| 1. |
- Hirvonen, M Karoliina, et al.
(författare)
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Serum APOC1 levels are decreased in young autoantibody positive children who rapidly progress to type 1 diabetes
- 2023
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Better understanding of the early events in the development of type 1 diabetes is needed to improve prediction and monitoring of the disease progression during the substantially heterogeneous presymptomatic period of the beta cell damaging process. To address this concern, we used mass spectrometry-based proteomics to analyse longitudinal pre-onset plasma sample series from children positive for multiple islet autoantibodies who had rapidly progressed to type 1 diabetes before 4 years of age (n = 10) and compared these with similar measurements from matched children who were either positive for a single autoantibody (n = 10) or autoantibody negative (n = 10). Following statistical analysis of the longitudinal data, targeted serum proteomics was used to verify 11 proteins putatively associated with the disease development in a similar yet independent and larger cohort of children who progressed to the disease within 5 years of age (n = 31) and matched autoantibody negative children (n = 31). These data reiterated extensive age-related trends for protein levels in young children. Further, these analyses demonstrated that the serum levels of two peptides unique for apolipoprotein C1 (APOC1) were decreased after the appearance of the first islet autoantibody and remained relatively less abundant in children who progressed to type 1 diabetes, in comparison to autoantibody negative children.
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| 2. |
- Kurko, Johanna, et al.
(författare)
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Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI)
- 2016
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Ingår i: Metabolism. - : Saunders Elsevier. - 0026-0495 .- 1532-8600. ; 65:9, s. 1361-1375
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Lysinuric protein intolerance (LPI [MIM 222700]) is an aminoaciduria with defective transport of cationic amino acids in epithelial cells in the small intestine and proximal kidney tubules due to mutations in the SLC7A7 gene. LPI is characterized by protein malnutrition, failure to thrive and hyperammonemia. Many patients also suffer from combined hyperlipidemia and chronic kidney disease (CKD) with an unknown etiology.METHODS: Here, we studied the plasma metabolomes of the Finnish LPI patients (n=26) and healthy control individuals (n=19) using a targeted platform for analysis of amino acids as well as two analytical platforms with comprehensive coverage of molecular lipids and polar metabolites.RESULTS: Our results demonstrated that LPI patients have a dichotomy of amino acid profiles, with both decreased essential and increased non-essential amino acids. Altered levels of metabolites participating in pathways such as sugar, energy, amino acid and lipid metabolism were observed. Furthermore, of these metabolites, myo-inositol, threonic acid, 2,5-furandicarboxylic acid, galactaric acid, 4-hydroxyphenylacetic acid, indole-3-acetic acid and beta-aminoisobutyric acid associated significantly (P<0.001) with the CKD status. Lipid analysis showed reduced levels of phosphatidylcholines and elevated levels of triacylglycerols, of which long-chain triacylglycerols associated (P<0.01) with CKD.CONCLUSIONS: This study revealed an amino acid imbalance affecting the basic cellular metabolism, disturbances in plasma lipid composition suggesting hepatic steatosis and fibrosis and novel metabolites correlating with CKD in LPI. In addition, the CKD-associated metabolite profile along with increased nitrite plasma levels suggests that LPI may be characterized by increased oxidative stress and apoptosis, altered microbial metabolism in the intestine and uremic toxicity.
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| 3. |
- Laajala, Essi, et al.
(författare)
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Permutation-based significance analysis reduces the type 1 error rate in bisulfite sequencing data analysis of human umbilical cord blood samples
- 2022
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Ingår i: Epigenetics. - : Taylor & Francis. - 1559-2294 .- 1559-2308. ; 17:12, s. 1608-1627
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation patterns are largely established in-utero and might mediate the impacts of in-utero conditions on later health outcomes. Associations between perinatal DNA methylation marks and pregnancy-related variables, such as maternal age and gestational weight gain, have been earlier studied with methylation microarrays, which typically cover less than 2% of human CpG sites. To detect such associations outside these regions, we chose the bisulphite sequencing approach. We collected and curated clinical data on 200 newborn infants; whose umbilical cord blood samples were analysed with the reduced representation bisulphite sequencing (RRBS) method. A generalized linear mixed-effects model was fit for each high coverage CpG site, followed by spatial and multiple testing adjustment of P values to identify differentially methylated cytosines (DMCs) and regions (DMRs) associated with clinical variables, such as maternal age, mode of delivery, and birth weight. Type 1 error rate was then evaluated with a permutation analysis. We discovered a strong inflation of spatially adjusted P values through the permutation analysis, which we then applied for empirical type 1 error control. The inflation of P values was caused by a common method for spatial adjustment and DMR detection, implemented in tools comb-p and RADMeth. Based on empirically estimated significance thresholds, very little differential methylation was associated with any of the studied clinical variables, other than sex. With this analysis workflow, the sex-associated differentially methylated regions were highly reproducible across studies, technologies, and statistical models.
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| 4. |
- Laajala, Essi, et al.
(författare)
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Umbilical cord blood DNA methylation in children who later develop type 1 diabetes
- 2021
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Ingår i: European Journal of Immunology. - : John Wiley & Sons. - 0014-2980 .- 1521-4141. ; 51:Suppl. 1, s. 291-291
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Distinct DNA methylation patterns have recently been observed to precede Type 1 Diabetes in whole blood collected from young children. Our aim was to determine if such methylation patterns are present already at the time of birth. Reduced representation bisulfite sequencing (RRBS) analysis was performed on a unique collection of umbilical cord blood samples collected within the Type 1 Diabetes Prediction and Prevention (DIPP) study. Children later diagnosed with Type 1 Diabetes and/or testing positive for multiple islet autoantibodies (N=43) were compared to control individuals (N=79), who remained autoantibody‐negative throughout the DIPP follow‐up until 15 years of age. Altogether 24 clinical and technical covariates related to the pregnancy and the mother were included in a binomial mixed effects model, which was fit separately for each high‐coverage CpG site, followed by spatial and multiple testing adjustment of P values. We discovered a strong inflation of P values, which was caused by a standard spatial adjustment method. Findings that were based on Benjamini‐Hochberg corrected spatially adjusted P values, could not be validated by Pyrosequencing. We therefore used permutation‐based significance analysis and showed that sex‐associated differentially methylated cytosines could be reproducibly detected with this approach. After empirical type 1 error control, no differences in cord blood methylation patterns were observed between cases and controls. Differences between children who progress to Type 1 Diabetes and those who remain healthy throughout childhood, are not yet present in the perinatal DNA methylome.
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| 5. |
- Laajala, Essi, et al.
(författare)
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Umbilical cord blood DNA methylation in children who later develop type 1 diabetes
- 2022
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 65:9, s. 1534-1540
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Distinct DNA methylation patterns have recently been observed to precede type 1 diabetes in whole blood collected from young children. Our aim was to determine whether perinatal DNA methylation is associated with later progression to type 1 diabetes.METHODS: Reduced representation bisulphite sequencing (RRBS) analysis was performed on umbilical cord blood samples collected within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study. Children later diagnosed with type 1 diabetes and/or who tested positive for multiple islet autoantibodies (n = 43) were compared with control individuals (n = 79) who remained autoantibody-negative throughout the DIPP follow-up until 15 years of age. Potential confounding factors related to the pregnancy and the mother were included in the analysis.RESULTS: No differences in the umbilical cord blood methylation patterns were observed between the cases and controls at a false discovery rate <0.05.CONCLUSIONS/INTERPRETATION: Based on our results, differences between children who progress to type 1 diabetes and those who remain healthy throughout childhood are not yet present in the perinatal DNA methylome. However, we cannot exclude the possibility that such differences would be found in a larger dataset.
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| 6. |
- Oresic, Matej, 1967-, et al.
(författare)
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Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 62:9, s. 3268-3274
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies show that children who later progress to type 1 diabetes (T1D) have decreased preautoimmune concentrations of multiple phospholipids as compared with nonprogressors. It is still unclear whether these changes associate with development of β-cell autoimmunity or specifically with clinical T1D. Here, we studied umbilical cord serum lipidome in infants who later developed T1D (N = 33); infants who developed three or four (N = 31) islet autoantibodies, two (N = 31) islet autoantibodies, or one (N = 48) islet autoantibody during the follow-up; and controls (N = 143) matched for sex, HLA-DQB1 genotype, city of birth, and period of birth. The analyses of serum molecular lipids were performed using the established lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry. We found that T1D progressors are characterized by a distinct cord blood lipidomic profile that includes reduced major choline-containing phospholipids, including sphingomyelins and phosphatidylcholines. A molecular signature was developed comprising seven lipids that predicted high risk for progression to T1D with an odds ratio of 5.94 (95% CI, 1.07-17.50). Reduction in choline-containing phospholipids in cord blood therefore is specifically associated with progression to T1D but not with development of β-cell autoimmunity in general.
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| 7. |
- Öhman, Tiina, et al.
(författare)
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Phosphoproteome characterization reveals that Sendai virus infection activates mTOR signaling in human epithelial cells.
- 2015
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Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 15:12, s. 2087-97
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Tidskriftsartikel (refereegranskat)abstract
- Sendai virus (SeV) is a common respiratory pathogen in mice, rats, and hamsters. Host cell recognition of SeV is mediated by pathogen recognition receptors, which recognize viral components and induce intracellular signal transduction pathways that activate the antiviral innate immune response. Viruses use host proteins to control the activities of signaling proteins and their downstream targets, and one of the most important host protein modifications regulated by viral infection is phosphorylation. In this study, we used phosphoproteomics combined with bioinformatics to get a global view of the signaling pathways activated during SeV infection in human lung epithelial cells. We identified altogether 1347 phosphoproteins, and our data shows that SeV infection induces major changes in protein phosphorylation affecting the phosphorylation of almost one thousand host proteins. Bioinformatics analysis showed that SeV infection activates known pathways including MAPK signaling, as well as signaling pathways previously not linked to SeV infection including Rho family of GTPases, HIPPO signaling, and mammalian target of rapamycin (mTOR)-signaling pathway. Further, we performed functional studies with mTOR inhibitors and siRNA approach, which revealed that mTOR signaling is needed for both the host IFN response as well as viral protein synthesis in SeV-infected human lung epithelial cells.
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