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Tidskriftsartikel (refereegranskat)
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- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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- Wang, QBS, et al.
(författare)
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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
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Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.
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- Ackloo, S, et al.
(författare)
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Target 2035 - an update on private sector contributions
- 2023
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Ingår i: RSC medicinal chemistry. - : Royal Society of Chemistry (RSC). - 2632-8682. ; 14:6, s. 1002-1011
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging ‘open’ principles to develop a pharmacological tool for every human protein.
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- Farrugia, C. J., et al.
(författare)
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MMS Observations of Reconnection at Dayside Magnetopause Crossings During Transitions of the Solar Wind to Sub-Alfvénic Flow
- 2017
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Ingår i: Journal of Geophysical Research - Space Physics. - : Blackwell Publishing Ltd. - 2169-9380 .- 2169-9402. ; 122:10, s. 9934-9951
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Tidskriftsartikel (refereegranskat)abstract
- We present MMS observations during two dayside magnetopause crossings under hitherto unexamined conditions: (i) when the bow shock is weakening and the solar wind transitioning to sub-Alfvénic flow and (ii) when it is reforming. Interplanetary conditions consist of a magnetic cloud with (i) a strong B (∼20 nT) pointing south and (ii) a density profile with episodic decreases to values of ∼0.3 cm−3 followed by moderate recovery. During the crossings the magnetosheath magnetic field is stronger than the magnetosphere field by a factor of ∼2.2. As a result, during the outbound crossing through the ion diffusion region, MMS observed an inversion of the relative positions of the X and stagnation (S) lines from that typically the case: the S line was closer to the magnetosheath side. The S line appears in the form of a slow expansion fan near which most of the energy dissipation is taking place. While in the magnetosphere between the crossings, MMS observed strong field and flow perturbations, which we argue to be due to kinetic Alfvén waves. During the reconnection interval, whistler mode waves generated by an electron temperature anisotropy (Te⊥>Te∥) were observed. Another aim of the paper is to distinguish bow shock-induced field and flow perturbations from reconnection-related signatures. The high-resolution MMS data together with 2-D hybrid simulations of bow shock dynamics helped us to distinguish between the two sources. We show examples of bow shock-related effects (such as heating) and reconnection effects such as accelerated flows satisfying the Walén relation.
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| 10. |
- Igawa, Y, et al.
(författare)
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Cystometric findings in mice lacking muscarinic M2 or M3 receptors
- 2004
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 172:6, Part 1 of 2, s. 2460-2464
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The physiological importance of muscarinic M-3 and M-2 receptors for bladder function was investigated in vivo using mice lacking M-3 or M-2 receptors and littermate WT controls. Materials and Methods: Unanesthetized mice of each sex underwent continuous cystometry before and after administration of atropine (1 mg/kg(-1)). Results: Male M-3 knockout (KO) mice had longer voiding intervals, and larger micturition volumes and bladder capacity than M-2 KO or WT males. There was no significant difference in any cystometric parameters between male M-2 KO and WT mice. In females M-3 KO and M-2 KO mice had longer voiding intervals and larger micturition volumes than WT animals. Atropine had marked inhibitory effects on voiding efficacy in WT and M-2 KO mice but it had no effect on any cystometric parameters in M-3 KO mice. Conclusions: The current results confirm that M-3 receptor is the principal muscarinic receptor subtype responsible for bladder contraction and the role of M-2 receptors is of minor importance. Functional impairments found in M-3 KO mice were milder than those elicited by acute blockade of muscarinic receptors by atropine in WT mice, suggesting that noncholinergic mechanisms can compensate for a chronic loss of M-3 receptors.
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