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- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 2. |
- Budhavant, Krishnakant, et al.
(författare)
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Changing optical properties of Black Carbon and Brown Carbon aerosols during long-range transport from the Indo-Gangetic Plain to the equatorial Indian Ocean
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Atmospheric aerosols strongly influence the global climate by their light absorption (e.g., black carbon, BC, brown carbon, BrC) and scattering (e.g., sulfate) properties. This study presents simultaneous measurements of ambient aerosol light absorption properties and chemical composition from three large-footprint South Asian receptor sites during the South Asian Pollution Experiment (SAPOEX) in December 2017 - March 2018. The BC mass absorption cross-section (BC-MAC678) values increased from 3.5 ± 1.3 at the Bhola Climate Observatory-Bangladesh (i.e., located at exit outflow of Indo-Gangetic Plain) to 6.4 ± 1.3 at the two regional receptor observatories at Maldives Climate Observatory-Hanimaadhoo (MCOH) and Maldives Climate Observatory-Gan (MCOG), an increase of 80%. This likely reflects a scavenging fractionation resulting in a population of finer BC with higher MAC678 having higher longevity. At the same time, the BrC-MAC365 decreased by a factor of three from the IGP exit to the equatorial Indian Ocean, likely due to photochemical bleaching of organic chromophores. The high chlorine-to-sodium ratio at the near-source-region BCOB suggests a significant contribution of chlorine from anthropogenic activities. This particulate Cl- has the potential to convert into Cl-radicals that can affect the oxidation capacity of the polluted air. Moreover, Cl- is shown to be near-fully consumed during the long-range transport. The results of this synoptic study over the large South Asian scale contribute rare observational constraints on optical properties of ambient BC (and BrC) aerosols over regional scales away from emission sources. It also contributes significantly to understanding the ageing effect of the optical and chemical properties of aerosols as the pollution from the Indo-Gangetic Plain disperses over the tropical ocean.
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- Nair, H. R. C. R., et al.
(författare)
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Source apportionment of black carbon using radiocarbon and stable carbon isotopes during COVID-19 societal slowdown in South Asia
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Black carbon (BC) aerosol emissions in South Asia perturb the regional climate system and significantly degrade the air quality, affecting the health and environment of approximately 1.5 billion people. This study investigates the alterations in BC sources during the societal slowdown during the 2020 COVID-19 pandemic, capitalizing on aerosol samples of the intercepted South Asian outflow at receptor stations of the Maldives Climate Observatory at Hanimaadhoo (MCOH) and the Bangladesh Climate Observatory at Bhola (BCOB). The study used dual-carbon isotopes (Δ14C and δ13C) to understand the impact of societal disruptions on BC levels and sources. The isotope source fingerprinting of BC in the outflow from the Indo-Gangetic Plain (at BCOB) revealed that for the COVID period, a decreasing contribution from fossil fuel (from 49% down to 35%) amidst an increase in the fraction from C3 biomass burning going from 31% to 55% with C4 biomass burning remaining as a minor contributor. Similarly, for MCOH, reflecting the outflow from the greater S Asian subcontinent, the contribution from fossil combustion decreased while C3 combustion correspondingly increased. This likely reflects both decreased transport and an increase in crop residue burning and the use of biomass for heating and cooking. These dual-isotope constraints demonstrate that a decisive shift in emissions of climate-forcing BC aerosols occurred during the pandemic slowdown, suggesting that a societal transformation away from fossil fuel reliance will quickly propagate into the aerosol composition over South Asia.
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