| 1. |
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| 2. |
- 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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| 3. |
- Feroci, M., et al.
(författare)
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The large observatory for x-ray timing
- 2014
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 9780819496126
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Konferensbidrag (refereegranskat)abstract
- The Large Observatory For x-ray Timing (LOFT) was studied within ESA M3 Cosmic Vision framework and participated in the final downselection for a launch slot in 2022-2024. Thanks to the unprecedented combination of effective area and spectral resolution of its main instrument, LOFT will study the behaviour of matter under extreme conditions, such as the strong gravitational field in the innermost regions of accretion flows close to black holes and neutron stars, and the supranuclear densities in the interior of neutron stars. The science payload is based on a Large Area Detector (LAD, 10 m2 effective area, 2-30 keV, 240 eV spectral resolution, 1° collimated field of view) and a Wide Field Monitor (WFM, 2-50 keV, 4 steradian field of view, 1 arcmin source location accuracy, 300 eV spectral resolution). The WFM is equipped with an on-board system for bright events (e.g. GRB) localization. The trigger time and position of these events are broadcast to the ground within 30 s from discovery. In this paper we present the status of the mission at the end of its Phase A study.
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| 4. |
- Bryois, J., et al.
(författare)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 5. |
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| 6. |
- 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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| 7. |
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| 8. |
- Shimwell, T. W., et al.
(författare)
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The LOFAR Two-metre Sky Survey: I. Survey description and preliminary data release
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 598, s. Art no A104-
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Tidskriftsartikel (refereegranskat)abstract
- The LOFAR Two-metre Sky Survey (LoTSS) is a deep 120-168 MHz imaging survey that will eventually cover the entire northern sky. Each of the 3170 pointings will be observed for 8 h, which, at most declinations, is sufficient to produce ~5? resolution images with a sensitivity of ~100 ?Jy/beam and accomplish the main scientific aims of the survey, which are to explore the formation and evolution of massive black holes, galaxies, clusters of galaxies and large-scale structure. Owing to the compact core and long baselines of LOFAR, the images provide excellent sensitivity to both highly extended and compact emission. For legacy value, the data are archived at high spectral and time resolution to facilitate subarcsecond imaging and spectral line studies. In this paper we provide an overview of the LoTSS. We outline the survey strategy, the observational status, the current calibration techniques, a preliminary data release, and the anticipated scientific impact. The preliminary images that we have released were created using a fully automated but direction-independent calibration strategy and are significantly more sensitive than those produced by any existing large-Area low-frequency survey. In excess of 44 000 sources are detected in the images that have a resolution of 25?, typical noise levels of less than 0.5 mJy/beam, and cover an area of over 350 square degrees in the region of the HETDEX Spring Field (right ascension 10h45m00s to 15h30m00s and declination 45°00?00? to 57°00?00?).
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| 9. |
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| 10. |
- Asbun, H.J., et al.
(författare)
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The Miami International Evidence-based Guidelines on Minimally Invasive Pancreas Resection
- 2020
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Ingår i: Annals of Surgery. - : Lippincott Williams and Wilkins. - 0003-4932 .- 1528-1140. ; 271:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to develop and externally validate the first evidence-based guidelines on minimally invasive pancreas resection (MIPR) before and during the International Evidence-based Guidelines on Minimally Invasive Pancreas Resection (IG-MIPR) meeting in Miami (March 2019).Summary Background Data: MIPR has seen rapid development in the past decade. Promising outcomes have been reported by early adopters from high-volume centers. Subsequently, multicenter series as well as randomized controlled trials were reported; however, guidelines for clinical practice were lacking. Methods: The Scottisch Intercollegiate Guidelines Network (SIGN) methodology was used, incorporating these 4 items: systematic reviews using PubMed, Embase, and Cochrane databases to answer clinical questions, whenever possible in PICO style, the GRADE approach for assessment of the quality of evidence, the Delphi method for establishing consensus on the developed recommendations, and the AGREE-II instrument for the assessment of guideline quality and external validation. The current guidelines are cosponsored by the International Hepato-Pancreato-Biliary Association, the Americas Hepato-Pancreato-Biliary Association, the Asian-Pacific Hepato-Pancreato-Biliary Association, the European-African Hepato-Pancreato-Biliary Association, the European Association for Endoscopic Surgery, Pancreas Club, the Society of American Gastrointestinal and Endoscopic Surgery, the Society for Surgery of the Alimentary Tract, and the Society of Surgical Oncology. Results: After screening 16,069 titles, 694 studies were reviewed, and 291 were included. The final 28 recommendations covered 6 topics; laparoscopic and robotic distal pancreatectomy, central pancreatectomy, pancreatoduodenectomy, as well as patient selection, training, learning curve, and minimal annual center volume required to obtain optimal outcomes and patient safety.Conclusion: The IG-MIPR using SIGN methodology give guidance to surgeons, hospital administrators, patients, and medical societies on the use and outcome of MIPR as well as the approach to be taken regarding this challenging type of surgery. © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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| 11. |
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| 12. |
- Tiegs, Scott D., et al.
(författare)
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Global patterns and drivers of ecosystem functioning in rivers and riparian zones
- 2019
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Ingår i: Science Advances. - Washington : American Association of Advancement in Science. - 2375-2548. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth's biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented "next-generation biomonitoring" by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale.
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| 13. |
- Costello, David M., et al.
(författare)
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Global patterns and controls of nutrient immobilization on decomposing cellulose in riverine ecosystems
- 2022
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Ingår i: Global Biogeochemical Cycles. - : John Wiley & Sons. - 0886-6236 .- 1944-9224. ; 36:3
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Tidskriftsartikel (refereegranskat)abstract
- Microbes play a critical role in plant litter decomposition and influence the fate of carbon in rivers and riparian zones. When decomposing low-nutrient plant litter, microbes acquire nitrogen (N) and phosphorus (P) from the environment (i.e., nutrient immobilization), and this process is potentially sensitive to nutrient loading and changing climate. Nonetheless, environmental controls on immobilization are poorly understood because rates are also influenced by plant litter chemistry, which is coupled to the same environmental factors. Here we used a standardized, low-nutrient organic matter substrate (cotton strips) to quantify nutrient immobilization at 100 paired stream and riparian sites representing 11 biomes worldwide. Immobilization rates varied by three orders of magnitude, were greater in rivers than riparian zones, and were strongly correlated to decomposition rates. In rivers, P immobilization rates were controlled by surface water phosphate concentrations, but N immobilization rates were not related to inorganic N. The N:P of immobilized nutrients was tightly constrained to a molar ratio of 10:1 despite wide variation in surface water N:P. Immobilization rates were temperature-dependent in riparian zones but not related to temperature in rivers. However, in rivers nutrient supply ultimately controlled whether microbes could achieve the maximum expected decomposition rate at a given temperature. Collectively, we demonstrated that exogenous nutrient supply and immobilization are critical control points for decomposition of organic matter.
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| 14. |
- Young, Iris D., et al.
(författare)
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Structure of photosystem II and substrate binding at room temperature
- 2016
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Ingår i: Nature. - : Macmillan Publishers Ltd.. - 0028-0836 .- 1476-4687. ; 540:7633, s. 453-457
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Tidskriftsartikel (refereegranskat)abstract
- Light-induced oxidation of water by photosystem II (PS II) in plants, algae and cyanobacteria has generated most of the dioxygen in the atmosphere. PS II, a membrane-bound multi-subunit pigment protein complex, couples the one-electron photochemistry at the reaction centre with the four-electron redox chemistry of water oxidation at the Mn4CaO5 cluster in the oxygen-evolving complex (OEC). Under illumination, the OEC cycles through five intermediate S-states (S0 to S4)1, in which S1 is the dark-stable state and S3 is the last semi-stable state before O–O bond formation and O2 evolution2,3. A detailed understanding of the O–O bond formation mechanism remains a challenge, and will require elucidation of both the structures of the OEC in the different S-states and the binding of the two substrate waters to the catalytic site4–6. Here we report the use of femtosecond pulses from an X-ray free electron laser (XFEL) to obtain damage-free, room temperature structures of dark-adapted (S1), two-flash illuminated (2F; S3-enriched), and ammonia-bound two-flash illuminated (2F-NH3; S3-enriched) PS II. Although the recent 1.95 Å resolution structure of PS II at cryogenic temperature using an XFEL7 provided a damage-free view of the S1 state, measurements at room temperature are required to study the structural landscape of proteins under functional conditions8,9, and also for in situ advancement of the S-states. To investigate the water-binding site(s), ammonia, a water analogue, has been used as a marker, as it binds to the Mn4CaO5 cluster in the S2 and S3 states10. Since the ammonia-bound OEC is active, the ammonia-binding Mn site is not a substrate water site10–13. This approach, together with a comparison of the native dark and 2F states, is used to discriminate between proposed O–O bond formation mechanisms.
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| 15. |
- Hautakangas, H, et al.
(författare)
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Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:2, s. 152-
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Tidskriftsartikel (refereegranskat)abstract
- Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.
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| 16. |
- Williams, W. L., et al.
(författare)
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LOFAR 150-MHz observations of the Bootes field: catalogue and source counts
- 2016
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 460:3, s. 2385-2412
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Tidskriftsartikel (refereegranskat)abstract
- We present the first wide area (19 deg(2)), deep (a parts per thousand 120-150 mu Jy beam(-1)), high-resolution (5.6 x 7.4 arcsec) LOFAR High Band Antenna image of the Bootes field made at 130-169 MHz. This image is at least an order of magnitude deeper and 3-5 times higher in angular resolution than previously achieved for this field at low frequencies. The observations and data reduction, which includes full direction-dependent calibration, are described here. We present a radio source catalogue containing 6 276 sources detected over an area of 19 deg(2), with a peak flux density threshold of 5 sigma. As the first thorough test of the facet calibration strategy, introduced by van Weeren et al., we investigate the flux and positional accuracy of the catalogue. We present differential source counts that reach an order of magnitude deeper in flux density than previously achieved at these low frequencies, and show flattening at 150-MHz flux densities below 10 mJy associated with the rise of the low flux density star-forming galaxies and radio-quiet AGN.
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| 17. |
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| 18. |
- Davies, Melvyn B, et al.
(författare)
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The MODEST questions: Challenges and future directions in stellar cluster research
- 2006
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Ingår i: New Astronomy. - : Elsevier BV. - 1384-1092 .- 1384-1076. ; 12:3, s. 201-214
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Forskningsöversikt (refereegranskat)abstract
- We present a review of some of the current major challenges in stellar cluster research, including young clusters, globular clusters, and galactic nuclei. Topics considered include: primordial mass segregation and runaway mergers, expulsion of gas from clusters, the production of stellar exotica seen in some clusters (e.g., blue stragglers and extreme horizontal-branch stars), binary populations within clusters, the black-hole population within stellar clusters, the final parsec problem, stellar dynamics around a massive black hole, and stellar collisions. The Modest Questions posed here are the outcome of discussions which took place at the Modest-6A workshop held in Lund, Sweden, in December, 2005. Modest-6A was organised as part of the activities of the Modest Collaboration (see www.manybody.org for further details).
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| 19. |
- Lindim, Claudia, et al.
(författare)
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Exposure and ecotoxicological risk assessment of mixtures of top prescribed pharmaceuticals in Swedish freshwaters
- 2019
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 220, s. 344-352
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Tidskriftsartikel (refereegranskat)abstract
- Surface water concentrations of 54 pharmaceuticals were predicted for seven major Swedish rivers and the Stockholm City area basins using the STREAM-EU model. These surface water concentrations were used to predict the ecotoxicological impact resulting from the exposure of aquatic organisms to this mixture of 54 pharmaceuticals. STREAM-EU model results indicated that <10 substances were present at median annual water concentrations greater than 10 with highest concentrations occurring mostly in the more densely populated area of the capital city, Stockholm. There was considerable spatial and temporal variability in the model predictions (1-3 orders of magnitude) due to natural variability (e.g. hydrology, temperature), variations in emissions and uncertainty sources. Local mixture ecotoxicological pressures based on acute EC50 data as well as on chronic NOEC data, expressed as multi-substance potentially affected fraction of species (msPAF), were quantified in 114 separate locations in the water bodies. It was estimated that 5% of the exposed aquatic species would experience exposure at or above their acute EC50 concentrations (so-called acute hazardous concentration for 5% of species, or aHC5) at only 7% of the locations analyzed (8 out of 114 locations). For the evaluation based on chronic NOEC concentrations, the chronic HC5 (cHC5) is exceeded at 27% of the locations. The acute mixture toxic pressure was estimated to be predominantly caused by only three substances in all waterbodies: Furosemide, Tramadol and Ibuprofen. A similar evaluation of chronic toxic pressure evaluation logically demonstrates that more substances play a significant role in causing a higher chronic toxic pressure at more sites as compared to the acute toxic pressure evaluation. In addition to the three substances contributing most to acute effects, the chronic effects are predominantly caused by another five substances: paracetamol, diclofenac, ethinylestradiol, erythromycin and ciprofloxacin. This study provides regulatory authorities and companies responsible for water quality valuable information for targeting remediation measures and monitoring on a substance and location basis.
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| 20. |
- Manser, Christopher J., et al.
(författare)
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A planetesimal orbiting within the debris disc around a white dwarf star
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 364:6435, s. 66-69
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Tidskriftsartikel (refereegranskat)abstract
- Many white dwarf stars show signs of having accreted smaller bodies, implying that they may host planetary systems. A small number of these systems contain gaseous debris discs, visible through emission lines. We report a stable 123.4-minute periodic variation in the strength and shape of the Ca II emission line profiles originating from the debris disc around the white dwarf SDSS J122859.93+104032.9. We interpret this short-period signal as the signature of a solid-body planetesimal held together by its internal strength.
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| 21. |
- Posthuma, L., et al.
(författare)
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Improved component-based methods for mixture risk assessment are key to characterize complex chemical pollution in surface waters
- 2019
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Ingår i: Environmental Sciences Europe. - : Springer Science and Business Media LLC. - 2190-4707 .- 2190-4715. ; 31:1
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Tidskriftsartikel (refereegranskat)abstract
- The present monitoring and assessment of water quality problems fails to characterize the likelihood that complex mixtures of chemicals affect water quality. The European collaborative project SOLUTIONS suggests that this likelihood can be estimated, amongst other methods, with improved component-based methods (CBMs). The use of CBMs is a well-established practice in the WFD, as one of the lines of evidence to evaluate chemical pollution on a per-chemical basis. However, this is currently limited to a pre-selection of 45 and approximately 300 monitored substances (priority substances and river basin-specific pollutants, respectively), of which only a few actually co-occur in relevant concentrations in real-world mixtures. Advanced CBM practices are therefore needed that consider a broader, realistic spectrum of chemicals and thereby improve the assessment of mixture impacts, diagnose the causes of observed impacts and provide more useful water management information. Various CBMs are described and illustrated, often representing improvements of well-established methods. Given the goals of the WFD and expanding on current guidance for risk assessment, these improved CBMs can be applied to predicted or monitored concentrations of chemical pollutants to provide information for management planning. As shown in various examples, the outcomes of the improved CBMs allow for the evaluation of the current likelihood of impacts, of alternative abatement scenarios as well as the expected consequences of future pollution scenarios. The outputs of the improved CBMs are useful to underpin programmes of measures to protect and improve water quality. The combination of CBMs with effect-based methods (EBMs) might be especially powerful to identify as yet underinvestigated emerging pollutants and their importance in a mixture toxicity context. The present paper has been designed as one in a series of policy briefs to support decisions on water quality protection, monitoring, assessment and management under the European Water Framework Directive (WFD).
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