| 1. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
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| 3. |
- Lumbers, R. T., et al.
(författare)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Tidskriftsartikel (refereegranskat)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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| 4. |
- de Graauw, Th., et al.
(författare)
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The Herschel-Heterodyne Instrument for the Far-Infrared (HIFI)
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518, s. L6-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: This paper describes the Heterodyne Instrument for the Far-Infrared (HIFI) that was launched onboard ESA's Herschel Space Observatory in May 2009. Methods: The instrument is a set of 7 heterodyne receivers that are electronically tuneable, covering 480-1250 GHz with SIS mixers and the 1410-1910 GHz range with hot electron bolometer (HEB) mixers. The local oscillator (LO) subsystem comprises a Ka-band synthesizer followed by 14 chains of frequency multipliers and 2 chains for each frequency band. A pair of auto-correlators and a pair of acousto-optical spectrometers process the two IF signals from the dual-polarization, single-pixel front-ends to provide instantaneous frequency coverage of 2 × 4 GHz, with a set of resolutions (125 kHz to 1 MHz) that are better than 0.1 km s-1. Results: After a successful qualification and a pre-launch TB/TV test program, the flight instrument is now in-orbit and completed successfully the commissioning and performance verification phase. The in-orbit performance of the receivers matches the pre-launch sensitivities. We also report on the in-orbit performance of the receivers and some first results of HIFI's operations. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.
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| 5. |
- Roelfsema, P. R., et al.
(författare)
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In-orbit performance of Herschel-HIFI
- 2012
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 537
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Tidskriftsartikel (refereegranskat)abstract
- Aims: In this paper the calibration and in-orbit performance of the Heterodyne Instrument for the Far-Infrared (HIFI) is described.Methods: The calibration of HIFI is based on a combination of ground and in-flight tests. Dedicated ground tests to determine those instrument parameters that can only be measured accurately using controlled laboratory stimuli were carried out in the instrument level test (ILT) campaign. Special in-flight tests during the commissioning phase (CoP) and performance verification (PV) allowed the determination of the remaining instrument parameters. The various instrument observing modes, as specified in astronomical observation templates (AOTs), were validated in parallel during PV by observing selected celestial sources.Results: The initial calibration and in-orbit performance of HIFI has been established. A first estimate of the calibration budget is given. The overall in-flight instrument performance agrees with the original specification. Issues remain at only a few frequencies. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.
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| 6. |
- Motte, F., et al.
(författare)
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Initial highlights of the HOBYS key program, the Herschel imaging survey of OB young stellar objects
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518, s. L77-
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Tidskriftsartikel (refereegranskat)abstract
- We present the initial highlights of the HOBYS key program, which are based on Herschel images of the Rosette molecular complex and maps of the RCW120 H II region. Using both SPIRE at 250/350/500 mu m and PACS at 70/160 mu m or 100/160 mu m, the HOBYS survey provides an unbiased and complete census of intermediate-to high-mass young stellar objects, some of which are not detected by Spitzer. Key core properties, such as bolometric luminosity and mass (as derived from spectral energy distributions), are used to constrain their evolutionary stages. We identify a handful of high-mass prestellar cores and show that their lifetimes could be shorter in the Rosette molecular complex than in nearby low-mass star-forming regions. We also quantify the impact of expanding H II regions on the star formation process acting in both Rosette and RCW 120.
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| 7. |
- Hennemann, M., et al.
(författare)
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Herschel observations of embedded protostellar clusters in the Rosette molecular cloud
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518, s. L84-
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Tidskriftsartikel (refereegranskat)abstract
- The Herschel OB young stellar objects survey (HOBYS) has observed the Rosette molecular cloud, providing an unprecedented view of its star formation activity. These new far-infrared data reveal a population of compact young stellar objects whose physical properties we aim to characterise. We compiled a sample of protostars and their spectral energy distributions that covers the near-infrared to submillimetre wavelength range. These were used to constrain key properties in the protostellar evolution, bolometric luminosity, and envelope mass and to build an evolutionary diagram. Several clusters are distinguished including the cloud centre, the embedded clusters in the vicinity of luminous infrared sources, and the interaction region. The analysed protostellar population in Rosette ranges from 0.1 to about 15 M-circle dot with luminosities between 1 and 150 L-circle dot, which extends the evolutionary diagram from low-mass protostars into the high-mass regime. Some sources lack counterparts at near-to mid-infrared wavelengths, indicating extreme youth. The central cluster and the Phelps & Lada 7 cluster appear less evolved than the remainder of the analysed protostellar population. For the central cluster, we find indications that about 25% of the protostars classified as Class I from near-to mid-infrared data are actually candidate Class 0 objects. As a showcase for protostellar evolution, we analysed four protostars of low-to intermediate-mass in a single dense core, and they represent different evolutionary stages from Class 0 to Class I. Their mid-to far-infrared spectral slopes flatten towards the Class I stage, and the 160 to 70 mu m flux ratio is greatest for the presumed Class 0 source. This shows that the Herschel observations characterise the earliest stages of protostellar evolution in detail.
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| 8. |
- Mcelhinney, L. M., et al.
(författare)
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High prevalence of Seoul hantavirus in a breeding colony of pet rats
- 2017
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Ingår i: Epidemiology and Infection. - 0950-2688 .- 1469-4409. ; 145:15, s. 3115-3124
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Tidskriftsartikel (refereegranskat)abstract
- As part of further investigations into three linked haemorrhagic fever with renal syndrome (HFRS) cases in Wales and England, 21 rats from a breeding colony in Cherwell, and three rats from a household in Cheltenham were screened for hantavirus. Hantavirus RNA was detected in either the lungs and/or kidney of 17/21 (81%) of the Cherwell rats tested, higher than previously detected by blood testing alone (7/21, 33%), and in the kidneys of all three Cheltenham rats. The partial L gene sequences obtained from 10 of the Cherwell rats and the three Cheltenham rats were identical to each other and the previously reported UK Cherwell strain. Seoul hantavirus (SEOV) RNA was detected in the heart, kidney, lung, salivary gland and spleen (but not in the liver) of an individual rat from the Cherwell colony suspected of being the source of SEOV. Serum from 20/20 of the Cherwell rats and two associated HFRS cases had high levels of SEOV-specific antibodies (by virus neutralisation). The high prevalence of SEOV in both sites and the moderately severe disease in the pet rat owners suggest that SEOV in pet rats poses a greater public health risk than previously considered.
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| 9. |
- Schneider, N., et al.
(författare)
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The Herschel view of star formation in the Rosette molecular cloud under the influence of NGC 2244
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518, s. L83-
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Tidskriftsartikel (refereegranskat)abstract
- Context. The Rosette molecular cloud is promoted as the archetype of a triggered star-formation site. This is mainly due to its morphology, because the central OB cluster NGC 2244 has blown a circular-shaped cavity into the cloud and the expanding H II-region now interacts with the cloud. Aims. Studying the spatial distribution of the different evolutionary states of all star-forming sites in Rosette and investigating possible gradients of the dust temperature will help to test the "triggered star-formation" scenario in Rosette. Methods. We use continuum data obtained with the PACS (70 and 160 mu m) and SPIRE instruments (250, 350, 500 mu m) of the Herschel telescope during the science demonstration phase of HOBYS. Results. Three-color images of Rosette impressively show how the molecular gas is heated by the radiative impact of the NGC 2244 cluster. A clear negative temperature gradient and a positive density gradient (running from the H II-region/molecular cloud interface into the cloud) are detected. Studying the spatial distribution of the most massive dense cores (size scale 0.05 to 0.3 pc), we find an age-sequence (from more evolved to younger) with increasing distance to the cluster NGC 2244. No clear gradient is found for the clump (size-scale up to 1 pc) distribution. Conclusions. The existence of temperature and density gradients and the observed age-sequence imply that star formation in Rosette may indeed be influenced by the radiative impact of the central NGC 2244 cluster. A more complete overview of the prestellar and protostellar population in Rosette is required to obtain a firmer result.
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