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Magnusson, Mattias
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Publications (10 of 30) Show all publications
Chenna Narendra, S., Prakash Chalise, J., Magnusson, M. & Uppugunduri, S. (2015). Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis. PLoS ONE, 10(10), e0141863
Open this publication in new window or tab >>Local but Not Systemic Administration of Uridine Prevents Development of Antigen-Induced Arthritis
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, p. e0141863-Article in journal (Refereed) Published
Abstract [en]

Objective Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis. Methods Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice preimmunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint. Results Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium. Conclusion Local, but not systemic administration of uridine efficiently prevented development of antigen- induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-123070 (URN)10.1371/journal.pone.0141863 (DOI)000363920300089 ()26512984 (PubMedID)
Note

Funding Agencies|Vetenskapsradet-Grant [521-2011-3095]; Reumatikerforbundet Grant [155261]; County Council of Ostergotland, Sweden; Linkoping University

Available from: 2015-12-04 Created: 2015-12-03 Last updated: 2017-12-01
Narendra, S. C., Chalise, J. P., Höök, N. & Magnusson, M. (2014). Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.. Journal of Leukocyte Biology, 95(4), 661-666
Open this publication in new window or tab >>Dendritic cells activated by double-stranded RNA induce arthritis via autocrine type I IFN signaling.
2014 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 95, no 4, p. 661-666Article in journal (Refereed) Published
Abstract [en]

Viral dsRNA can be found at the site of inflammation in RA patients, and intra-articular injection of dsRNA induces arthritis by activating type I IFN signaling in mice. Further, DCs, a major source of IFN-α, can be found in the synovium of RA patients. We therefore determined the occurrence of DCs in dsRNA-induced arthritis and their ability to induce arthritis. Here, we show, by immunohistochemistry, that cells expressing the pan-DC marker CD11c and the pDC marker 120G8 are present in the inflamed synovium in dsRNA-induced arthritis. Flt3L-generated and splenic DCs preactivated with dsRNA before intra-articular injection, but not mock-stimulated cells, clearly induced arthritis. Induction of arthritis was dependent on type I IFN signaling in the donor DCs, whereas IFNAR expression in the recipient was not required. Sorting of the Flt3L-DC population into cDCs (CD11c(+), PDCA-1(-)) and pDCs (CD11c(+), PDCA-1(+)) revealed that both subtypes were arthritogenic and produced type I IFN if treated with dsRNA. Taken together, these results demonstrate that viral nucleic acids can elicit arthritis by activating type I IFN signaling in DCs. Once triggered, autocrine type I IFN signaling in dsRNA-activated DCs is sufficient to propagate arthritis.

Place, publisher, year, edition, pages
Society for Leukocyte Biology, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-102370 (URN)10.1189/jlb.0613320 (DOI)000335346300011 ()24304616 (PubMedID)
Available from: 2013-12-09 Created: 2013-12-09 Last updated: 2017-12-06
Chalise, J. P., Narendra, S. C., Paudyal, B. R. & Magnusson, M. (2013). Interferon alpha inhibits antigen-specific production of proinflammatory cytokines and enhances antigen-specific transforming growth factor beta production in antigen-induced arthritis. Arthritis Research and Therapy, 15(5), R143
Open this publication in new window or tab >>Interferon alpha inhibits antigen-specific production of proinflammatory cytokines and enhances antigen-specific transforming growth factor beta production in antigen-induced arthritis
2013 (English)In: Arthritis Research and Therapy, ISSN 1478-6354, Vol. 15, no 5, p. R143-Article in journal (Refereed) Published
Abstract [en]

Introduction: Interferon alpha (IFN-α) has a complex role in autoimmunity, in that it may both enhance and prevent inflammation. We have previously shown that the presence of IFN-α at sensitization protects against subsequent antigen-triggered arthritis. To understand this tolerogenic mechanism, we performed a descriptive, hypothesis-generating study of cellular and humoral responses associated with IFN-α-mediated protection against arthritis.Methods: Arthritis was evaluated at day 28 in mice given a subcutaneous injection of methylated bovine serum albumin (mBSA), together with Freund adjuvant and 0 to 5,000 U IFN-α at days 1 and 7, followed by intraarticular injection of mBSA alone at day 21. The effect of IFN-α on mBSA-specific IgG1, IgG2a, IgG2b, IgA, and IgE was evaluated by enzyme-linked immunosorbent assay (ELISA). Cytokines in circulation and in ex vivo cultures on mBSA restimulation was evaluated with ELISA and Luminex, and the identity of cytokine-producing cells by fluorescence-activated cell sorting (FACS) analysis.Results: Administration of IFN-α protected mice from arthritis in a dose-dependent manner but had no effect on antigen-specific antibody levels. However, IFN-α did inhibit the initial increase of IL-6, IL-10, IL-12, and TNF, and the recall response induced by intraarticular mBSA challenge of IL-1β, IL-10, IL-12, TNF, IFN-γ, and IL-17 in serum. IFN-α decreased both macrophage and CD4+ T cell-derived IFN-γ production, whereas IL-17 was decreased only in CD4+ T cells. Ex vivo, in mBSA-restimulated spleen and lymph node cell cultures, the inhibitory effect of in vivo administration of IFN-α on proinflammatory cytokine production was clearly apparent, but had a time limit. An earlier macrophage-derived, and stronger activation of the antiinflammatory cytokine transforming growth factor beta (TGF-β) was observed in IFN-α-treated animals, combined with an increase in CD4+ T cells producing TGF-β when arthritis was triggered by mBSA (day 21). Presence of IFN-α at immunizations also prevented the reduction in TGF-β production, which was induced by the intraarticular mBSA injection triggering arthritis in control animals.Conclusions: Administration of IFN-α has a profound effect on the cellular response to mBSA plus adjuvant, but does not affect antigen-specific Ig production. By including IFN-α at immunizations, spleen and lymph node cells inhibit their repertoire of antigen-induced proinflammatory cytokines while enhancing antiinflammatory TGF-β production, first in macrophages, and later also in CD4+ T cells. On intraarticular antigen challenge, this antiinflammatory state is reenforced, manifested as inhibition of proinflammatory recall responses and preservation of TGF-β levels. This may explain why IFN-α protects against antigen-induced arthritis. © 2013 Chalise et al.; licensee BioMed Central Ltd.

Place, publisher, year, edition, pages
London, UK: BioMed Central, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-102367 (URN)10.1186/ar4326 (DOI)000329737400043 ()
Available from: 2013-12-09 Created: 2013-12-09 Last updated: 2015-11-03Bibliographically approved
Forsman, H., Islander, U., Andréasson, E., Andersson, A., Önnheim, K., Karlström, A., . . . Karlsson, A. (2011). Galectin 3 Aggravates Joint Inflammation and Destruction in Antigen-Induced Arthritis. ARTHRITIS AND RHEUMATISM, 63(2), 445-454
Open this publication in new window or tab >>Galectin 3 Aggravates Joint Inflammation and Destruction in Antigen-Induced Arthritis
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2011 (English)In: ARTHRITIS AND RHEUMATISM, ISSN 0004-3591, Vol. 63, no 2, p. 445-454Article in journal (Refereed) Published
Abstract [en]

Objective. Galectin 3, an endogenous beta galactoside-binding lectin, plays an important role in the modulation of immune responses. The finding that galectin 3 is present in the inflamed synovium in patients with rheumatoid arthritis suggests that the protein is associated with the pathogenesis of this disease. We undertook this study to investigate the influence of galectin 3 deficiency in a murine model of arthritis. Methods. Wild-type (WT) and galectin 3-deficient (galectin 3(-/-)) mice were subjected to antigen-induced arthritis (AIA) through immunization with methylated bovine serum albumin. The concentration of serum cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF alpha]) and antigen-specific antibodies was evaluated using a cytometric bead array platform and enzyme-linked immunosorbent assay (ELISA). Cellular IL-17 responses were examined by flow cytometry, ELISA, and enzyme-linked immunospot assay. Results. The joint inflammation and bone erosion of AIA were markedly suppressed in galectin 3(-/-) mice as compared with WT mice. The reduced arthritis in galectin 3(-/-) mice was accompanied by decreased levels of antigen-specific IgG and proinflammatory cytokines. The frequency of IL-17-producing cells in the spleen was reduced in galectin 3(-/-) mice as compared with WT mice. Exogenously added recombinant galectin 3 could partially restore the reduced arthritis and cytokines in galectin 3(-/-) mice. Conclusion. Our findings show that galectin 3 plays a pathogenic role in the development and progression of AIA and that the disease severity is accompanied by alterations of antigen-specific IgG levels, systemic levels of TNF alpha and IL-6, and frequency of IL-17-producing T cells. To our knowledge, this is the first report of in vivo evidence that galectin 3 plays a crucial role in the development of arthritis.

Place, publisher, year, edition, pages
John Wiley and Sons, Ltd, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-66323 (URN)10.1002/art.30118 (DOI)000287202600020 ()
Available from: 2011-03-11 Created: 2011-03-11 Last updated: 2012-03-25
Fei, Y., Wang, W., Kwiecinski, J., Josefsson, E., Pullerits, R., Jonsson, I.-M., . . . Jin, T. (2011). The Combination of a Tumor Necrosis Factor Inhibitor and Antibiotic Alleviates Staphylococcal Arthritis and Sepsis in Mice. JOURNAL OF INFECTIOUS DISEASES, 204(3), 348-357
Open this publication in new window or tab >>The Combination of a Tumor Necrosis Factor Inhibitor and Antibiotic Alleviates Staphylococcal Arthritis and Sepsis in Mice
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2011 (English)In: JOURNAL OF INFECTIOUS DISEASES, ISSN 1537-6613, Vol. 204, no 3, p. 348-357Article in journal (Refereed) Published
Abstract [en]

Background. Despite advances in medical practices, in recent decades permanent reductions in joint function have not been achieved, and the high mortality rate of patients with staphylococcal septic arthritis has not substantially improved. Methods. We evaluated the effects of a combined tumor necrosis factor (TNF) inhibitor and antibiotic therapy on the course of Staphylococcus aureus arthritis and sepsis in mice. Results. Treatment with the combination of a TNF inhibitor and an antibiotic resulted in a quicker relief of clinical arthritis in mice with septic arthritis, compared with an antibiotic monotherapy. Both histopathologically verified synovitis and the extent of joint destruction were reduced by this combined treatment. Importantly, anti-TNF treatment significantly improved the survival rate of mice with S. aureus sepsis and staphylococcal enterotoxin shock syndrome; this effect might be the result of a partial restoration of the hemostatic balance between coagulation and fibrinolysis. Finally, we demonstrated that anti-TNF treatment downregulates high-mobility group protein B1 in staphylococcal enterotoxin shock syndrome. Conclusions. Thus, simultaneous systemic TNF inhibition and antibiotic therapy has beneficial effects on the outcome of S. aureus arthritis and sepsis in a mouse model, suggesting that the combination of a TNF inhibitor and antibiotics represents a novel therapeutic strategy for the treatment of staphylococcal infections.

Place, publisher, year, edition, pages
University of Chicago Press, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69783 (URN)10.1093/infdis/jir266 (DOI)000292562300006 ()
Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2012-03-25
Magnusson, M. (2011). Typ I IFN skyddar mot antigeninducerad artrit. Best Practice, 7, 12-14
Open this publication in new window or tab >>Typ I IFN skyddar mot antigeninducerad artrit
2011 (Swedish)In: Best Practice, Vol. 7, p. 12-14Article in journal (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-88018 (URN)
Available from: 2013-01-29 Created: 2013-01-29 Last updated: 2013-02-12
Ying, F., Chalise, J. P., Chenna Narendra, S. & Magnusson, M. (2011). Type I IFN protects against antigen-induced arthritis. European Journal of Immunology, 41(6), 1687-1695
Open this publication in new window or tab >>Type I IFN protects against antigen-induced arthritis
2011 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, no 6, p. 1687-1695Article in journal (Refereed) Published
Abstract [en]

Autoimmune diseases including rheumatoid arthritis (RA) involve immune reactions against specific antigens. The type I IFN system is suspected to promote autoimmunity in systemic lupus erythematosus, but may also dampen immune reactions in e. g. inflammatory bowel disease. This prompted us to investigate the role of type I IFN in antigen-induced arthritis (AIA). The importance of type I IFN in methylated (m) BSA-induced arthritis was studied by using mice deficient for the type I IFN receptor (IFNAR) and by administration of the IFN-alpha activator viral double-stranded (ds) RNA or recombinant IFN-alpha at antigen sensitization. In IFNAR knock-out mice, arthritis severity was significantly higher than in WT mice. Administration of dsRNA at antigen sensitization protected WT but not IFNAR KO mice from arthritis. Also, addition of recombinant IFN-alpha during the immunization, but not the induction phase of arthritis, almost abolished arthritis. Protection mediated by IFN-alpha was accompanied by delayed and decreased antigen-specific proliferative responses, including impaired lymph node recall responses after intra-articular antigenic challenge. In conclusion, we demonstrate that type I IFN can prevent joint inflammation by downregulating antigen-specific cellular immunity.

Place, publisher, year, edition, pages
John Wiley and Sons, Ltd, 2011
Keywords
Arthritis; Tolerance; Type I IFN
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69898 (URN)10.1002/eji.201040956 (DOI)000291559700019 ()
Available from: 2011-08-09 Created: 2011-08-08 Last updated: 2017-12-08
Kwiecinski, J., Josefsson, E., Mitchell, J., Higgins, J., Magnusson, M., Foster, T., . . . Bokarewa, M. (2010). Activation of Plasminogen by Staphylokinase Reduces the Severity of Staphylococcus aureusSystemic Systemic Infection. Journal of Infectious Diseases, 202(7), 1041-1049
Open this publication in new window or tab >>Activation of Plasminogen by Staphylokinase Reduces the Severity of Staphylococcus aureusSystemic Systemic Infection
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2010 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 202, no 7, p. 1041-1049Article in journal (Refereed) Published
Abstract [en]

 

Background. Theoretical and experimental data support the geographic differentiation strategy as a valuable tool for detecting loci under selection. In the context of Plasmodium falciparum malaria, few populations have been studied, with limited genomic coverage.

Methods. Wild-type S. aureus strain LS-1, which lacks the ability to produce SAK, was modified by an insertion of the sak gene into its chromosome. The sak gene was integrated in 2 forms—(1) linked to its own promoter and (2) fused to the promoter of the protein A gene—which resulted in the overexpression of SAK. SAK is highly specific for human plg and exhibits almost no activity toward murine plg. To investigate the role played by SAK in a murine infection model, human plg transgenic mice and their wild-type counterparts were inoculated intravenously with congenic S. aureus strains differing in SAK production.

Results. Human plg transgenic mice inoculated with SAK-expressing strains displayed significantly reduced mortality, less weight loss, and lower bacterial loads in kidneys than did the wild-type mice. No difference in the severity of sepsis was observed between transgenic and wild-type mice infected with a SAK-deficient strain.

Conclusions. The results suggest that expression of SAK followed by activation of plg alleviates the course of S. aureus sepsis. 

 

 

 

 

 

 

 

 

 

  

 

 

 

 

 

 

 

 

 

 

 

 

 

Background.

 

Staphylokinase (SAK) is produced by the majority of Staphylococcus aureus strains. It is an extracellular protein that activates the conversion of human plasminogen (plg) to plasmin. The role played by SAK in staphylococcal infection is unclear.Methods. Wild-type S. aureus strain LS-1, which lacks the ability to produce SAK, was modified by an insertion of the sak gene into its chromosome. The sak gene was integrated in 2 forms—(1) linked to its own promoter and (2) fused to the promoter of the protein A gene—which resulted in the overexpression of SAK. SAK is highly specific for human plg and exhibits almost no activity toward murine plg. To investigate the role played by SAK in a murine infection model, human plg transgenic mice and their wild-type counterparts were inoculated intravenously with congenic S. aureus strains differing in SAK production.Results. Human plg transgenic mice inoculated with SAK-expressing strains displayed significantly reduced mortality, less weight loss, and lower bacterial loads in kidneys than did the wild-type mice. No difference in the severity of sepsis was observed between transgenic and wild-type mice infected with a SAK-deficient strain.Conclusions. The results suggest that expression of SAK followed by activation of plg alleviates the course of S. aureus

sepsis.

Place, publisher, year, edition, pages
Oxford University Press, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-64346 (URN)10.1086/656140 (DOI)
Available from: 2011-01-19 Created: 2011-01-19 Last updated: 2017-12-11
Magnusson, M., Brisslert, M., Zendjanchi, K., Lindh, M. & Bokarewa, M. (2010). Epstein–Barr virus in bone marrow of rheumatoidarthritis patients predicts response to rituximabtreatment. British Journal of Rheumatology, 49, 1911-1919
Open this publication in new window or tab >>Epstein–Barr virus in bone marrow of rheumatoidarthritis patients predicts response to rituximabtreatment
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2010 (English)In: British Journal of Rheumatology, ISSN 0263-7103, E-ISSN 1460-2172, Vol. 49, p. 1911-1919Article in journal (Refereed) Published
Abstract [en]

 

Objectives. Viruses may contribute to RA. This prompted us to monitor viral load and response to anti-CD20 therapy in RA patients.

Methods. Blood and bone marrow from 35 RA patients were analysed for CMV, EBV, HSV-1, HSV-2, parvovirus B19 and polyomavirus using real-time PCR before and 3 months after rituximab (RTX) treatment and related to the levels of autoantibodies and B-cell depletion. Clinical response to RTX was defined as decrease in the 28-joint disease activity score (DAS-28) >1.3 at 6 months.

Results. Before RTX treatment, EBV was identified in 15 out of 35 patients (EBV-positive group), of which 4 expressed parvovirus. Parvovirus was further detected in eight patients (parvo-positive group). Twelve patients were negative for the analysed viruses. Following RTX, EBV was cleared, whereas parvovirus was unaffected. Eighteen patients were responders, of which 12 were EBV positive. The decrease in the DAS-28 was significantly higher in EBV-positive group compared with parvo-positive group (P = 0.002) and virus-negative patients (P = 0.04). Most of EBV-negative patients that responded to RTX (75%) required retreatment within the following 11 months compared with only 8% of responding EBV-positive patients. A decrease of RF, Ig-producing cells and CD19+ B cells was observed following RTX but did not distinguish between viral infections. However, EBV-infected patients had significantly higher levels of Fas-expressing B cells at baseline as compared with EBV-negative groups.

Conclusions. EBV and parvovirus genomes are frequently found in bone marrow of RA patients. The presence of EBV genome was associated with a better clinical response to RTX. Thus, presence of EBV genome may predict clinical response to RTX.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65518 (URN)10.1093/rheumatology/keq159 (DOI)
Available from: 2011-02-09 Created: 2011-02-09 Last updated: 2017-12-11
Bian, L., Josefsson, E., Jonsson, I.-M., Verdrengh, M., Ohlsson, C., Bokarewa, M., . . . Magnusson, M. (2009). Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice. ARTHRITIS RESEARCH and THERAPY, 11(5)
Open this publication in new window or tab >>Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice
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2009 (English)In: ARTHRITIS RESEARCH and THERAPY, ISSN 1478-6354, Vol. 11, no 5Article in journal (Refereed) Published
Abstract [en]

Introduction Dichloroacetate (DCA) has been in clinical use for the treatment of lactacidosis and inherited mitochondrial disorders. It has potent anti-tumor effects both in vivo and in vitro, facilitating apoptosis and inhibiting proliferation. The proapoptotic and anti-proliferative properties of DCA prompted us to investigate the effects of this compound in arthritis. Methods In the present study, we used DCA to treat murine collagen type II (CII)-induced arthritis (CIA), an experimental model of rheumatoid arthritis. DBA/1 mice were treated with DCA given in drinking water. Results Mice treated with DCA displayed much slower onset of CIA and significantly lower severity (P less than 0.0001) and much lower frequency (36% in DCA group vs. 86% in control group) of arthritis. Also, cartilage and joint destruction was significantly decreased following DCA treatment (P = 0.005). Moreover, DCA prevented arthritis-induced cortical bone mineral loss. This clinical picture was also reflected by lower levels of anti-CII antibodies in DCA-treated versus control mice, indicating that DCA affected the humoral response. In contrast, DCA had no effect on T cell-or granulocyte-mediated responses. The beneficial effect of DCA was present in female DBA/1 mice only. This was due in part to the effect of estrogen, since ovariectomized mice did not benefit from DCA treatment to the same extent as sham-operated controls (day 30, 38.7% of ovarectomized mice had arthritis vs. only 3.4% in sham-operated group). Conclusion Our results indicate that DCA delays the onset and alleviates the progression of CIA in an estrogen-dependent manner.

Place, publisher, year, edition, pages
BioMed Central, 2009
National Category
Engineering and Technology Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-87930 (URN)10.1186/ar2799 (DOI)000273338400025 ()
Available from: 2013-01-28 Created: 2013-01-28 Last updated: 2013-03-22
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