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Sökning: WFRF:(Friebe A)

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  • 2019
  • Tidskriftsartikel (refereegranskat)
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  • Baronti, Lorenzo, et al. (författare)
  • Base-pair conformational switch modulates miR-34a targeting of Sirt1 mRNA
  • 2020
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 583:7814, s. 139-144
  • Tidskriftsartikel (refereegranskat)abstract
    • MicroRNAs (miRNAs) regulate the levels of translation of messenger RNAs (mRNAs). At present, the major parameter that can explain the selection of the target mRNA and the efficiency of translation repression is the base pairing between the 'seed' region of the miRNA and its counterpart mRNA(1). Here we use R-1 rho relaxation-dispersion nuclear magnetic resonance(2) and molecular simulations(3) to reveal a dynamic switch-based on the rearrangement of a single base pair in the miRNA-mRNA duplex-that elongates a weak five-base-pair seed to a complete seven-base-pair seed. This switch also causes coaxial stacking of the seed and supplementary helix fitting into human Argonaute 2 protein (Ago2), reminiscent of an active state in prokaryotic Ago(4,5). Stabilizing this transient state leads to enhanced repression of the target mRNA in cells, revealing the importance of this miRNA-mRNA structure. Our observations tie together previous findings regarding the stepwise miRNA targeting process from an initial 'screening' state to an 'active' state, and unveil the role of the RNA duplex beyond the seed in Ago2. Repression of a messenger RNA by a cognate microRNA depends not only on complementary base pairing, but also on the rearrangement of a single base pair, producing a conformation that fits better within the human Ago2 protein.
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  • Mauersberger, C, et al. (författare)
  • Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation
  • 2022
  • Ingår i: Nature cardiovascular research. - : Springer Science and Business Media LLC. - 2731-0590. ; 1:12, s. 1174-1186
  • Tidskriftsartikel (refereegranskat)abstract
    • Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here, by using histology, flow cytometry and intravital microscopy, we show that functional loss of sGC in platelets of atherosclerosis-prone Ldlr−/− mice contributes to atherosclerotic plaque formation, particularly via increasing in vivo leukocyte adhesion to atherosclerotic lesions. In vitro experiments revealed that supernatant from activated platelets lacking sGC promotes leukocyte adhesion to endothelial cells (ECs) by activating ECs. Profiling of platelet-released cytokines indicated that reduced platelet angiopoietin-1 release by sGC-depleted platelets, which was validated in isolated human platelets from carriers of GUCY1A1 risk alleles, enhances leukocyte adhesion to ECs. Importantly, pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in atherosclerosis-prone Ldlr−/− mice. Therefore, pharmacological sGC stimulation might represent a potential therapeutic strategy to prevent and treat CAD.
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  • Resultat 1-6 av 6

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