cell Research
    priming In conclusion TCS may be useful as a Th2 adjuvant and innate immune cells such as eosinophils may be a good target to study the initiation of Th2 response The involvement of hypoxia inducible factor 1 alpha in Toll like receptor 7 8 mediated inflammatory response Sally A Nicholas and Vadim V Sumbayev Cell Research 2009 19 973 983 doi 10 1038 cr 2009 44 published online 21 April 2009 Full Text PDF Toll like receptors TLRs 7 and 8 are crucial in host defence against single stranded RNA ssRNA viruses Such viruses cause severe illnesses which remain a serious medical burden in both industrialised and developing countries TLR7 8 downstream signaling leads to a dramatic cellular stress associated with energy consumption However the molecular mechanisms of cell survival and adaptation to TLR7 8 induced stress which give the cells an opportunity to initiate proper inflammatory reactions are not clear at all Here we report for the first time that ligand induced activation of TLR7 8 leads to the accumulation of hypoxia inducible factor 1 alpha HIF 1α protein in THP 1 human myeloid macrophages via redox and reactive nitrogen species dependent mechanisms MAP kinases and phosphoinositol 3K are not involved in TLR7 8 mediated HIF 1α accumulation Experiments with HIF 1α knockdown THP 1 cells have clearly demonstrated that HIF 1α is important for the protection of these cells against TLR7 8 induced depletion of ATP Thus HIF 1α might support both cell survival and the production of pro inflammatory cytokines upon TLR7 8 activation An agonistic monoclonal antibody against DR5 induces ROS production sustained JNK activation and Endo G release in Jurkat leukemia cells Caifeng Chen Yanxin Liu and Dexian Zheng We have previously reported that AD5 10 a novel agonistic monoclonal antibody against DR5 possessed a strong cytotoxic activity in various tumor cells via induction of caspase dependent and independent signaling pathways The present study further dem Full Text PDF We have previously reported that AD5 10 a novel agonistic monoclonal antibody against DR5 possessed a strong cytotoxic activity in various tumor cells via induction of caspase dependent and independent signaling pathways The present study further demonstrates that reactive oxygen species ROS were generated in abundance in Jurkat leukemia cells upon AD5 10 stimulation and that ROS accumulation subsequently evoked sustained activation of c Jun N terminal kinase JNK loss of mitochondrial membrane potential and release of endonuclease G Endo G from mitochondria into the cytosol The reducing agent N acetylcysteine NAC effectively inhibited the sustained activation of JNK release of Endo G and cell death in Jurkat cells treated by AD5 10 Moreover a dominant negative form of JNK but not of p38 enhanced NF B activation suppressed caspase 8 recruitment in death inducing signaling complexes DISCs and reduced adverse effects on mitochondria thereby inhibiting AD5 10 induced cell death in Jurkat leukemia cells These data provide novel information on the DR5 mediated cell death signaling pathway and may shed new light on effective strategies

    Original URL path: http://www.cell-research.com/artsmore.asp?id=47 (2016-02-14)
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  • Cell Research
    phosphorylation accompanied by an increase in N1 C1 cleavage Mouse PrP C harboring the human N1 C1 cleavage site assumed more human like profiles basally and in response to copper and altered membrane environments Our results demonstrate that the PrP C primary sequence around the N1 C1 cleavage site influences endoproteolytic processing at this location which appears linked to MAP kinase signal transduction both basally and in response to copper Further the primary sequence appears to confer a mutual dependence of N1 C1 cleavage and membrane integrity on the fidelity of PrP C related signal transduction in response to exogenous stimuli Enhancement of TRAIL cytotoxicity by AG 490 in human ALL cells is characterized by downregulation of cIAP 1 and cIAP 2 through inhibition of Jak2 Stat3 Paola Lanuti 1 2 Valeria Bertagnolo 3 Laura Pierdomenico 1 2 Adriana Bascelli 1 2 Eugenio Santavenere 1 Lapo Alinari 4 5 Silvano Capitani 3 Sebastiano Miscia 1 2 and Marco Marchisio 1 2 Cell Research 2009 19 1079 1089 doi 10 1038 cr 2009 80 published online 30 June 2009 Full Text PDF The ability of death inducing tumor necrosis factor related apoptosis inducing ligand TRAIL to selectively kill a variety of cancer cells has been largely described but one of the major concerns with the treatment is the occurrence of drug resistance and possible toxic side effects Here we report that TRAIL induces apoptosis in Jurkat and SUPT1 T cell lines and in human T ALL blasts but not in healthy subject derived peripheral blood mononuclear cells In parallel the treatment with TRAIL and Tyrphostin AG 490 a selective Janus kinase 2 inhibitor produces an evident enhancement of cytotoxicity characterized by a significant inhibition of Stat3 phosphorylation compared to controls or to TRAIL alone treated samples and associated with a dramatic decrease of both cIAP 1 and cIAP 2 mRNA levels Downregulation of cIAP 1 and cIAP 2 by specific small interference RNAs significantly amplifies TRAIL reduced cytotoxicity All together these findings strongly indicate that cIAP 1 and cIAP 2 downregulation is a fundamental step in the signaling pathways mediating the combinatorial effect of TRAIL and AG 490 on T cell leukemia These findings may help to open new routes for the development of less toxic pharmacological strategies in the treatment of patients affected by TRAIL sensitive leukemias RUVBL2 a novel AS160 binding protein regulates insulin stimulated GLUT4 translocation Xiangyang Xie 1 2 Yu Chen 1 2 Peng Xue 1 Yong Fan 1 2 Yongqiang Deng 1 2 Gong Peng 1 2 Fuquan Yang 1 and Tao Xu 1 Cell Research 2009 19 1090 1097 doi 10 1038 cr 2009 96 published online 16 June 2009 Full Text PDF In fat and muscle cells insulin stimulated glucose uptake is mainly mediated by glucose transporter 4 GLUT4 which translocates from intracellular compartments to the cell surface in response to insulin stimulation AS160 is one of the substrates of Akt and plays important roles in insulin regulated GLUT4 translocation In this study RuvB

    Original URL path: http://www.cell-research.com/artsmore.asp?id=46 (2016-02-14)
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  • Cell Research
    those seen in adjacent non cancerous tissue In vitro inhibition of BYSL by short hairpin RNA decreased HCC cell proliferation induced apoptosis and partially arrested the cell cycle in the G2 M phase In vivo HCC cells treated with BYSL siRNA failed to form tumors in nude mice after subcutaneous implantation To determine the cellular basis for BYSL RNAi induced cell growth arrest BYSL subcellular localization in mitotic and interphase HepG2 cells was examined BYSL was present at multiple stages during nucleologenesis including in nucleolus derived foci NDF perichromosomal regions and the prenucleolar body PNB during mitosis BYSL depletion remarkably suppressed NDF and PNB formation and disrupted nucleoli assembly after mitosis resulting in increased apoptosis and reduced tolerance of HCC cells to serum starvation Taken together our studies indicate that upregulated BYSL expression plays a role in hepatocarcinogenesis FGF receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway Wenchao Zhou 1 Xiujing Feng 1 Yingjie Wu 2 Johannes Benge 3 Zhe Zhang 1 and Zhengjun Chen 1 Cell Research 2009 19 1165 1177 doi 10 1038 cr 2009 95 published online 4 August 2009 Full Text PDF Fibroblast growth factor FGF receptor substrate 2α FRS2α is the main mediator of signaling in the FGF pathway Recent studies have shown that mitogen activated protein kinase MAPK phosphorylates serine and threonine residues in FRS2 negatively affecting FGF induced tyrosine phosphorylation PY of FRS2 Several kinds of stimuli can induce serine threonine phosphorylation PS T of FRS2 indicating that FRS2 may be useful for studying crosstalk between growth factor signaling pathways Here we report that FGF induced PY of FRS2 can be attenuated by EGF co stimulation in PC12 cells this inhibitory effect could be completely reversed by U0126 an inhibitor of MEK We further identified the ERK1 2 binding motif in FRS2 and generated FRS2 3KL a mutant lacking MAPK binding and PT upon FGF and or EGF stimulation Unlike wild type WT FRS2 FGF induced PY of FRS2 3KL could not be inhibited by EGF co stimulation and FRS2 3KL expressing PC12 cells exhibited more differentiating potential than FRS2 WT expressing cells in response to FGF treatment These results suggest that PS T of FRS2 mediated by the FRS2 MAPK negative regulatory loop may function as a molecular switch integrating negative regulatory signals from other pathways into FGFR generated signal transduction Genome wide comparative analysis of type A Arabidopsis response regulator genes by overexpression studies reveals their diverse roles and regulatory mechanisms in cytokinin signaling Bo Ren 1 2 Yan Liang 1 Yan Deng 1 2 Qingguo Chen 1 2 Jian Zhang 1 Xiaohui Yang 1 and Jianru Zuo 1 Cell Research 2009 19 1178 1190 doi 10 1038 cr 2009 88 published online 21 July 2009 Full Text PDF Cytokinin is a critical growth regulator for various aspects of plant growth and development In Arabidopsis cytokinin signaling is mediated by a two component system based phosphorelay that transmits a signal from the receptors

    Original URL path: http://www.cell-research.com/artsmore.asp?id=45 (2016-02-14)
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  • Cell Research
    10 1038 cr 2009 91 published online 28 July 2009 Full Text PDF In quorum sensing QS process bacteria regulate gene expression by utilizing small signaling molecules called autoinducers in response to a variety of environmental cues Autoinducer 2 AI 2 a QS signaling molecule proposed to be involved in interspecies communication is produced by many species of gram negative and gram positive bacteria In Escherichia coli and Salmonella typhimurium the extracellular AI 2 is imported into the cell by a transporter encoded by the lsr operon Upstream of the lsr operon there is a divergently transcribed gene encoding LsrR which was reported previously to repress the transcription of the lsr operon and itself Here we have demonstrated for the first time that LsrR represses the transcription of the lsr operon and itself by directly binding to their promoters using gel shift and DNase I footprinting assays The β galactosidase reporter assays further suggest that two motifs in both the lsrR and lsrA promoter regions are crucial for the LsrR binding Furthermore in agreement with the conclusion that phosphorylated AI 2 can relieve the repression of LsrR in previous studies our data show that phospho AI 2 renders LsrR unable to bind to its own promoter in vitro Downregulation of cyclooxygenase 1 is involved in gastric mucosal apoptosis via death signaling in portal hypertensive rats Bin Wu 1 Lixian Zeng 1 Ying Lin 1 Zhuofu Wen 1 Guihua Chen 2 Ryuichi Iwakiri 3 and Kazuma Fujimoto 3 Cell Research 2009 19 1269 1278 doi 10 1038 cr 2009 97 published online 11 August 2009 Full Text PDF Portal hypertension PHT gastropathy is a frequent complication of liver cirrhosis and one of the leading causes of death from cirrhosis Apoptosis is widely considered to be an active energy dependent mode of cell death and a distinct entity from necrotic cell death It is unclear whether gastric mucosal apoptosis is involved in PHT gastropathy Prostaglandins PGs produced through cyclooxygenase COX are thought to play a key role in protection of the gastrointestinal mucosa from injury and apoptosis However the role of COX in PHT gastropathy is still not clearly understood The aims of this study were to investigate whether 1 gastric mucosal apoptosis is involved in PHT gastropathy and 2 downregulation of COX contributes to this apoptosis In this study we show that gastric mucosal apoptosis was remarkably increased while mucosal proliferation was inhibited in PHT rats Gastric mucosal COX 1 was significantly suppressed at both the mRNA and protein levels and PGE 2 was reduced in PHT rats Further PGE 2 treatment suppressed gastric mucosal apoptosis in PHT rats However gastric mucosal COX 2 levels did not differ between sham operated rats and PHT rats Gastric mucosal levels of tumor necrosis factor α TNF α and Fas ligand but not TNF related apoptosis inducing ligand were increased and activated caspase 8 and caspase 3 levels were upregulated in PHT rats The release of cytochrome c from the mitochondria to the cytosol

    Original URL path: http://www.cell-research.com/artsmore.asp?id=44 (2016-02-14)
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