| 1. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 2. |
- Saevarsdottir, S., et al.
(author)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Journal article (peer-reviewed)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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| 3. |
- Schöttelndreier, Marion, et al.
(author)
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Organic acid exudation by wild herbs in response to elevated Al concentrations
- 2001
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In: Annals of Botany. - : Oxford University Press (OUP). - 0305-7364. ; 87:6, s. 769-775
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Journal article (peer-reviewed)abstract
- In acidic soils, monomeric aluminium (Al3+) can reach levels that are toxic to plants, thus preventing many species from growing there. Organic acids chelate Al and render it non-toxic. It has been shown that exudation of organic acids by Al-tolerant crops increases their tolerance to Al. We have extended this observation to wild plants by comparing the ability of ten herbs to exude organic acids in response to elevated Al levels. We hypothesized that exudation of organic acids was related to the ability of plants to grow on Al-rich soils. Two grasses were grown in rhizotrons in soils with 41 and 63 muM reactive Al. Organic acids were sampled from root tips connected to an intact plant-root system. Deschampsia flexuosa (L.) Trin. exuded more malic acid when grown in the soil with the highest Al content. Five forbs and five grasses were also exposed to three Al levels (0, 25 and 75 muM) in a hydroponic system. Rumex acetosella L, and Viscaria vulgaris Bernh. increased exudation of oxalic acid and Galium saxatile auct. non L. and Veronica officinalis L, increased exudation of citric acid in response to elevated Al. The distribution of the forbs in the field as described by soil pH was negatively related to the amount of organic acids exuded in response to Al. In contrast, none of the grasses exuded higher amounts of organic acids with increasing Al concentration in the hydroponic experiment. (C) 2001 Annals of Botany Company.
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| 4. |
- Ugale, A., et al.
(author)
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MLL-ENL-mediated leukemia initiation at the interface of lymphoid commitment
- 2017
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In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 36, s. 3207-3212
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Journal article (peer-reviewed)abstract
- Translocations involving the mixed lineage leukemia-1 are recurrent events in acute leukemia and associate with lymphoid (ALL), myeloid (AML) or mixed lineage (MLL) subtypes. Despite an association with ALL in humans, murine MLL fusion models are persistently restricted to AML. We here explored this issue using an inducible mixed lineage leukemia-eleven nineteen leukemia (MLL-ENL) mouse model. Although multiple progenitor cell types with myeloid potential are potent AML leukemia-initiating cells, also the earliest lymphoid progenitors were capable of initiating AML. This ability to evoke a latent myeloid potential in the earliest lymphoid progenitors was lost upon further lymphoid commitment. At the same time, more downstream/committed lymphoid precursors also failed to initiate lymphoid leukemia. Co-expression of MLL-ENL with a constitutively active RAS allele, the most common co-mutation in MLL fusion leukemias, could influence on both disease latency and lineage assignment of developing leukemia in what appears to be a mutation-order-dependent manner. Finally, CEBPB-mediated transdifferentation of committed and otherwise leukemia-incompetent B-cell progenitors imbued these cells with leukemic competence for AML. Therefore, apart from providing detailed insight into the differential responsiveness of candidate target cells to a first-hit MLL fusion event, our data warrants caution to therapeutic approaches based on the concept of transdifferentiation.Oncogene advance online publication, 9 January 2017; doi:10.1038/onc.2016.470.
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| 5. |
- Norddahl, Gudmundur, et al.
(author)
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Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging
- 2011
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In: Cell Stem Cell. - Cambridge Mass. : Cell Press. - 1934-5909 .- 1875-9777. ; 8:5, s. 499-510
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Journal article (peer-reviewed)abstract
- Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading-defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging.
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