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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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- Macdonald-Dunlop, Erin, et al.
(författare)
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Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
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- Mikheenkova, Anastasiia, et al.
(författare)
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Ageing of High Energy Density Automotive Li-ion Batteries: The Effect of Temperature and State-of-Charge
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Lithium ion batteries (LIB) have become a cornerstone of the shift to electric transportation. In an attempt to decrease the production load and prolong battery life, understanding different degradation mechanisms in state-of-the-art LIBs is essential. Here, we analyze how operational temperature and state-of-charge (SoC) range in cycling influence the ageing of automotive grade 21700 batteries, extracted from a Tesla 3 Long Range 2018 battery pack with positive electrode containing LiNixCoyAlzO2 (NCA) and negative electrode containing SiOx-C. In the given study we use a combination of electrochemical and material analysis to understand degradation sources in the cell. Herein we show that loss of lithium inventory is the main degradation mode in the cells, with loss of material on the negative electrode as there is a significant contributor when cycled in the low SoC range. Degradation of NCA dominates at elevated temperatures with combination of cycling to high SoC (beyond 50%).
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- Roy Chowdhury, Niladri, et al.
(författare)
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The state of charge dependence of degradation in lithium-ion cells from a Tesla Model 3
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The Tesla Model 3 is currently one of the most popular electric vehicles (EV)and was the best selling EV in 2020. In this article, performance and degradation are studied for 21700 cylindrical cells from a Tesla Model 3 cycledwithin nine, sequential state of charge (SOC) windows, each using 10% ofthe cell capacity is studied. Cells tested in either very high and very low SOCwindows show faster degradation than at moderate SOC. In particular, theshortest service life was for cells cycled below 25% SOC. The ageing mechanisms of the cells cycled in these most extreme windows have been monitoredby non-destructive electrochemical methods including analyses of differentialvoltage, incremental capacity, and voltage hysteresis. The combination ofloss of active material (LAM) and loss of lithium inventory (LLI) are responsible for the most rapid ageing observed in the cells cycled in the 5-15%SOC window. Calendar ageing, however, is not accelerated by storage atlow SOC. The results from this study offer an understanding of the distinct,SOC-dependent ageing patterns observed in the cells. This understanding ofthe ageing mechanisms in different cycling and storage conditions can be usedto recommend improved customer usage patterns and substantially extendthe lifetime of lithium-ion batteries in operation.
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