| 1. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 2. |
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| 3. |
- Derkacheva, Maria, et al.
(författare)
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H2A deubiquitinases UBP12/13 are part of the Arabidopsis polycomb group protein system
- 2016
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Ingår i: Nature plants. - 2055-026X .- 2055-0278. ; 2:9
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Tidskriftsartikel (refereegranskat)abstract
- Polycomb group (PcG) proteins form an epigenetic memory system in plants and animals, but interacting proteins are poorly known in plants. Here, we have identified Arabidopsis UBIQUITIN SPECIFIC PROTEASES (USP; UBP in plant and yeasts) 12 and 13 as partners of the plant-specific PcG protein LIKE HETEROCHROMATIN PROTEIN 1 (LHP1). UBP12 binds to chromatin of PcG target genes and is required for histone H3 lysine 27 trimethylation and repression of a subset of PcG target genes. Plants lacking UBP12 and UBP13 developed autonomous endosperm in the absence of fertilization. We have identified UBP12 and UBP13 as new proteins in the plant PcG regulatory network. UBP12 and UBP13 belong to an ancient gene family and represent plant homologues of metazoan USP7. We have found that Drosophila USP7 shares a function in heterochromatic gene repression with UBP12/13 and their homologue UBP26. In summary, we demonstrate that USP7-like proteins are essential for gene silencing in diverse genomic contexts.
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| 4. |
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| 5. |
- Ottosson, Lars, et al.
(författare)
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Structural, functional and immunologic characterization of folded subdomains in the Ro52 protein targeted in Sjögren's syndrome
- 2006
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 43:6, s. 588-598
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Tidskriftsartikel (refereegranskat)abstract
- Ro52, one of the major autoantigens in the rheumatic disease Sjögren's syndrome (SS), belongs to the tripartite motif (TRIM) or RING-B-box-coiled-coil (RBCC) protein family, thus comprising an N-terminal RING, followed by a B-box and a coiled-coil region. Several different proteomic functions have been suggested for Ro52, including DNA binding, protein interactions and Zn 2+-binding. To analyze the presence and/or absence of these functions and, in particular, map those to different subregions, the modular composition of the Ro52 protein was experimentally characterized. Two structured parts of Ro52 were identified, corresponding to the RING-B-box and the coiled-coil regions, respectively. Secondary structure analysis by circular dichroism (CD) spectroscopy indicated that the two subregions are independently structured. The entire RING-B-box region displayed Zn2+-dependent stabilization against proteolysis in the presence of Zn2+, indicating functional Zn2+-binding sites in both the RING and the B-box. However, no stabilization with DNA was detected, irrespective of Zn2+, thus suggesting that the RING-B-box region does not bind DNA. Oligomerization of the coiled-coil was investigated by analytical ultracentrifugation and in a mammalian two-hybrid system. Both methods show weak homodimer affinity, in parity with other coiled-coil domains involved in regulatory interactions. The C-terminal B30.2 region was rapidly degraded both during cellular expression and refolding, indicating a less stable structure. Immunologic analysis of the stable protein regions with sera from patients with Sjögren's syndrome shows that immunodominant epitopes to a large extent are localized in the structurally stable parts of Ro52. The results form a basis for further Ro52 functional studies on the proteome level. © 2005 Elsevier Ltd. All rights reserved.
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| 6. |
- Reifarth, R., et al.
(författare)
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Nuclear astrophysics with radioactive ions at FAIR
- 2016
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 665:1
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Konferensbidrag (refereegranskat)abstract
- The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process beta-decay chains. These nuclei are attributed to the p and rp process. For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections. The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes.
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| 7. |
- Svedberg, Jesper, 1981-, et al.
(författare)
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The effect of genomic conflict on genome evolution in Neurospora intermedia
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Genomic conflicts are predicted to have a major influence on genome evolution, but empirical data is needed in order to confirm or refute this prediction. In this study, we used a genomic approach to address the influence of genomic conflicts, caused by selfish genetic elements, on genome evolution in the model fungus Neurospora intermedia. We gathered high-quality genomic data from sixteen strains of Neurospora by using the PacBio RSII long-read sequencing platform. Six of these strains carry the meiotic drive element Sk-2 or Sk-3, which are multigene systems of killer and resistance loci linked together in haplotypes. We show that in the N. intermedia genomes, in which an array of protective mechanisms act to limit the negative effects of selfish DNA, both the Sk-2 and Sk-3 haplotypes have accumulated a dense set of inversions that are interspersed with transposable elements. The inversions are unique for each killer type, showing that they have a long separated evolutionary history and likely have established themselves as meiotic drivers independently. For the Sk-2 haplotype, for which we have polymorphism-data, we see signs of relaxed selection, which is consistent with the hypothesis that recombination suppression reduces the efficacy of selection in this region. Thus, our data indicates that albeit N. intermedia possesses an active genome defence system, selfish genetic elements have worked in concert and significantly affected the evolutionary trajectory of chromosome 3 in this species.
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| 8. |
- Wennerstrand, Patricia, et al.
(författare)
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Different mechanisms behind low enzyme activity in vivo of two different variants of Thiopurine S-methyltransferase, TPMT
- 2010
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Ingår i: The FEBS Journal. - : Wiley-Blackwell. - 1742-464X .- 1742-4658. ; 277:Suppl. 1, s. 257-258
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In treatment of acute lymphoblastic leukemia and inflammatorybowel disease (IBD) thiopurines such as azathioprine and 6-mercaptopurineare used. All of these drugs are prodrugs and are, inthe cell, converted to 6-thioguanines (6-TGNs) and incorporatedinto DNA or inhibiting purine synthesis. A key enzyme for thisregulation is the cytosolic enzyme thiopurine S-methyltransferase(TPMT). This enzyme degrades azathioprine and 6-mercaptopurineto methylmercapto-purine and thereby reduces the bioavailabilityof the 6-TGNs incorporated into DNA. TPMT is apolymorphic enzyme with at least 29 different allelic variantsknown today and is one of the more classical examples of pharmacogeneticswhere the TPMT enzyme activity of the allelic variantsis directly correlated to the clinical dosages of the thiopurines, with a 10–15 fold dosage reduction for an allelic variantwith low TPMT enzyme activity. Even though TPMT is awell studied protein. Many studies have been performed in yeast‘‘suspensions’’ and not on pure protein solutions. It has beenspeculated and in a few cases shown that the reason for the lowactivity for most of the allelic variants is mainly due to the lowstability and/or tendency to aggregate. The mutations in thisstudy TPMT *2 (A80P) and TPMT * 5 (L49S) are both situatedat a distance far from the active site, however the enzyme activitiesare severely affected at 37°C. Preliminary results, using a repertoireof techniques such as CD, fluorescence and limitedproteolysis experiments suggest two different mechanisms for thelow enzyme activity at a temperature corresponding to in vivo conditions.
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| 9. |
- Wennerstrand, Patricia, et al.
(författare)
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Structural Characteristics Determine the Cause of the Low Enzyme Activity of Two Thiopurine S-Methyltransferase Allelic Variants : A Biophysical Characterization of TPMT*2 and TPMT*5
- 2012
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 51:30, s. 5912-5920
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Tidskriftsartikel (refereegranskat)abstract
- The enzyme thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurine drugs used to treat acute lymphoblastic leukemia and inflammatory bowel disease. Thus far, at least 29 variants of the TPMT gene have been described, many of which encode proteins that have low enzyme activity and in some cases become more prone to aggregation and degradation. Here, the two naturally occurring variants, TPMT*2 (Ala80 → Pro) and TPMT*5 (Leu49 → Ser), were cloned and expressed in Escherichia coli. Far-UV circular dichroism spectroscopy showed that TPMT*2 was substantially destabilized whereas TPMT*5 showed much greater stability comparable to that of wild-type TPMT (TPMTwt). The extrinsic fluorescent molecule anilinonaphthalene sulfonate (ANS) was used to probe the tertiary structure during thermal denaturation. In contrast to TPMTwt, neither of the variants bound ANS to a large extent. To explore the morphology of the TPMT aggregates, we performed luminescent conjugated oligothiophene staining and showed fibril formation for TPMT*2 and TPMT*5. The differences in the flexibility of TPMTwt, TPMT*2, and TPMT*5 were evaluated in a limited proteolysis experiment to pinpoint stable regions. Even though there is only one amino acid difference between the analyzed TPMT variants, a clear disparity in the cleavage patterns was observed. TPMT*2 displays a protected region in the C-terminus, which differs from TPMTwt, whereas the protected regions in TPMT*5 are located mainly in the N-terminus close to the active site. In conclusion, this in vitro study, conducted to probe structural changes during unfolding of TPMT*2 and TPMT*5, demonstrates that the various causes of the low enzyme activity in vivo could be explained on a molecular level.
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