| 1. |
|
|
| 2. |
- Manry, Jérémy, et al.
(författare)
-
The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.
- 2022
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:21
-
Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
|
|
| 3. |
- Mas e Braga, Martim, et al.
(författare)
-
Antarctic ice stream thickening under Pliocene warmth
- 2024
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Ice streams regulate most ice mass loss in Antarctica. Determining their response to Pliocene warmth could provide insights into their future behaviour, but is hindered by poor representation of subglacial topography in ice-sheet models. We address this limitation using a high-resolution regional model for Dronning Maud Land (East Antarctica). We show that the region’s largest ice stream, Jutulstraumen, thickens by 700 m under warm late-Pliocene conditions despite ice-shelf collapse and a retrograde bed slope, while nearby ice streams thin. While it is known that unstable retreat on a retrograde slope can be slowed under certain conditions, this finding illustrates that an ice stream can thicken and gain mass. We attribute thickening to high lateral stresses at its flux gate, which constrict ice drainage. Similar stress balances occur today in 27% of East Antarctica, and understanding how lateral stresses regulate ice-stream discharge is necessary for accurately assessing Antarctica’s sea-level rise contribution.
|
|
| 4. |
- Mas e Braga, Martim, et al.
(författare)
-
Nunataks as barriers to ice flow : implications for palaeo ice sheet reconstructions
- 2021
-
Ingår i: The Cryosphere. - : Copernicus GmbH. - 1994-0416 .- 1994-0424. ; 15:10, s. 4929-4947
-
Tidskriftsartikel (refereegranskat)abstract
- Numerical models predict that discharge from the polar ice sheets will become the largest contributor to sea-level rise over the coming centuries. However, the predicted amount of ice discharge and associated thinning depends on how well ice sheet models reproduce glaciological processes, such as ice flow in regions of large topographic relief, where ice flows around bedrock summits (i.e. nunataks) and through outlet glaciers. The ability of ice sheet models to capture long-term ice loss is best tested by comparing model simulations against geological data. A benchmark for such models is ice surface elevation change, which has been constrained empirically at nunataks and along margins of outlet glaciers using cosmogenic exposure dating. However, the usefulness of this approach in quantifying ice sheet thinning relies on how well such records represent changes in regional ice surface elevation. Here we examine how ice surface elevations respond to the presence of strong topographic relief that acts as an obstacle by modelling ice flow around and between idealised nunataks during periods of imposed ice sheet thinning. We find that, for realistic Antarctic conditions, a single nunatak can exert an impact on ice thickness over 20 km away from its summit, with its most prominent effect being a local increase (decrease) of the ice surface elevation of hundreds of metres upstream (downstream) of the obstacle. A direct consequence of this differential surface response for cosmogenic exposure dating is a delay in the time of bedrock exposure upstream relative to downstream of a nunatak summit. A nunatak elongated transversely to ice flow is able to increase ice retention and therefore impose steeper ice surface gradients, while efficient ice drainage through outlet glaciers produces gentler gradients. Such differences, however, are not typically captured by continent-wide ice sheet models due to their coarse grid resolutions. Their inability to capture site-specific surface elevation changes appears to be a key reason for the observed mismatches between the timing of ice-free conditions from cosmogenic exposure dating and model simulations. We conclude that a model grid refinement over complex topography and information about sample position relative to ice flow near the nunatak are necessary to improve data-model comparisons of ice surface elevation and therefore the ability of models to simulate ice discharge in regions of large topographic relief.
|
|
| 5. |
- Matuozzo, Daniela, et al.
(författare)
-
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.
- 2023
-
Ingår i: Genome medicine. - 1756-994X. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in~80% of cases.We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1×10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1×10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4×10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7×10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68×10-5).Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60years old.
|
|
