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Mayans, Sofia
Publications (10 of 13) Show all publications
Bäckström, D., Eriksson Domellöf, M., Granåsen, G., Linder, J., Mayans, S., Elgh, E., . . . Forsgren, L. (2018). Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson's disease. Acta Neurologica Scandinavica, 137(1), 91-98
Open this publication in new window or tab >>Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson's disease
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2018 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 137, no 1, p. 91-98Article in journal (Refereed) Published
Abstract [en]

Objectives: Cognitive decline is common in Parkinson's disease (PD), but the underlying mechanisms for this complication are incompletely understood. Genotypes affecting dopamine transmission may be of importance. This study investigates whether genotypes associated with reduced prefrontal dopaminergic tone and/or reduced dopamine D2-receptor availability (Catechol-O-methyltransferase [COMT] Val(158)Met genotype and DRD2 (CT)-T-957 genotype) affect the development of cognitive deficits in PD.

Materials and methods: One hundred and 34 patients with idiopathic PD, participating in a regional, population-based study of incident parkinsonism, underwent genotyping. After extensive baseline investigations (including imaging and biomarker analyses), the patients were followed prospectively during 6-10 years with neuropsychological evaluations, covering six cognitive domains. Cognitive decline (defined as the incidence of either Parkinson's disease mild cognitive impairment [PD-MCI] or dementia [PDD], diagnosed according to published criteria and blinded to genotype) was studied as the primary outcome.

Results: Both genotypes affected cognition, as shown by Cox proportional hazards models. While the COMT(158)Val/Val genotype conferred an increased risk of mild cognitive impairment in patients with normal cognition at baseline (hazard ratio: 2.13, P=.023), the DRD2(957)T/T genotype conferred an overall increased risk of PD dementia (hazard ratio: 3.22, P<.001). The poorer cognitive performance in DRD2(957)T/T carriers with PD occurred mainly in episodic memory and attention.

Conclusions: The results favor the hypothesis that dopamine deficiency in PD not only relate to mild cognitive deficits in frontostriatal functions, but also to a decline in memory and attention. This could indicate that dopamine deficiency impairs a wide network of brain areas.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
COMT, dementia, DRD2, mild cognitive impairment, neurodegeneration, Parkinson's disease, Parkinson's disease genetics, population-based
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-143002 (URN)10.1111/ane.12812 (DOI)000417029600014 ()
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2019-11-25Bibliographically approved
Bäckström, D., Eriksson Domellöf, M., Granåsen, G., Linder, J., Mayans, S., Elgh, E., . . . Forsgren, L. (2017). PITX3 genotype and risk of dementia in Parkinson's disease: A population-based study. Journal of the Neurological Sciences, 381, 278-284
Open this publication in new window or tab >>PITX3 genotype and risk of dementia in Parkinson's disease: A population-based study
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2017 (English)In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 381, p. 278-284Article in journal (Refereed) Published
Abstract [en]

Dementia is a devastating manifestation of Parkinson's disease (PD). This study investigates whether a common polymorphism in the PITX3 gene (rs2281983), which is of importance for the function of dopaminergic neurons, affects the risk of developing dementia in PD and whether it affects dopamine transporter (DAT) uptake. We PITX3 genotyped 133 patients with new-onset, idiopathic PD, participating in a population-based study in Sweden. Patients were followed prospectively during 6-11 years with extensive investigations, including neuropsychology and DAT-imaging with I-123 FP-CIT. The primary outcome was the incidence of PD dementia (PDD), diagnosed according to published criteria, studied by the Kaplan-Meier method and Cox proportional hazards. Performance in individual cognitive domains, the incidence of visual hallucinations, disease progression and striatal DAT uptake on imaging was also investigated. PD patients carrying the PITX3 C allele had an increased risk of developing PDD (hazard ratio: 2.87, 95% CI: 1.42-5.81, p = 0.003), compared to the PD patients homozygous for the T-allele. Furthermore, the PITX3 C allele carriers with PD had a poorer cognitive performance in the visuospatial domain (p < 0.001) and a higher incidence of visual hallucinations. A trend towards a lower striatal DAT uptake in the PITX3 C allele carriers was suggested, but could not be confirmed. Our results show that a common polymorphism in the PITX3 gene affects the risk of developing PDD and visuospatial dysfunction in idiopathic PD. If validated, these findings can provide new insights into the neurobiology and genetics of non-motor symptoms in PD.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
Keywords
Parkinson's disease, PITX3, Dementia, Parkinson's disease genetics, DAT scan
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-142267 (URN)10.1016/j.jns.2017.08.3259 (DOI)000414819100057 ()28991698 (PubMedID)
Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2019-01-23Bibliographically approved
Fransen-Pettersson, N., Duarte, N., Nilsson, J., Lundholm, M., Mayans, S., Larefalk, Å., . . . Holmberg, D. (2016). A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis. PLoS ONE, 11(7), Article ID e0159850.
Open this publication in new window or tab >>A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159850Article in journal (Refereed) Published
Abstract [en]

Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-126338 (URN)10.1371/journal.pone.0159850 (DOI)000380797500147 ()27441847 (PubMedID)
Funder
Swedish Research Council, K2013-67X-07929-27-3
Available from: 2016-10-25 Created: 2016-10-03 Last updated: 2018-06-09Bibliographically approved
Holmberg, D., Ruikka, K., Lindgren, P., Eliasson, M. & Mayans, S. (2016). Association of CD247 (CD3ζ) gene polymorphisms with T1D and AITD in the population of northern Sweden. BMC Medical Genetics, 17(1), Article ID 70.
Open this publication in new window or tab >>Association of CD247 (CD3ζ) gene polymorphisms with T1D and AITD in the population of northern Sweden
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2016 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 17, no 1, article id 70Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: T1D and AITD are autoimmune disorders commonly occurring in the same family and even in the same individual. The genetic contribution to these disorders is complex making uncovering of susceptibility genes very challenging. The general aim of this study was to identify loci and genes contributing to T1D/AITD susceptibility. Our strategy was to perform linkage and association studies in the relatively genetically homogenous population of northern Sweden. We performed a GWLS to find genomic regions linked to T1D/AITD in families from northern Sweden and we performed an association study in the families to test for association between T1D/AITD and variants in previously published candidate genes as well as a novel candidate gene, CD247.

METHODS: DNA prepared from 459 individuals was used to perform a linkage and an association study. The ABI PRISM Linkage Mapping Set v2.5MD10 was employed for an initial 10-cM GWLS, and additional markers were added for fine mapping. Merlin was used for linkage calculations. For the association analysis, a GoldenGate Custom Panel from Illumina containing 79 SNPs of interest was used and FBAT was used for association calculations.

RESULTS: Our study revealed linkage to two previously identified chromosomal regions, 4q25 and 6p22, as well as to a novel chromosomal region, 1q23. The association study replicated association to PTPN22, HLA-DRB1, INS, IFIH1, CTLA4 and C12orf30. Evidence in favor of association was also found for SNPs in the novel susceptibility gene CD247.

CONCLUSIONS: Several risk loci for T1D/AITD identified in published association studies were replicated in a family material, of modest size, from northern Sweden. This provides evidence that these loci confer disease susceptibility in this population and emphasizes that small to intermediate sized family studies in this population can be used in a cost-effective manner for the search of genes involved in complex diseases. The linkage study revealed a chromosomal region in which a novel T1D/AITD susceptibility gene, CD247, is located. The association study showed association between T1D/AITD and several variants in this gene. These results suggests that common susceptibility genes act in concert with variants of CD247 to generate genetic risk for T1D/AITD in this population

Place, publisher, year, edition, pages
BioMed Central, 2016
Keywords
Linkage, Association, Family, Type 1 diabetes, Autoimmune thyroid disease
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-127025 (URN)10.1186/s12881-016-0333-z (DOI)000442378500001 ()27716086 (PubMedID)
Available from: 2016-10-26 Created: 2016-10-26 Last updated: 2019-02-01Bibliographically approved
Mayans, S., Stepniak, D., Palida, S. F., Larange, A., Dreux, J., Arlian, B. M., . . . Lambolez, F. (2014). αβT Cell Receptors Expressed by CD4(-)CD8αβ(-) Intraepithelial T Cells Drive Their Fate into a Unique Lineage with Unusual MHC Reactivities. Immunity, 41(2), 207-218
Open this publication in new window or tab >>αβT Cell Receptors Expressed by CD4(-)CD8αβ(-) Intraepithelial T Cells Drive Their Fate into a Unique Lineage with Unusual MHC Reactivities
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2014 (English)In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 41, no 2, p. 207-218Article in journal (Refereed) Published
Abstract [en]

Coreceptor CD4 and CD8αβ double-negative (DN) TCRαβ(+) intraepithelial T cells, although numerous, have been greatly overlooked and their contribution to the immune response is not known. Here we used T cell receptor (TCR) sequencing of single cells combined with retrogenic expression of TCRs to study the fate and the major histocompatibility complex (MHC) restriction of DN TCRαβ(+) intraepithelial T cells. The data show that commitment of thymic precursors to the DN TCRαβ(+) lineage is imprinted by their TCR specificity. Moreover, the TCRs they express display a diverse and unusual pattern of MHC restriction that is nonoverlapping with that of CD4(+) or CD8αβ(+) T cells, indicating that they sense antigens that are not recognized by the conventional T cell subsets. The new insights indicate that DN TCRαβ(+) T cells form a third lineage of TCRαβ T lymphocytes expressing a variable TCR repertoire, which serve nonredundant immune functions.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-92700 (URN)10.1016/j.immuni.2014.07.010 (DOI)000341455300009 ()25131531 (PubMedID)
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2018-06-07Bibliographically approved
Parsa, R., Andresen, P., Gillett, A., Mia, S., Zhang, X.-M., Mayans, S., . . . Harris, R. A. (2012). Adoptive transfer of immunomodulatory M2 Macrophages prevents type 1 Diabetes in NOD Mice. Diabetes, 61(11), 2881-2892
Open this publication in new window or tab >>Adoptive transfer of immunomodulatory M2 Macrophages prevents type 1 Diabetes in NOD Mice
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2012 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, no 11, p. 2881-2892Article in journal (Refereed) Published
Abstract [en]

Macrophages are multifunctional immune cells that may either drive or modulate disease pathogenesis depending on their activation phenotype. Autoimmune type 1 diabetes (T1D) is a chronic proinflammatory condition characterized by unresolved destruction of pancreatic islets. Adoptive cell transfer of macrophages with immunosuppressive properties represents a novel immunotherapy for treatment of such chronic autoimmune diseases. We used a panel of cytokines and other stimuli to discern the most effective regimen for in vitro induction of immunosuppressive macrophages (M2r) and determined interleukin (IL)-4/IL-10/transforming growth factor-beta (TGF-beta) to be optimal. M2r cells expressed programmed cell death 1 ligand-2, fragment crystallizable region gamma receptor IIlb, IL-10, and TGF-beta, had a potent deactivating effect on proinflammatory lipopolysaccharide/interferon-gamma-stimulated macrophages, and significantly suppressed T-cell proliferation. Clinical therapeutic efficacy was assessed after adoptive transfer in NOD T1D mice, and after a single transfer of M2r macrophages, >80% of treated NOD mice were protected against T1D for at least 3 months, even when transfer was conducted just prior to clinical onset. Fluorescent imaging analyses revealed that adoptively transferred M2r macrophages specifically homed to the inflamed pancreas, promoting 3-cell survival. We suggest that M2r macrophage therapy represents a novel intervention that stops ongoing autoimmune T1D and may have relevance in a clinical setting. Diabetes 61:2881-2892, 2012

Place, publisher, year, edition, pages
American diabetes Association, 2012
National Category
Immunology in the medical area Basic Medicine
Identifiers
urn:nbn:se:umu:diva-63774 (URN)10.2337/db11-1635 (DOI)000312041600026 ()
Available from: 2013-01-14 Created: 2013-01-07 Last updated: 2018-06-08Bibliographically approved
Kalis, M., Bolmeson, C., Esguerra, J. L., Gupta, S., Edlund, A., Tormo-Badia, N., . . . Cilio, C. M. (2011). Beta-cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus. PLoS ONE, 6(12), e29166
Open this publication in new window or tab >>Beta-cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, p. e29166-Article in journal (Refereed) Published
Abstract [en]

Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting beta-cells, we have generated mice with a beta-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Delta/wt)), RIP-Cre(+/-) Dicer1(flox/flox) mice (RIP-Cre Dicer1(Delta/Delta)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased beta-cell mass, reduced numbers of granules within the beta-cells and reduced granule docking in adult RIP-Cre Dicer1(Delta/Delta) mice. beta-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal beta-cell development as 2-week old RIP-Cre Dicer1(Delta/Delta) mice showed ultrastructurally normal beta-cells and intact insulin secretion. In conclusion, we have demonstrated that a beta-cell specific disruption of the miRNAs network, although allowing for apparently normal beta-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.

Keywords
gene-expression; microrna expression; mouse development; pancreas; differentiation; quantification; identification; dysfunction; pathway; driven
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:umu:diva-53404 (URN)10.1371/journal.pone.0029166 (DOI)000300674900019 ()
Available from: 2012-03-23 Created: 2012-03-23 Last updated: 2018-06-08Bibliographically approved
Alanentalo, T., Hörnblad, A., Mayans, S., Nilsson, A. K., Sharpe, J., Larefalk, Å., . . . Holmberg, D. (2010). Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes. Diabetes, 59(7), 1756-1764
Open this publication in new window or tab >>Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes
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2010 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 7, p. 1756-1764Article in journal (Refereed) Published
Abstract [en]

Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.

Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.

Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.

Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.

Keywords
pancreas, mouse, mice
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-33656 (URN)10.2337/db09-1400 (DOI)000279615100025 ()20393145 (PubMedID)
Available from: 2010-04-30 Created: 2010-04-30 Last updated: 2018-06-08Bibliographically approved
Lundholm, M., Mayans, S., Motta, V., Löfgren-Burström, A., Danska, J. & Holmberg, D. (2010). Variation in the Cd3 zeta (Cd247) gene correlates with altered T cell activation and is associated with autoimmune diabetes.. Journal of Immunology, 184(10), 5537-5544
Open this publication in new window or tab >>Variation in the Cd3 zeta (Cd247) gene correlates with altered T cell activation and is associated with autoimmune diabetes.
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2010 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 184, no 10, p. 5537-5544Article in journal (Refereed) Published
Abstract [en]

Tuning of TCR-mediated activation was demonstrated to be critical for lineage fate in T cell development, as well as in the control of autoimmunity. In this study, we identify a novel diabetes susceptibility gene, Idd28, in the NOD mouse and provide evidence that Cd3zeta (Cd247) constitutes a prime candidate gene for this locus. Moreover, we show that the allele of the Cd3zeta gene expressed in NOD and DBA/2 mouse strains confers lower levels of T cell activation compared with the allele expressed by C57BL/6 (B6), BALB/c, and C3H/HeJ mice. These results support a model in which the development of autoimmune diabetes is dependent on a TCR signal mediated by a less-efficient NOD allele of the Cd3zeta gene.

National Category
Immunology in the medical area
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-41762 (URN)10.4049/jimmunol.0904012 (DOI)000277530700014 ()20400699 (PubMedID)
Available from: 2011-04-01 Created: 2011-04-01 Last updated: 2018-06-08Bibliographically approved
Mayans, S., Lackovic, K., Nyholm, C., Lindgren, P., Ruikka, K., Eliasson, M., . . . Holmberg, D. (2007). CT60 genotype does not affect CTLA-4 isoform expression despite association to T1D and AITD in northern Sweden. BMC Medical Genetics, 8, Article ID 3.
Open this publication in new window or tab >>CT60 genotype does not affect CTLA-4 isoform expression despite association to T1D and AITD in northern Sweden
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2007 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 8, article id 3Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Polymorphisms in and around the CTLA-4 gene have previously been associated to T1D and AITD in several populations. One such single nucleotide polymorphism (SNP), CT60, has been reported to affect the expression level ratio of the soluble (sCTLA-4) to full length CTLA-4 (flCTLA-4) isoforms. The aims of our study were to replicate the association previously published by Ueda et al. of polymorphisms in the CTLA-4 region to T1D and AITD and to determine whether the CT60 polymorphism affects the expression level ratio of sCTLA-4/flCTLA-4 in our population.

METHODS: Three SNPs were genotyped in 253 cases (104 AITD cases and 149 T1D cases) and 865 ethnically matched controls. Blood from 23 healthy individuals was used to quantify mRNA expression of CTLA-4 isoforms in CD4+ cells using real-time PCR. Serum from 102 cases and 59 healthy individuals was used to determine the level of sCTLA-4 protein.

RESULTS: Here we show association of the MH30, CT60 and JO31 polymorphisms to T1D and AITD in northern Sweden. We also observed a higher frequency of the CT60 disease susceptible allele in our controls compared to the British, Italian and Dutch populations, which might contribute to the high frequency of T1D in Sweden. In contrast to previously published findings, however, we were unable to find differences in the sCTLA-4/flCTLA-4 expression ratio based on the CT60 genotype in 23 healthy volunteers, also from northern Sweden. Analysis of sCTLA-4 protein levels in serum showed no correlation between sCTLA-4 protein levels and disease status or CT60 genotype.

CONCLUSION: Association was found between T1D/AITD and all three polymorphisms investigated. However, in contrast to previous investigations, sCTLA-4 RNA and protein expression levels did not differ based on CT60 genotype. Our results do not rule out the CT60 SNP as an important polymorphism in the development of T1D or AITD, but suggest that further investigations are necessary to elucidate the effect of the CTLA-4 region on the development of T1D and AITD.

Keywords
CT60 Genotype, Sandwich Immunoassay, AITD Patient, Mouth Swab, CT60 Polymorphism
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-7751 (URN)10.1186/1471-2350-8-3 (DOI)000244329100001 ()17280620 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2018-06-09Bibliographically approved
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