| 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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| 8. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 9. |
- Medema, M. H., et al.
(författare)
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Minimum Information about a Biosynthetic Gene cluster
- 2015
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Ingår i: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 11:9, s. 625-631
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Forskningsöversikt (refereegranskat)abstract
- A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
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| 10. |
- 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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| 11. |
- Izumi, T., et al.
(författare)
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ALMA OBSERVATIONS OF THE SUBMILLIMETER DENSE MOLECULAR GAS TRACERS IN THE LUMINOUS TYPE-1 ACTIVE NUCLEUS OF NGC 7469
- 2015
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 811:1, s. Article Number: 39-
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Tidskriftsartikel (refereegranskat)abstract
- We present Atacama Large Millimeter/submillimeter Array (ALMA) Cycle 1 observations of the central kiloparsec region of the luminous type. 1 Seyfert galaxy NGC 7469 with unprecedented high resolution (0.'' 5x0.'' 4 = 165 x 132 pc) at submillimeter wavelengths. Utilizing the wide. bandwidth of ALMA, we simultaneously obtained HCN(4-3), HCO+(4-3), CS(7-6), and partially CO(3-2) line maps, as well as the 860 mu m continuum. The region consists of the central similar to 1 '' component and the surrounding starburst ring with a radius of similar to 1.'' 5-2.'' 5. Several structures connect these components. Except for CO(3-2), these dense gas tracers are significantly concentrated toward the central similar to 1 '', suggesting their suitability to probe the nuclear regions of galaxies. Their spatial distribution resembles well those of centimeter and mid-infrared continuum emissions, but it is anticorrelated with the optical one, indicating the existence of dust-obscured star formation. The integrated intensity ratios of HCN(4-3)/HCO+(4-3) and HCN(4-3)/CS(7-6) are higher at the active galactic nucleus (AGN) position than at the starburst ring, which is consistent with our previous findings (submillimeter-HCN enhancement). However, the HCN(4-3)/HCO+(4-3) ratio at the AGN position of NGC 7469 (1.11 +/- 0.06) is almost half of the corresponding value of the low-luminosity type. 1 Seyfert galaxy NGC 1097 (2.0 +/- 0.2), despite the more than two orders of magnitude higher X-ray luminosity of NGC 7469. But the ratio is comparable to that of the close vicinity of the AGN of NGC 1068 (similar to 1.5). Based on these results, we speculate that some heating mechanisms other than X-ray (e.g., mechanical heating due to an AGN jet) can contribute significantly for shaping the chemical composition in NGC 1097.
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| 14. |
- 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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| 19. |
- Martin, S., et al.
(författare)
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Multimolecule ALMA observations toward the Seyfert 1 galaxy NGC 1097
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 573
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Tidskriftsartikel (refereegranskat)abstract
- Context. The nearby Sy 1 galaxy NGC 1097 represents an ideal laboratory for exploring the molecular chemistry in the surroundings of an active galactic nucleus (AGN). Aims. Exploring the distribution of different molecular species allows us to understand the physical processes affecting the interstellar medium both in the AGN vicinity and in the outer star forming molecular ring. Methods. We carried out 3 mm ALMA observations that include seven different molecular species, namely HCN, HCO+, CCH, CS, HNCO, SiO, HC3N, and SO, as well as the C-13 isotopologues of the first two. Spectra were extracted from selected positions and all species were imaged over the central 2 kpc (similar to 30 '') of the galaxy at a resolution of similar to 2.2 '' x 1.5 '' (150 pc x 100 pc). Results. HCO+ and CS appear to be slightly enhanced in the star forming ring. CCH shows the largest variations across NGC 1097 and is suggested to be a good tracer of both obscured and early stage star formation. HNCO, SiO, and HC3N are significantly enhanced in the inner circumnuclear disk surrounding the AGN. Conclusions. Differences in the molecular abundances are observed between the star forming ring and the inner circumnuclear disk. We conclude that the HCN/HCO+ and HCN/CS differences observed between AGN-dominated and starburst (SB) galaxies are not due to a HCN enhancement due to X-rays, but rather this enhancement is produced by shocked material at distances of 200 pc from the AGN. Additionally, we claim that lower HCN/CS is a combination of a small underabundance of CS in AGNs, together with excitation effects, where a high density gas component (similar to 10(6) cm(-3)) may be more prominent in SB galaxies. However, the most promising are the differences found among the dense gas tracers that, at our modest spatial resolution, seem to outline the physical structure of the molecular disk around the AGN. In this picture, HNCO probes the well-shielded gas in the disk, surrounding the dense material moderately exposed to the X-ray radiation traced by HC3N. Finally SiO might be the innermost molecule in the disk structure.
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| 28. |
- 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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| 34. |
- Miethke, Marcus, et al.
(författare)
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Towards the sustainable discovery and development of new antibiotics
- 2021
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Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 5:10, s. 726-749
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Forskningsöversikt (refereegranskat)abstract
- An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
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| 50. |
- Scourfield, M., et al.
(författare)
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ALMA observations of CS in NGC 1068: chemistry and excitation
- 2020
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 496:4, s. 5308-5329
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Tidskriftsartikel (refereegranskat)abstract
- We present results from Atacama Large Millimeter/submillimeter Array (ALMA) observations of CS from the nearby galaxy NGC 1068 (similar to 14 Mpc). This Seyfert 2 barred galaxy possesses a circumnuclear disc (CND, r similar to 200 pc) and a starburst ring (SB ring, r similar to 1.3 kpc). These high-resolution maps (similar to 0.5 arcsec, similar to 35 pc) allow us to analyse specific sub-regions in the galaxy and investigate differences in line intensity ratios and physical conditions, particularly those between the CND and SB ring. Local thermodynamic equilibrium (LTE) analysis of the gas is used to calculate CS densities in each sub-region, followed by the non-LTE analysis conducted using the radiative transfer code RADEX to fit observations and constrain gas temperature, CS column density and hydrogen density. Finally, the chemical code UCLCHEM is used to reconstruct the gas, allowing an insight into its origin and chemical history. The density of hydrogen in the CND is found to be >= 10(5) cm(-2), although exact values vary, reaching 10(6) cm(-2) at the active galactic nucleus. The conditions in the two arms of the SB ring appear similar to one another, though the density found (similar to 10(4) cm(-2)) is lower than in the CND. The temperature in the CND increases from east to west, and is also overall greater than found in the SB ring. These modelling methods indicate the requirement for multiphase gas components in order to fit the observed emission over the galaxy. A larger number of high-resolution transitions across the SLED may allow for further constraining of the conditions, particularly in the SB ring.
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