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- Fliegauf, M, et al.
(author)
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Detrimental NFKB1 missense variants affecting the Rel-homology domain of p105/p50
- 2022
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In: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13, s. 965326-
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Journal article (peer-reviewed)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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- Prikhna, T., et al.
(author)
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Effects of high pressure on the physical properties of MgB2
- 2011
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In: Journal of Superconductivity and Novel Magnetism. - : Springer Science and Business Media LLC. - 1557-1939 .- 1557-1947. ; 24:5, s. 137-150
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Journal article (peer-reviewed)abstract
- The synthesis of MgB2-based materials under high pressure gave the possibility to suppress the evaporation of magnesium and to obtain near theoretically dense nanograined structures with high superconducting, thermal conducting, and mechanical characteristics: critical current densities of 1.8-1.0×106 A/cm2 in the self-field and 103 A/cm2 in a magnetic field of 8 T at 20 K, 5-3×105 A/cm2 in self-field at 30 K, the corresponding critical fields being Hc2=15 T at 22 K and irreversible fields Hirr=13 T at 20 K, and Hirr=3.5 T at 30 K, thermal conduction of 53±2 W/(m{dot operator}K), the Vickers hardness HV=10.12±0.2 GPa under a load of 148.8 N and the fracture toughness K1 C=7.6±2.0 MPa{dot operator}m0.5 under the same load, the Young modulus E=213 GPa. Estimation of quenching current and AC losses allowed the conclusion that high-pressure-prepared materials are promising for application in transformer-type fault current limiters working at 20-30 K.
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