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Zhang, T., Liu, X., Li, H., Wang, Z., Chi, L., Li, J.-P. & Tan, T. (2019). Characterization of epimerization and composition of heparin and dalteparin using a UHPLC-ESI-MS/MS method. Carbohydrate Polymers, 203, 87-94
Open this publication in new window or tab >>Characterization of epimerization and composition of heparin and dalteparin using a UHPLC-ESI-MS/MS method
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2019 (English)In: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 203, p. 87-94Article in journal (Refereed) Published
Abstract [en]

Heparin is a significant anticoagulant that has been used in clinic over decades. Although numerous efforts have been made to characterize the molecular structure of heparin and its derivatives for safety of the medicine, technical barriers still exist because of their structural complexity. In this study, we have established a method capable to evaluate both the epimerization and composition of heparin and dalteparin by a UHPLC-HILIC/WAXMS/MS approach. Ten major disaccharide building blocks retaining the epimerization configuration of parental heparin chains were generated and well separated, 9 of which were unambiguously identified. Isomer identifications were achieved through high-resolution tandem mass spectrometry analysis with reference to elaborately prepared standards. The method was successfully applied for the sameness study of generic dalteparins in combination with an isotopic labelling procedure. We believe this robust method maybe adapted to quality control in pharmaceutical production of heparin and LMWHs.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2019
Keywords
Heparin, Dalteparin, Disaccharides, UHPLC-HILIC/WAX-MS/MS, Isotopic labelling
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-369026 (URN)10.1016/j.carbpol.2018.08.108 (DOI)000447377700010 ()30318238 (PubMedID)
Funder
Swedish Research Council, 2515-02595
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-12Bibliographically approved
Aldi, S., Eriksson, L., Kronqvist, M., Lengquist, M., Löfling, M., Folkersen, L., . . . Hedin, U. (2019). Dual roles of heparanase in human carotid plaque calcification. Atherosclerosis, 283, 127-136
Open this publication in new window or tab >>Dual roles of heparanase in human carotid plaque calcification
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2019 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 283, p. 127-136Article in journal (Refereed) Published
Abstract [en]

Background and aims: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-beta-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro.

Methods: Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively.

Results: HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation.

Conclusions: We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2019
Keywords
Atherosclerosis, Calcification, Heparanase, Bone remodeling, Heparan sulfate proteoglycans
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-381114 (URN)10.1016/j.atherosclerosis.2018.12.027 (DOI)000461636300019 ()30665614 (PubMedID)
Funder
Swedish Research Council, 2015-02595Swedish Research Council, 2017-01070Swedish Research Council, 2013-03590Swedish Heart Lung Foundation, 20140131Swedish Heart Lung Foundation, 20170584Swedish Cancer Society, CAN2015/496Åke Wiberg Foundation, M15-0222
Available from: 2019-04-05 Created: 2019-04-05 Last updated: 2019-04-05Bibliographically approved
Xie, M. & Li, J.-P. (2019). Heparan sulfate proteoglycan - A common receptor for diverse cytokines. Cellular Signalling, 54, 115-121
Open this publication in new window or tab >>Heparan sulfate proteoglycan - A common receptor for diverse cytokines
2019 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 54, p. 115-121Article in journal (Refereed) Published
Abstract [en]

Heparan sulfate proteoglycans (HSPG) are macromolecular glyco-conjugates expressed ubiquitously on the cell surface and in the extracellular matrix where they interact with a wide range of ligands to regulate many aspects of cellular function. The capacity of the side glycosaminoglycan chain heparan sulfate (HS) being able to interact with diverse protein ligands relies on its complex structure that is generated by a controlled biosynthesis process, involving the actions of glycosyl-transferases, sulfotransferases and the glucuronyl C5-epimerase. It is believed that activities of the modification enzymes control the HS structures that are designed to serve the biological functions in a given cell or biological status. In this review, we briefly discuss recent understandings on the roles of HSPG in cytokine stimulated cellular signaling, focusing on FGF, TGF-beta, Wnt, Hh, HGF and VEGF.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Heparan sulfate proteoglycan, Cytokines, Cellular signaling, Heparin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-376715 (URN)10.1016/j.cellsig.2018.11.022 (DOI)000456752900012 ()30500378 (PubMedID)
Funder
Swedish Research Council, 2015-02595Swedish Cancer Society, CAN2015/496
Available from: 2019-02-12 Created: 2019-02-12 Last updated: 2019-02-12Bibliographically approved
Khanna, M., Ranasinghe, C., Browne, A. M., Li, J.-P., Vlodaysky, I. & Parish, C. R. (2019). Is host heparanase required for the rapid spread of heparan sulfate binding viruses?. Virology, 529, 1-6
Open this publication in new window or tab >>Is host heparanase required for the rapid spread of heparan sulfate binding viruses?
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2019 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 529, p. 1-6Article in journal (Refereed) Published
Abstract [en]

Vaccinia virus (VACV), like many other viruses, binds to cell surface heparan sulfate (HS) prior to infecting cells. Since HS is ubiquitously expressed extracellularly, it seemed likely that VACV-HS interaction may impede virus spread, with host heparanase, the only known mammalian endoglycosidase that can degrade HS, potentially overcoming this problem. In support of this hypothesis, we found that, compared to wild type, mice deficient in heparanase showed a 1-3 days delay in the spread of VACV to distant organs, such as ovaries, following intranasal inoculation, or to ovaries and spleen following intramuscular inoculation. These delays in spread occurred despite heparanase deficiency having no effect on VACV replication at inoculation sites. Subsequent in vitro studies revealed that heparanase treatment released VACV from HS expressing, but not HS deficient, infected cell monolayers. Collectively these data suggest that VACV relies on host heparanase to degrade HS in order to spread to distant sites.

Keywords
Vaccinia virus, Poxviruses, Heparanase, Heparan sulfate, Virus spread
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-379334 (URN)10.1016/j.virol.2019.01.001 (DOI)000460195900001 ()30622027 (PubMedID)
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-03-19Bibliographically approved
Zhang, R., Zhang, T., Lv, Y., Qin, P., Li, H., Li, J.-P. & Tan, T. (2019). Selective binding of heparin oligosaccharides in a magnetic thermoresponsive molecularly imprinted polymer. Talanta: The International Journal of Pure and Applied Analytical Chemistry, 201, 441-449
Open this publication in new window or tab >>Selective binding of heparin oligosaccharides in a magnetic thermoresponsive molecularly imprinted polymer
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2019 (English)In: Talanta: The International Journal of Pure and Applied Analytical Chemistry, ISSN 0039-9140, E-ISSN 1873-3573, Vol. 201, p. 441-449Article, review/survey (Refereed) Published
Abstract [en]

Heparin is a highly sulfated polysaccharide, applied in clinic for treatment of thrombotic diseases. The biological activity is closely related to its molecular structure e.g. compositions of disaccharides and oligosaccharides units. The classical method to isolate the oligosaccharides after depolymerization by heparinases or nitrous acid I s by size exclusion chromatography which is a time-consuming process. In this study, we explored the possibility for rapid separation of oligosaccharides using a novel polymer material. The magnetic thermoresponsive molecularly imprinted polymers (MIPs) were synthesized using heparin disaccharide as a template, AEM, NIPAAm, and AAm as functional monomer, and MBAA as crosslinker by surface radical polymerization in an aqueous media. Incubation of the MIP with hepairn oligosaccharides demonstrated specific binding to the template molecule. This binding to the targeted molecule was affected by reaction temperature with regard to binding capacity and specificity. The recognition specificity and selectivity can be modulated by varying the compositions of multifunctional monomers. The pseudo-second-order kinetic model and Langmuir isotherm model provide the best fit to the equilibrium adsorption of heparin disaccharides by MIPs. The results suggest that the new material can be used for rapid separation of di- and tetra-saccharides of heparin, which can also be adapted to the applications for isolation of oligosaccharides from other polysaccharides, e.g. heparan sulfate and chondoriting sulfate.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Heparin disaccharide, Magnetic, Molecularly imprinted polymer, Thermoresponsive, Selective binding
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-389914 (URN)10.1016/j.talanta.2019.04.050 (DOI)000471084300059 ()31122447 (PubMedID)
Available from: 2019-08-02 Created: 2019-08-02 Last updated: 2019-08-02Bibliographically approved
Jendresen, C., Digre, A., Cui, H., Zhang, X., Vlodavsky, I., Li, J.-P. & Nilsson, L. N. G. (2019). Systemic LPS-induced A beta-solubilization and clearance in A beta PP-transgenic mice is diminished by heparanase overexpression. Scientific Reports, 9, Article ID 4600.
Open this publication in new window or tab >>Systemic LPS-induced A beta-solubilization and clearance in A beta PP-transgenic mice is diminished by heparanase overexpression
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4600Article in journal (Refereed) Published
Abstract [en]

Amyloid-beta (A(beta) is the main constituent of amyloid deposits in Alzheimer's disease (AD). The neuropathology is associated with neuroinflammation. Here, we investigated effects of systemic lipopolysaccharide (LPS)-treatment on neuroinflammation and A beta deposition in A beta PP-mice and doubletransgenic mice with brain expression of A beta PP and heparanase, an enzyme that degrades HS and generates an attenuated LPS-response. At 13 months of age, the mice received a single intraperitoneal injection of 50 mu g LPS or vehicle, and were sacrificed 1.5 months thereafter. A beta in the brain was analyzed histologically and biochemically after sequential detergent extraction. Neuroinflammation was assessed by CD45 immunostaining and mesoscale cytokine/chemokine ELISA. In single-transgenic mice, LPS-treatment reduced total A beta deposition and increased Tween-soluble A beta. This was associated with a reduced CXCL1, IL-1 beta, TNF-alpha-level and microgliosis, which correlated with amyloid deposition and total A beta. In contrast, LPS did not change A beta accumulation or inflammation marker in the doubletransgenic mice. Our findings suggest that a single pro-inflammatory LPS-stimulus, if given sufficient time to act, triggers A beta-clearance in A beta PP-transgenic mouse brain. The effects depend on HS and heparanase.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-380445 (URN)10.1038/s41598-019-40999-4 (DOI)000461159600077 ()30872722 (PubMedID)
Funder
Swedish Research Council, K2012-67X-21128-01-4
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28Bibliographically approved
Batool, T., Fang, J., Jansson, V., Zhao, H., Gallant, C. J., Moustakas, A. & Li, J.-P. (2019). Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells. Cellular Signalling, 54, 122-129
Open this publication in new window or tab >>Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells
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2019 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 54, p. 122-129Article in journal (Refereed) Published
Abstract [en]

Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of glucuronic acid to iduronic acid in the process of heparan sulfate biosynthesis. Targeted interruption of the gene, Glce,in mice resulted in neonatal lethality with varied defects in organ development. To understand the molecular mechanisms of the phenotypes, we used mouse embryonic fibroblasts (MEF) as a model to examine selected signaling pathways. Our earlier studies found reduced activities of FGF-2, GDNF, but increased activity of sonic hedgehog in the mutant cells. In this study, we focused on the bone morphogenetic protein (BMP) signaling pathway. Western blotting detected substantially elevated endogenous Smad1/5/8 phosphorylation in the Hsepi mutant (KO) MEF cells, which is reverted by re-expression of the enzyme in the KO cells. The mutant cells displayed an enhanced proliferation and elevated alkaline phosphatase activity, marking higher differentiation, when cultured in osteogenic medium. The high level of Smad1/5/8 phosphorylation was also found in primary calvarial cells isolated from the KO mice. Analysis of the genes involved in the BMP signaling pathway revealed upregulation of a number of BMP ligands, but reduced expression of several Smads and BMP antagonist (Grem1) in the KO MEF cells. The results suggest that Hsepi expression modulates BMP signaling activity, which, at least partially, is associated with defected molecular structure of heparan sulfate expressed in the cells.   

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
BMP signaling, Heparan sulfate, MEF cells, Smad, Glucuronyl C5-epimerase, Bone Morphogenetic Protein
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-363254 (URN)10.1016/j.cellsig.2018.11.010 (DOI)000456752900013 ()30458230 (PubMedID)
Funder
Swedish Cancer Society, CAN2015/496Swedish Research Council, 2015-02595Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2019-02-12Bibliographically approved
O'Callaghan, P., Zhang, X. & Li, J.-P. (2018). Heparan Sulfate Proteoglycans as Relays of Neuroinflammation. Journal of Histochemistry and Cytochemistry, 66(4), 305-319
Open this publication in new window or tab >>Heparan Sulfate Proteoglycans as Relays of Neuroinflammation
2018 (English)In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 66, no 4, p. 305-319Article, review/survey (Refereed) Published
Abstract [en]

Heparan sulfate proteoglycans (HSPGs) are implicated as inflammatory mediators in a variety of settings, including chemokine activation, which is required to recruit circulating leukocytes to infection sites. Heparan sulfate (HS) polysaccharide chains are highly interactive and serve co-receptor roles in multiple ligand:receptor interactions. HS may also serve as a storage depot, sequestering ligands such as cytokines and restricting their access to binding partners. Heparanase, through its ability to fragment HS chains, is a key regulator of HS function and has featured prominently in studies of HS's involvement in inflammatory processes. This review focuses on recent discoveries regarding the role of HSPGs, HS, and heparanase during inflammation, with particular focus on the brain. HS chains emerge as critical go-betweens in multiple aspects of the inflammatory responserelaying signals between receptors and cells. The molecular interactions proposed to occur between HSPGs and the pathogen receptor toll-like receptor 4 (TLR4) are discussed, and we summarize some of the contrasting roles that HS and heparanase have been assigned in diseases associated with chronic inflammatory states, including Alzheimer's disease (AD). We conclude by briefly discussing how current knowledge could potentially be applied to augment HS-mediated events during sustained neuroinflammation, which contributes to neurodegeneration in AD.

Place, publisher, year, edition, pages
SAGE PUBLICATIONS LTD, 2018
Keywords
Alzheimer's disease (AD), extracellular matrix (ECM), heparan sulfate (HS), heparan sulfate proteoglycans (HSPGs), heparanase, inflammation, innate immunity, microglia, neuroinflammation, toll-like receptor 4 (TLR4)
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-357172 (URN)10.1369/0022155417742147 (DOI)000429872800008 ()29290138 (PubMedID)
Funder
Swedish Research Council, 2015-02595
Available from: 2018-08-14 Created: 2018-08-14 Last updated: 2018-08-14Bibliographically approved
Barash, U., Lapidot, M., Zohar, Y., Loomis, C., Moreira, A., Feld, S., . . . Vlodavsky, I. (2018). Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications. Journal of the National Cancer Institute, 110(10), 1102-1114
Open this publication in new window or tab >>Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications
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2018 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 110, no 10, p. 1102-1114Article in journal (Refereed) Published
Abstract [en]

Background: Mammalian cells express a single functional heparanase, an endoglycosidase that cleaves heparan sulfate and thereby promotes tumor metastasis, angiogenesis, and inflammation. Malignant mesothelioma is highly aggressive and has a poor prognosis because of the lack of markers for early diagnosis and resistance to conventional therapies. The purpose of this study was to elucidate the mode of action and biological significance of heparanase in mesothelioma and test the efficacy of heparanase inhibitors in the treatment of this malignancy.

Methods: The involvement of heparanase in mesothelioma was investigated by applying mouse models of mesothelioma and testing the effect of heparanase gene silencing (n = 18 mice per experiment; two different models) and heparanase inhibitors (ie, PG545, defibrotide; n = 18 per experiment; six different models). Synchronous pleural effusion and plasma samples from patients with mesothelioma (n = 35), other malignancies (12 non-small cell lung cancer, two small cell lung carcinoma, four breast cancer, three gastrointestinal cancers, two lymphomas), and benign effusions (five patients) were collected and analyzed for heparanase content (enzyme-linked immunosorbent assay). Eighty-one mesothelioma biopsies were analyzed by H-Score for the prognostic impact of heparanase using immunohistochemistry. All statistical tests were two-sided.

Results: Mesothelioma tumor growth, measured by bioluminescence or tumor weight at termination, was markedly attenuated by heparanase gene silencing (P = .02) and by heparanase inhibitors (PG545 and defibrotide; P < .001 and P = .01, respectively). A marked increase in survival of the mesothelioma-bearing mice (P < .001) was recorded. Heparanase inhibitors were more potent in vivo than conventional chemotherapy. Clinically, heparanase levels in patients' pleural effusions could distinguish between malignant and benign effusions, and a heparanase H-score above 90 was associated with reduced patient survival (hazard ratio = 1.89, 95% confidence interval = 1.09 to 3.27, P = .03).

Conclusions: Our results imply that heparanase is clinically relevant in mesothelioma development. Given these preclinical and clinical data, heparanase appears to be an important mediator of mesothelioma, and heparanase inhibitors are worthy of investigation as a new therapeutic modality in mesothelioma clinical trials.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-375582 (URN)10.1093/jnci/djy032 (DOI)000455206400008 ()29579286 (PubMedID)
Available from: 2019-01-31 Created: 2019-01-31 Last updated: 2019-01-31Bibliographically approved
Tan, Y.-X., Cui, H., Wan, L.-M., Gong, F., Zhang, X., Vlodavsky, I. & Li, J.-P. (2018). Overexpression of heparanase in mice promoted megakaryopoiesis. Glycobiology, 28(5), 269-275
Open this publication in new window or tab >>Overexpression of heparanase in mice promoted megakaryopoiesis
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2018 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 28, no 5, p. 269-275Article in journal (Refereed) Published
Abstract [en]

Heparanase, an endo-glucuronidase that specifically cleaves heparan sulfate (HS), is upregulated in several pathological conditions. In this study, we aimed to find a correlation of heparanase expression and platelets production. In the transgenic mice overexpressing human heparanase (Hpa-tg), hematological analysis of blood samples revealed a significantly higher number of platelets in comparison with wild-type (Ctr) mice, while no significant difference was found in leukocytes and red blood cell number between the two groups. Total number of thiazole orange positive platelets was increased in Hpa-tg vs. Ctr blood, reflecting a higher rate of platelets production. Concomitantly, megakaryocytes from Hpa-tg mice produced more and shorter HS fragments that were shed into the medium. Further, thrombopoietin (TPO) level was elevated in the liver and plasma of Hpa-tg mice. Together, the data indicate that heparanase expression promoted megakaryopoiesis, which may be through upregulated expression of TPO and direct effect of released HS fragments expressed in the megakaryocytes.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2018
Keywords
heparan sulfate, heparanase, megakaryopoiesis, platelets
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-352573 (URN)10.1093/glycob/cwy011 (DOI)000429486500003 ()
Funder
Swedish Research Council, 2015-02595
Available from: 2018-08-07 Created: 2018-08-07 Last updated: 2018-08-07Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4255-3581

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