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- Davis, Kasey N., et al.
(författare)
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Mutations in human DNA methyltransferase DNMT1 induce specific genome-wide epigenomic and transcriptomic changes in neurodevelopment
- 2023
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 32:21, s. 3105-3120
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Tidskriftsartikel (refereegranskat)abstract
- DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPSCs) and induced neurons (iNs) generated from patients with ADCA-DN and controls, to explore the epigenomic and transcriptomic effects of mutations in DNMT1. We show cell type–specific changes in gene expression and DNA methylation patterns. DNA methylation and gene expression changes were negatively correlated in iPSCs and iNs. In addition, we identified a group of genes associated with clinical phenotypes of ADCA-DN, including PDGFB and PRDM8 for cerebellar ataxia, psychosis and dementia and NR2F1 for deafness and optic atrophy. Furthermore, ZFP57, which is required to maintain gene imprinting through DNA methylation during early development, was hypomethylated in promoters and exhibited upregulated expression in patients with ADCA-DN in both iPSC and iNs. Our results provide insight into the functions of DNMT1 and the molecular changes associated with ADCA-DN, with potential implications for genes associated with related phenotypes.
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| 2. |
- Hegglin, Michaela I., et al.
(författare)
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Overview and update of the SPARC Data Initiative: comparison of stratospheric composition measurements from satellite limb sounders
- 2021
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Ingår i: Earth System Science Data. - : Copernicus GmbH. - 1866-3516 .- 1866-3508. ; 13:5, s. 1855-1903
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Forskningsöversikt (refereegranskat)abstract
- The Stratosphere-troposphere Processes and their Role in Climate (SPARC) Data Initiative (SPARC, 2017) performed the first comprehensive assessment of currently available stratospheric composition measurements obtained from an international suite of space-based limb sounders. The initiative's main objectives were (1) to assess the state of data availability, (2) to compile time series of vertically resolved, zonal monthly mean trace gas and aerosol fields, and (3) to perform a detailed intercomparison of these time series, summarizing useful information and highlighting differences among datasets. The datasets extend over the region from the upper troposphere to the lower mesosphere (300-0.1 hPa) and are provided on a common latitude-pressure grid. They cover 26 different atmospheric constituents including the stratospheric trace gases of primary interest, ozone (O-3) and water vapor (H2O), major long-lived trace gases (SF6, N2O, HF, CCl3F, CCl2F2, NO y), trace gases with intermediate lifetimes (HCl, CH4, CO, HNO3), and shorter-lived trace gases important to stratospheric chemistry including nitrogen-containing species (NO, NO2, NOx, N2O5, HNO4), halogens (BrO, ClO, ClONO2, HOCl), and other minor species (OH, HO2, CH2O, CH3CN), and aerosol. This overview of the SPARC Data Initiative introduces the updated versions of the SPARC Data Initiative time series for the extended time period 1979-2018 and provides information on the satellite instruments included in the assessment: LIMS, SAGE I/II/III, HALOE, UARS-MLS, POAM II/III, OSIRIS, SMR, MIPAS, GOMOS, SCIAMACHY, ACE-FTS, ACEMAESTRO, Aura-MLS, HIRDLS, SMILES, and OMPS-LP. It describes the Data Initiative's top-down climatological validation approach to compare stratospheric composition measurements based on zonal monthly mean fields, which provides upper bounds to relative inter-instrument biases and an assessment of how well the instruments are able to capture geophysical features of the stratosphere. An update to previously published evaluations of O-3 and H2O monthly mean time series is provided. In addition, example trace gas evaluations of methane (CH4), carbon monoxide (CO), a set of nitrogen species (NO, NO2, and HNO3), the reactive nitrogen family (NOy), and hydroperoxyl (HO2) are presented. The results highlight the quality, strengths and weaknesses, and representativeness of the different datasets. As a summary, the current state of our knowledge of stratospheric composition and variability is provided based on the overall consistency between the datasets. As such, the SPARC Data Initiative datasets and evaluations can serve as an atlas or reference of stratospheric composition and variability during the "golden age" of atmospheric limb sounding. The updated SPARC Data Initiative zonal monthly mean time series for each instrument are publicly available and accessible via the Zenodo data archive (Hegglin et al., 2020).
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