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- Fliegauf, M, et al.
(författare)
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Detrimental NFKB1 missense variants affecting the Rel-homology domain of p105/p50
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13, s. 965326-
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Tidskriftsartikel (refereegranskat)abstract
- Most of the currently known heterozygous pathogenic NFKB1 (Nuclear factor kappa B subunit 1) variants comprise deleterious defects such as severe truncations, internal deletions, and frameshift variants. Collectively, these represent the most frequent monogenic cause of common variable immunodeficiency (CVID) identified so far. NFKB1 encodes the transcription factor precursor p105 which undergoes limited proteasomal processing of its C-terminal half to generate the mature NF-κB subunit p50. Whereas p105/p50 haploinsufficiency due to devastating genetic damages and protein loss is a well-known disease mechanism, the pathogenic significance of numerous NFKB1 missense variants still remains uncertain and/or unexplored, due to the unavailability of accurate test procedures to confirm causality. In this study we functionally characterized 47 distinct missense variants residing within the N-terminal domains, thus affecting both proteins, the p105 precursor and the processed p50. Following transient overexpression of EGFP-fused mutant p105 and p50 in HEK293T cells, we used fluorescence microscopy, Western blotting, electrophoretic mobility shift assays (EMSA), and reporter assays to analyze their effects on subcellular localization, protein stability and precursor processing, DNA binding, and on the RelA-dependent target promoter activation, respectively. We found nine missense variants to cause harmful damage with intensified protein decay, while two variants left protein stability unaffected but caused a loss of the DNA-binding activity. Seven of the analyzed single amino acid changes caused ambiguous protein defects and four variants were associated with only minor adverse effects. For 25 variants, test results were indistinguishable from those of the wildtype controls, hence, their pathogenic impact remained elusive. In summary, we show that pathogenic missense variants affecting the Rel-homology domain may cause protein-decaying defects, thus resembling the disease-mechanisms of p105/p50 haploinsufficiency or may cause DNA-binding deficiency. However, rare variants (with a population frequency of less than 0.01%) with minor abnormalities or with neutral tests should still be considered as potentially pathogenic, until suitable tests have approved them being benign.
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- Kerré, B., et al.
(författare)
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Historical soil amendment with charcoal increases sequestration of non-charcoal carbon : a comparison among methods of black carbon quantification
- 2016
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Ingår i: European Journal of Soil Science. - : Wiley. - 1351-0754 .- 1365-2389. ; 67:3, s. 324-331
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Tidskriftsartikel (refereegranskat)abstract
- We have shown previously that soil with historical (>150 years) applications of charcoal had larger recent (C4-maize derived) carbon content than adjacent soil; however, we could not determine whether there was an effect on older, C3-plant-derived, soil organic carbon (SOC). Therefore, we assessed the effect of historical additions of charcoal on the sequestration of recent and older SOC with a combination of delta C-13 analysis and different quantification techniques for black carbon (BC): dichromate oxidation (Cr2O7), chemo-thermal oxidation (CTO-285) and differential scanning calorimetry (DSC). Topsoils cropped with maize (Zea mays) under former charcoal production sites (N = 12) were identified in the field as black spots and had a larger (3.5%, P < 0.05) percentage of organic carbon (OC) contents than adjacent soil outside these spots (2.0%). The charcoal content varied with the detection technique used as follows: CTO-285 > DSC > Cr2O7. Black spots contained 1.6-1.7 times more (P < 0.05) maize-derived OC content than adjacent soil, irrespective of the BC quantification technique. The content of non-charcoal OC was 1.0-1.4 times larger in black spots than in adjacent soil, but differences were significant only for the Cr2O7 method. Soil physicochemical fractionation showed that at charcoal production sites more OC was recovered in the particulate organic matter and silt and clay fractions. The delta C-13 analysis suggested that additional maize-OC in black spots was in the physically more protected silt and clay fraction. Overall, this study shows that historical charcoal amendment in soil enhances the accumulation of recent maize-derived OC in a temperate climate without replacing the older C stocks.
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- Taveirne, S, et al.
(författare)
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The transcription factor ETS1 is an important regulator of human NK cell development and terminal differentiation
- 2020
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 136:3, s. 288-298
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells are important in the immune defense against tumor cells and pathogens, and regulate other immune cells by cytokine secretion. Whereas murine NK cell biology has been extensively studied, knowledge about transcriptional circuitries controlling human NK cell development and maturation is limited. By generating ETS1-deficient human embryonic stem cells (hESC) and by expressing the dominant-negative ETS1 p27 isoform in cord blood (CB) hematopoietic progenitor cells (HPCs), we show that the transcription factor ETS1 is critically required for human NK cell differentiation. Genome-wide transcriptome analysis determined by RNA-sequencing combined with chromatin immunoprecipitation-sequencing (ChIP-seq) analysis reveals that human ETS1 directly induces expression of key transcription factors that control NK cell differentiation, i.e. E4BP4, TXNIP, TBET, GATA3, HOBIT and BLIMP1. In addition, ETS1 regulates expression of genes involved in apoptosis and NK cell activation. Our study provides important molecular insights into the role of ETS1 as an important regulator of human NK cell development and terminal differentiation.
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