| 1. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
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| 4. |
- 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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| 5. |
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| 6. |
- 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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| 7. |
- Martin, S., et al.
(författare)
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ALCHEMI, an ALMA Comprehensive High-resolution Extragalactic Molecular Inventory: Survey presentation and first results from the ACA array
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 656
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Tidskriftsartikel (refereegranskat)abstract
- Context. The interstellar medium is the locus of physical processes affecting the evolution of galaxies which drive or are the result of star formation activity, supermassive black hole growth, and feedback. The resulting physical conditions determine the observable chemical abundances that can be explored through molecular emission observations at millimeter and submillimeter wavelengths. Aims. Our goal is to unveiling the molecular richness of the central region of the prototypical nearby starburst galaxy NGC 253 at an unprecedented combination of sensitivity, spatial resolution, and frequency coverage. Methods. We used the Atacama Large Millimeter/submillimeter Array (ALMA), covering a nearly contiguous 289 GHz frequency range between 84.2 and 373.2 GHz, to image the continuum and spectral line emission at 1.6″(∼28 pc) resolution down to a sensitivity of 30 - 50 mK. This article describes the ALMA Comprehensive High-resolution Extragalactic Molecular Inventory (ALCHEMI) large program. We focus on the analysis of the spectra extracted from the 15″ (∼255 pc) resolution ALMA Compact Array data. Results. We modeled the molecular emission assuming local thermodynamic equilibrium with 78 species being detected. Additionally, multiple hydrogen and helium recombination lines are identified. Spectral lines contribute 5 to 36% of the total emission in frequency bins of 50 GHz. We report the first extragalactic detections of C2H5OH, HOCN, HC3HO, and several rare isotopologues. Isotopic ratios of carbon, oxygen, sulfur, nitrogen, and silicon were measured with multiple species. Concluison. Infrared pumped vibrationaly excited HCN, HNC, and HC3N emission, originating in massive star formation locations, is clearly detected at low resolution, while we do not detect it for HCO+. We suggest high temperature conditions in these regions driving a seemingly "carbon-rich"chemistry which may also explain the observed high abundance of organic species close to those in Galactic hot cores. The Lvib/LIR ratio was used as a proxy to estimate a 3% contribution from the proto super star cluster to the global infrared emission. Measured isotopic ratios with high dipole moment species agree with those within the central kiloparsec of the Galaxy, while those derived from 13C/18O are a factor of five larger, confirming the existence of multiple interstellar medium components within NGC 253 with different degrees of nucleosynthesis enrichment. The ALCHEMI data set provides a unique template for studies of star-forming galaxies in the early Universe.
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| 8. |
- Harada, N., et al.
(författare)
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The ALCHEMI Atlas: Principal Component Analysis Reveals Starburst Evolution in NGC 253
- 2024
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Ingår i: Astrophysical Journal, Supplement Series. - 1538-4365 .- 0067-0049. ; 271:2
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Tidskriftsartikel (refereegranskat)abstract
- Molecular lines are powerful diagnostics of the physical and chemical properties of the interstellar medium (ISM). These ISM properties, which affect future star formation, are expected to differ in starburst galaxies from those of more quiescent galaxies. We investigate the ISM properties in the central molecular zone of the nearby starburst galaxy NGC 253 using the ultrawide millimeter spectral scan survey from the Atacama Large Millimeter/submillimeter Array Large Program ALCHEMI. We present an atlas of velocity-integrated images at a 1.″6 resolution of 148 unblended transitions from 44 species, including the first extragalactic detection of HCNH+ and the first interferometric images of C3H+, NO, and HCS+. We conduct a principal component analysis (PCA) on these images to extract correlated chemical species and to identify key groups of diagnostic transitions. To the best of our knowledge, our data set is currently the largest astronomical set of molecular lines to which PCA has been applied. The PCA can categorize transitions coming from different physical components in NGC 253 such as (i) young starburst tracers characterized by high-excitation transitions of HC3N and complex organic molecules versus tracers of on-going star formation (radio recombination lines) and high-excitation transitions of CCH and CN tracing photodissociation regions, (ii) tracers of cloud-collision-induced shocks (low-excitation transitions of CH3OH, HNCO, HOCO+, and OCS) versus shocks from star formation-induced outflows (high-excitation transitions of SiO), as well as (iii) outflows showing emission from HOC+, CCH, H3O+, CO isotopologues, HCN, HCO+, CS, and CN. Our findings show these intensities vary with galactic dynamics, star formation activities, and stellar feedback.
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| 9. |
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| 10. |
- Johannsson, Gudmundur, 1960, et al.
(författare)
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Once-weekly Somapacitan is Effective and Well Tolerated in Adults with GH Deficiency: A Randomized Phase 3 Trial.
- 2020
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 105:4
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Tidskriftsartikel (refereegranskat)abstract
- Growth hormone (GH) replacement requires daily GH injections, which is burdensome for some adult patients with GH deficiency (AGHD).To demonstrate efficacy and safety of somapacitan, a once-weekly reversible albumin-binding GH derivative, versus placebo in AGHD.Randomized, parallel-group, placebo-controlled (double-blind) and active-controlled (open-label) phase 3 trial, REAL 1 (NCT02229851).Clinics in 17 countries.Treatment-naïve patients with AGHD (n = 301 main study period, 272 extension period); 257 patients completed the trial.Patients were randomized 2:2:1 to once-weekly somapacitan, daily GH, or once-weekly placebo for 34 weeks (main period). During the 52-week extension period, patients continued treatment with somapacitan or daily GH.Body composition measured using dual-energy x-ray absorptiometry (DXA). The primary endpoint was change in truncal fat percentage to week 34. Insulin-like growth factor 1 (IGF-I) standard deviation score (SDS) values were used to dose titrate.At 34 weeks, somapacitan significantly reduced truncal fat percentage (estimated difference: -1.53% [-2.68; -0.38]; P = 0.0090), demonstrating superiority compared with placebo, and it improved other body composition parameters (including visceral fat and lean body mass) and IGF-I SDS. At 86 weeks, improvements were maintained with both somapacitan and daily GH. Somapacitan was well tolerated, with similar adverse events (including injection-site reactions) compared with daily GH.In AGHD patients, somapacitan administered once weekly demonstrated superiority over placebo, and the overall treatment effects and safety of somapacitan were in accordance with known effects and safety of GH replacement for up to 86 weeks of treatment. Somapacitan may provide an effective alternative to daily GH in AGHD. A short visual summary of our work is available (1).
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