| 1. |
- Manry, Jérémy, et al.
(författare)
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The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.
- 2022
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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
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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.
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| 2. |
- Carpenter, S. R., et al.
(författare)
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General resilience to cope with extreme events
- 2012
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Ingår i: Sustainability. - : MDPI AG. - 2071-1050. ; 4:12, s. 3248-3259
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Tidskriftsartikel (refereegranskat)abstract
- Resilience to specified kinds of disasters is an active area of research and practice. However, rare or unprecedented disturbances that are unusually intense or extensive require a more broad-spectrum type of resilience. General resilience is the capacity of social-ecological systems to adapt or transform in response to unfamiliar, unexpected and extreme shocks. Conditions that enable general resilience include diversity, modularity, openness, reserves, feedbacks, nestedness, monitoring, leadership, and trust. Processes for building general resilience are an emerging and crucially important area of research.
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| 3. |
- Chalise, Jaya Prakash, et al.
(författare)
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Regulatory T cells manifest IFN-α mediated protection during antigen induced arthritis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionType I interferon induces tolerance against arthritogenic antigen and protects against antigen induced arthritis (AIA). Regulatory T cells (Treg cells) resolve aberrant immune reaction, maintain self-tolerance and prevent the development of autoimmune diseases. We here investigated the impact of Interferon alpha (IFN-α) on Treg cells development and function during antigen induced arthritis.MethodsFor AIA, mice were immunized with methylated bovine serum albumin (mBSA) at day 1 and 7 in presence or absence of IFN-α. At day 21, arthritis was induced by intra-articular injection of mBSA and arthritis was evaluated at day 28. At various days of AIA, CD4, CD25, Foxp3 and CTLA-4 expression was quantified by FACS in blood cells, splenocytes, lymph nodes cells and in ex vivo re-stimulated leucocytes (pooled splenocytes and lymph nodes cells) isolated at same days. To investigate the importance of Treg cells in IFN-α protection in AIA, Foxp3DTReGFP+mice were used, where Treg cells can be depleted transiently by administration of diptherin toxin. CFSE based suppression assay was used to assess the suppression by Treg cells isolated day 4, 10, 20 of AIA against proliferation of mBSA or anti-CD3 stimulated responder T cells (Tresp cells) isolated at same days. For adoptive transfer experiments, 250,000 Treg cells from IFN-α treated or untreated mice day 20 of AIA were intravenously injected to recipient pre-immunized mice without IFN-α treatment during the induction of arthritis. The importance of IFN-α signalling on T cells for the IFN-α protection was evaluated by using CD4-Cre+/- IFNAR flox/flox mice.ResultsProtective effects of IFN-α in AIA were associated with significant TGF-β dependent increase in Foxp3+ T cells in blood at day 4 and minor increase of Foxp3+T cells in spleen and lymph node cells. However IFN-α signalling in T cells is not required for IFN-α-protection. Upon ex vivo re-stimulation in presence of IFN-α with mBSA but not anti-CD3, the Treg cells numbers were increased in leucocytes isolated from day 4 and day 10 of AIA. Transient depletion of Treg cells during induction of arthritis (day 21) abolished IFN-α-protection however the protection was not affected when Treg cells are depleted during immunization phase (day 1 and day 7). Against mBSA-stimulated proliferation of Tresp cells, suppression by Treg cells isolated from day 10 and day 20 from IFN-α treated mice are significantly higher than Treg cells from untreated mice. Treg cells isolated from IFN-α or untreated mice at day 20 of AIA when transferred to pre-immunized untreated mice prevent the development of arthritis.ConclusionTreg cells are critically associated with IFN-α protective effects in AIA. IFN-α enhances TGF-β dependent early development of Treg cells and later IFN-α enhances their suppressive capacity against T cells proliferation in antigen specific manner during AIA.
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| 4. |
- Chapin III, F. Stuart, et al.
(författare)
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Earth stewardship : Shaping a sustainable future through interacting policy and norm shifts
- 2022
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 51:9, s. 1907-1920
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Tidskriftsartikel (refereegranskat)abstract
- Transformation toward a sustainable future requires an earth stewardship approach to shift society from its current goal of increasing material wealth to a vision of sustaining built, natural, human, and social capital—equitably distributed across society, within and among nations. Widespread concern about earth’s current trajectory and support for actions that would foster more sustainable pathways suggests potential social tipping points in public demand for an earth stewardship vision. Here, we draw on empirical studies and theory to show that movement toward a stewardship vision can be facilitated by changes in either policy incentives or social norms. Our novel contribution is to point out that both norms and incentives must change and can do so interactively. This can be facilitated through leverage points and complementarities across policy areas, based on values, system design, and agency. Potential catalysts include novel democratic institutions and engagement of non-governmental actors, such as businesses, civic leaders, and social movements as agents for redistribution of power. Because no single intervention will transform the world, a key challenge is to align actions to be synergistic, persistent, and scalable.
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| 5. |
- Chenna Narendra, Sudeep, et al.
(författare)
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Regulatory T-Cells Mediate IFN-alpha-Induced Resistance against Antigen-Induced Arthritis
- 2018
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Objective: CD4(+)FoxP3(+)CD25(+) regulatory T-cells (T-regs) are important for preventing tissue destruction. Here, we investigate the role of T-regs for protection against experimental arthritis by IFN-alpha. Methods: Arthritis was triggered by intra-articular injection of methylated bovine serum albumin (mBSA) in wild-type mice, Foxp3DTReGFP(+/-) mice [allowing selective depletion of T-regs by diphtheria toxin (DT)] and CD4-Cre(+/-) IFNA1R flox/flox mice (devoid of IFNAR signaling in T-cells) earlier immunized with mBSA, with or without treatment with IFN-alpha or the indoleamine 2,3-dioxygenase (IDO)-metabolite kynurenine. T-regs were depleted in DT-treated Foxp3DTReGFP(+/-) mice and enumerated by FoxP3 staining. Suppressive capacity of FACS-sorted CD25(+high)CD4(+) T-regs was tested in vivo by adoptive transfer and ex vivo in cocultures with antigen-stimulated CFSE-stained T-responder (CD25-CD4(+)) cells. IDO was inhibited by 1-methyl tryptophan. Results: Both control mice and mice devoid of IFNAR-signaling in T helper cells were protected from arthritis by IFN-alpha. Depletion of T-regs in the arthritis phase, but not at immunization, abolished the protective effect of IFN-alpha and kynurenine against arthritis. IFN-alpha increased the number of T-regs in ex vivo cultures upon antigen recall stimulation but not in naive cells. IFN-alpha also increased the suppressive capacity of T-regs against mBSA-induced T-responder cell proliferation ex vivo and against arthritis when adoptively transferred. The increased suppressive activity against proliferation conferred by IFN-alpha was clearly reduced by in vivo inhibition of IDO at immunization, which also abolished the protective effect of IFN-alpha against arthritis. Conclusion: By activating IDO during antigen sensitization, IFN-alpha activates T-regs, which prevent arthritis triggered by antigen rechallenge. This is one way by which IFN-alpha suppresses inflammation.
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| 6. |
- Gawel, Danuta, et al.
(författare)
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A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases
- 2019
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. Methods: The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. Results: We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Conclusions: Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.
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| 7. |
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| 8. |
- Homer-Dixon, Thomas, et al.
(författare)
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Synchronous failure : the emerging causal architecture of global crisis
- 2015
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Ingår i: Ecology and Society. - 1708-3087. ; 20:3
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Tidskriftsartikel (refereegranskat)abstract
- Recent global crises reveal an emerging pattern of causation that could increasingly characterize the birth and progress of future global crises. A conceptual framework identifies this pattern's deep causes, intermediate processes, and ultimate outcomes. The framework shows how multiple stresses can interact within a single social-ecological system to cause a shift in that system's behavior, how simultaneous shifts of this kind in several largely discrete social-ecological systems can interact to cause a far larger intersystemic crisis, and how such a larger crisis can then rapidly propagate across multiple system boundaries to the global scale. Case studies of the 2008-2009 financial-energy and food-energy crises illustrate the framework. Suggestions are offered for future research to explore further the framework's propositions.
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| 9. |
- Polasky, Stephen, et al.
(författare)
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Corridors of Clarity : Four Principles to Overcome Uncertainty Paralysis in the Anthropocene
- 2020
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Ingår i: BioScience. - : Oxford University Press (OUP). - 0006-3568 .- 1525-3244. ; 70:12, s. 1139-1144
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Tidskriftsartikel (refereegranskat)abstract
- Global environmental change challenges humanity because of its broad scale, long-lasting, and potentially irreversible consequences. Key to an effective response is to use an appropriate scientific lens to peer through the mist of uncertainty that threatens timely and appropriate decisions surrounding these complex issues. Identifying such corridors of clarity could help understanding critical phenomena or causal pathways sufficiently well to justify taking policy action. To this end, we suggest four principles: Follow the strongest and most direct path between policy decisions on outcomes, focus on finding sufficient evidence for policy purpose, prioritize no-regrets policies by avoiding options with controversial, uncertain, or immeasurable benefits, aim for getting the big picture roughly right rather than focusing on details.
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