| 1. |
- Niemi, MEK, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 2. |
- Kanai, M, et al.
(författare)
-
- 2023
-
swepub:Mat__t
|
|
| 3. |
- Namkoong, H, et al.
(författare)
-
DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
-
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.
|
|
| 4. |
|
|
| 5. |
- Wang, QBS, et al.
(författare)
-
The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
- 2022
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 4830-
-
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.
|
|
| 6. |
- Abdo, A. A., et al.
(författare)
-
FERMI LARGE AREA TELESCOPE VIEW OF THE CORE OF THE RADIO GALAXY CENTAURUS A
- 2010
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 719:2, s. 1433-1444
-
Tidskriftsartikel (refereegranskat)abstract
- We present gamma-ray observations with the Large Area Telescope (LAT) on board the Fermi Gamma-Ray Space Telescope of the nearby radio galaxy Centaurus A (Cen A). The previous EGRET detection is confirmed, and the localization is improved using data from the first 10 months of Fermi science operation. In previous work, we presented the detection of the lobes by the LAT; in this work, we concentrate on the gamma-ray core of Cen A. Flux levels as seen by the LAT are not significantly different from that found by EGRET, nor is the extremely soft LAT spectrum (Gamma = 2.67 +/- 0.10(stat) +/- 0.08(sys) where the photon flux is Phi alpha E-Gamma). The LAT core spectrum, extrapolated to higher energies, is marginally consistent with the non-simultaneous HESS spectrum of the source. The LAT observations are complemented by simultaneous observations from Suzaku, the Swift Burst Alert Telescope and X-ray Telescope, and radio observations with the Tracking Active Galactic Nuclei with Austral Milliarcsecond Interferometry program, along with a variety of non-simultaneous archival data from a variety of instruments and wavelengths to produce a spectral energy distribution (SED). We fit this broadband data set with a single-zone synchrotron/synchrotron self-Compton model, which describes the radio through GeV emission well, but fails to account for the non-simultaneous higher energy TeV emission observed by HESS from 2004 to 2008. The fit requires a low Doppler factor, in contrast to BL Lac objects which generally require larger values to fit their broadband SEDs. This indicates that the gamma-ray emission originates from a slower region than that from BL Lac objects, consistent with previous modeling results from Cen A. This slower region could be a slower moving layer around a fast spine, or a slower region farther out from the black hole in a decelerating flow. The fit parameters are also consistent with Cen A being able to accelerate ultra-high energy cosmic-rays, as hinted at by results from the Auger observatory.
|
|
| 7. |
- Menden, MP, et al.
(författare)
-
Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
-
Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
|
|
| 8. |
- Hopfner, M., et al.
(författare)
-
Validation of MIPAS ClONO2 measurements
- 2007
-
Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 7, s. 257-281
-
Tidskriftsartikel (refereegranskat)abstract
- Altitude profiles of ClONO2 retrieved with the IMK (Institut fur Meteorologie und Klimaforschung) science-oriented data processor from MIPAS/Envisat (Michelson Interferometer for Passive Atmospheric Sounding on Envisat) mid-infrared limb emission measurements between July 2002 and March 2004 have been validated by comparison with balloon-borne (Mark IV, FIRS2, MIPAS-B), airborne (MIPAS-STR), ground-based (Spitsbergen, Thule, Kiruna, Harestua, Jungfraujoch, Izana, Wollongong, Lauder), and spaceborne (ACE-FTS) observations. With few exceptions we found very good agreement between these instruments and MIPAS with no evidence for any bias in most cases and altitude regions. For balloon-borne measurements typical absolute mean differences are below 0.05 ppbv over the whole altitude range from 10 to 39 km. In case of ACE-FTS observations mean differences are below 0.03 ppbv for observations below 26 km. Above this altitude the comparison with ACE-FTS is affected by the photochemically induced diurnal variation of ClONO2. Correction for this by use of a chemical transport model led to an overcompensation of the photochemical effect by up to 0.1 ppbv at altitudes of 30-35 km in case of MIPAS-ACE-FTS comparisons while for the balloon-borne observations no such inconsistency has been detected. The comparison of MIPAS derived total column amounts with ground-based observations revealed no significant bias in the MIPAS data. Mean differences between MIPAS and FTIR column abundances are 0.11 +/- 0.12 x 10(14) cm(-2) (1.0 +/- 1.1%) and -0.09 +/- 0.19 x 10(14) cm(-2) (-0.8 +/- 1.7%), depending on the coincidence criterion applied. chi(2) tests have been performed to assess the combined precision estimates of MIPAS and the related instruments. When no exact coincidences were available as in case of MIPAS-FTIR or MIPAS-ACE-FTS comparisons it has been necessary to take into consideration a coincidence error term to account for chi(2) deviations. From the resulting chi(2) profiles there is no evidence for a systematic over/underestimation of the MIPAS random error analysis.
|
|
| 9. |
- de Laat, A. T. J., et al.
(författare)
-
Validation of five years (2003-2007) of SCIAMACHY CO total column measurements using ground-based spectrometer observations
- 2010
-
Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 3:5, s. 1457-1471
-
Tidskriftsartikel (refereegranskat)abstract
- This paper presents a validation study of SCanning Imaging Absorption spectroMeter for Atmospheric CHartographY (SCIAMACHY) carbon monoxide (CO) total column measurements from the Iterative Maximum Likelihood Method (IMLM) algorithm using ground-based spectrometer observations from twenty surface stations for the five year time period of 2003-2007. Overall we find a good agreement between SCIAMACHY and ground-based observations for both mean values as well as seasonal variations. For high-latitude Northern Hemisphere stations absolute differences between SCIAMACHY and ground-based measurements are close to or fall within the SCIAMACHY CO 2 sigma precision of 0.2 x 10(18) molecules/cm(2) (similar to 10%) indicating that SCIAMACHY can observe CO accurately at high Northern Hemisphere latitudes. For Northern Hemisphere mid-latitude stations the validation is complicated due to the vicinity of emission sources for almost all stations, leading to higher ground-based measurements compared to SCIAMACHY CO within its typical sampling area of 8 degrees x 8 degrees. Comparisons with Northern Hemisphere mountain stations are hampered by elevation effects. After accounting for these effects, the validation provides satisfactory results. At Southern Hemisphere mid-to high latitudes SCIAMACHY is systematically lower than the ground-based measurements for 2003 and 2004, but for 2005 and later years the differences between SCIAMACHY and ground-based measurements fall within the SCIAMACHY precision. The 2003-2004 bias is consistent with previously reported results although its origin remains under investigation. No other systematic spatial or temporal biases could be identified based on the validation presented in this paper. Validation results are robust with regard to the choices of the instrument-noise error filter, sampling area, and time averaging required for the validation of SCIAMACHY CO total column measurements. Finally, our results show that the spatial coverage of the ground-based measurements available for the validation of the 2003-2007 SCIAMACHY CO columns is sub-optimal for validation purposes, and that the recent and ongoing expansion of the ground-based network by carefully selecting new locations may be very beneficial for SCIAMACHY CO and other satellite trace gas measurements validation efforts.
|
|
| 10. |
- Wang, D.Y., et al.
(författare)
-
Validation of nitric acid retrieved by the IMK-IAA processor from MIPAS/ENVISAT measurements
- 2007
-
Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 7, s. 721-738
-
Tidskriftsartikel (refereegranskat)abstract
- The Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) onboard the ENVISAT satellite provides profiles of temperature and various trace-gases from limb-viewing mid-infrared emission measurements. The stratospheric nitric acid (HNO(3)) from September 2002 to March 2004 was retrieved from the MIPAS observations using the science-oriented data processor developed at the Institut fur Meteorologie und Klimaforschung (IMK), which is complemented by the component of non-local thermodynamic equilibrium (non-LTE) treatment from the Instituto de Astrofisica de Andalucia (IAA). The IMK-IAA research product, different from the ESA operational product, is validated in this paper by comparison with a number of reference data sets. Individual HNO3 profiles of the IMK-IAA MIPAS show good agreement with those of the balloon-borne version of MIPAS (MIPAS-B) and the infrared spectrometer MkIV, with small differences of less than 0.5 ppbv throughout the entire altitude range up to about 38 km, and below 0.2 ppbv above 30 km. However, the degree of consistency is largely affected by their temporal and spatial coincidence, and differences of 1 to 2 ppbv may be observed between 22 and 26 km at high latitudes near the vortex boundary, due to large horizontal inhomogeneity of HNO(3). Statistical comparisons of MIPAS IMK-IAA HNO(3) VMRs with respect to those of satellite measurements of Odin/SMR, ILAS-II, ACE-FTS, as well as the MIPAS ESA product show good consistency. The mean differences are generally +/- 0.5 ppbv and standard deviations of the differences are of 0.5 to 1.5 ppbv. The maximum differences are 2.0 ppbv around 20 to 25 km. This gives confidence in the general reliability of MIPAS HNO(3) VMR data and the other three satellite data sets.
|
|
