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- Garcia-Garcia, A, et al.
(författare)
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Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia
- 2023
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 220:5
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Tidskriftsartikel (refereegranskat)abstract
- X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4–dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8–207.8, P < 0.001). The patients’ susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.
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| 2. |
- Kreins, AY, et al.
(författare)
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Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome
- 2015
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 212:10, s. 1641-1662
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17+ T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
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| 5. |
- 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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| 6. |
- Jeppsson, Ulf, et al.
(författare)
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Benchmark simulation models, quo vadis?
- 2013
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Ingår i: Water Science and Technology. - : IWA Publishing. - 0273-1223 .- 1996-9732. ; 68:1, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- As the work of the IWA Task Group on Benchmarking of Control Strategies for wastewater treatment plants (WWTPs) is coming to an end, it is essential to disseminate the knowledge gained. For this reason, all authors of the IWA Scientific and Technical Report on benchmarking have come together to provide their insights, highlighting areas where knowledge may still be deficient and where new opportunities are emerging, and to propose potential avenues for future development and application of the general benchmarking framework and its associated tools. The paper focuses on the topics of temporal and spatial extension, process modifications within the WWTP, the realism of models, control strategy extensions and the potential for new evaluation tools within the existing benchmark system. We find that there are major opportunities for application within all of these areas, either from existing work already being done within the context of the benchmarking simulation models (BSMs) or applicable work in the wider literature. Of key importance is increasing capability, usability and transparency of the BSM package while avoiding unnecessary complexity.
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| 7. |
- Onstein, R. E., et al.
(författare)
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To adapt or go extinct? The fate of megafaunal palm fruits under past global change
- 2018
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Ingår i: Proceedings of the Royal Society B-Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 285:1880
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Tidskriftsartikel (refereegranskat)abstract
- Past global change may have forced animal-dispersed plants with megafaunal fruits to adapt or go extinct, but these processes have remained unexplored at broad spatio-temporal scales. Here, we combine phylogenetic, distributional and fruit size data for more than 2500 palm (Arecaceae) species in a time-slice diversification analysis to quantify how extinction and adaptation have changed over deep time. Our results indicate that extinction rates of palms with megafaunal fruits have increased in the New World since the onset of the Quaternary (2.6 million years ago). In contrast, Old World palms show a Quaternary increase in transition rates towards evolving small fruits from megafaunal fruits. We suggest that Quaternary climate oscillations and concurrent habitat fragmentation and defaunation of megafaunal frugivores in the New World have reduced seed dispersal distances and geographical ranges of palms with megafaunal fruits, resulting in their extinction. The increasing adaptation to smaller fruits in the Old World could reflect selection for seed dispersal by ocean-crossing frugivores (e.g. medium-sized birds and bats) to colonize Indo-Pacific islands against a background of Quaternary sea-level fluctuations. Our macro-evolutionary results suggest that megafaunal fruits are increasingly being lost from tropical ecosystems, either due to extinctions or by adapting to smaller fruit sizes.
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| 8. |
- Rachmeler, L. A., et al.
(författare)
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Quiet Sun Center to Limb Variation of the Linear Polarization Observed by CLASP2 Across the Mg ıı h and k Lines
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 936:1
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Tidskriftsartikel (refereegranskat)abstract
- The CLASP2 (Chromospheric LAyer Spectro-Polarimeter 2) sounding rocket mission was launched on 2019 April 11. CLASP2 measured the four Stokes parameters of the Mg ıı h and k spectral region around 2800 Å along a 200'' slit at three locations on the solar disk, achieving the first spatially and spectrally resolved observations of the solar polarization in this near-ultraviolet region. The focus of the work presented here is the center-to-limb variation of the linear polarization across these resonance lines, which is produced by the scattering of anisotropic radiation in the solar atmosphere. The linear polarization signals of the Mg ıı h and k lines are sensitive to the magnetic field from the low to the upper chromosphere through the Hanle and magneto-optical effects. We compare the observations to theoretical predictions from radiative transfer calculations in unmagnetized semiempirical models, arguing that magnetic fields and horizontal inhomogeneities are needed to explain the observed polarization signals and spatial variations. This comparison is an important step in both validating and refining our understanding of the physical origin of these polarization signatures, and also in paving the way toward future space telescopes for probing the magnetic fields of the solar upper atmosphere via ultraviolet spectropolarimetry.
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| 10. |
- Hill, Adrian, et al.
(författare)
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Apparent effect of range size and fruit colour on palm diversification may be spurious
- 2023
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Ingår i: Journal of Biogeography. - 0305-0270. ; 50:10, s. 1724-1736
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Tidskriftsartikel (refereegranskat)abstract
- Aim Fruit selection by animal dispersers with different mobility directly impacts plant geographical range size, which, in turn, may impact plant diversification. Here, we examine the interaction between fruit colour, range size and diversification rate in palms by testing two hypotheses: (1) species with fruit colours attractive to birds have larger range sizes due to high dispersal ability and (2) disperser mobility affects whether small or large range size has higher diversification, and intermediate range size is expected to lead to the highest diversification rate regardless of disperser.Location Global.Time Period Contemporary (or present).Major Taxa Studied Palms (Arecaceae).Methods Palm species were grouped based on likely animal disperser group for given fruit colours. Range sizes were estimated by constructing alpha convex hull polygons from distribution data. We examined disperser group, range size or an interaction of both as possible drivers of change in diversification rate over time in a likelihood dynamic model (Several Examined State-dependent Speciation and Extinction [SecSSE]). Models were fitted, rate estimates were retrieved and likelihoods were compared to those of appropriate null models.Results Species with fruit colours associated with mammal dispersal had larger ranges than those with colours associated with bird dispersal. The best fitting SecSSE models indicated that the examined traits were not the primary driver of the heterogeneity in diversification rates in the model. Extinction rate complexity had a marked impact on model performance and on diversification rates.Main Conclusions Two traits related to dispersal mobility, range size and fruit colour, were not identified as the main drivers of diversification in palms. Increased model extinction rate complexity led to better performing models, which indicates that net diversification should be estimated rather than speciation alone. However, increased complexity may lead to incorrect SecSSE model conclusions without careful consideration. Finally, we find palms with more mobile dispersers do not have larger range sizes, meaning other factors are more important determinants of range size.
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