| 1. |
|
|
| 2. |
- Wang, Z., et al.
(författare)
-
Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
- 2022
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 54:9, s. 1332-1344
-
Tidskriftsartikel (refereegranskat)abstract
- Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention. Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.
|
|
| 3. |
- Abdalla, H., et al.
(författare)
-
Detection of very-high-energy gamma-ray emission from the colliding wind binary eta Car with HESS
- 2020
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 635, s. 1-8
-
Tidskriftsartikel (refereegranskat)abstract
- Aims. Colliding wind binary systems have long been suspected to be high-energy (HE; 100 MeV < E < 100 GeV) gamma-ray emitters. eta Car is the most prominent member of this object class and is confirmed to emit phase-locked HE gamma rays from hundreds of MeV to 100 GeV energies. This work aims to search for and characterise the very-high-energy (VHE; E >100 GeV) gamma-ray emission from eta Car around the last periastron passage in 2014 with the ground-based High Energy Stereoscopic System (H.E.S.S.).Methods. The region around eta Car was observed with H.E.S.S. between orbital phase p = 0.78-1.10, with a closer sampling at p approximate to 0.95 and p approximate to 1.10 (assuming a period of 2023 days). Optimised hardware settings as well as adjustments to the data reduction, reconstruction, and signal selection were needed to suppress and take into account the strong, extended, and inhomogeneous night sky background (NSB) in the eta Car field of view. Tailored run-wise Monte-Carlo simulations (RWS) were required to accurately treat the additional noise from NSB photons in the instrument response functions.Results. H.E.S.S. detected VHE gamma-ray emission from the direction of eta Car shortly before and after the minimum in the X-ray light-curve close to periastron. Using the point spread function provided by RWS, the reconstructed signal is point-like and the spectrum is best described by a power law. The overall flux and spectral index in VHE gamma rays agree within statistical and systematic errors before and after periastron. The gamma-ray spectrum extends up to at least 400 GeV. This implies a maximum magnetic field in a leptonic scenario in the emission region of 0.5 Gauss. No indication for phase-locked flux variations is detected in the H.E.S.S. data.
|
|
| 4. |
- Abdalla, H., et al.
(författare)
-
HESS detection of very high-energy gamma-ray emission from the quasar PKS 0736+017
- 2020
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 633, s. 1-11
-
Tidskriftsartikel (refereegranskat)abstract
- Context. Flat-spectrum radio-quasars (FSRQs) are rarely detected at very high energies (E& x2004;>=& x2004;100 GeV) due to their low-frequency-peaked spectral energy distributions. At present, only six FSRQs are known to emit very high-energy (VHE) photons, representing only 7% of the VHE extragalactic catalog, which is largely dominated by high-frequency-peaked BL Lacertae objects. Aims. Following the detection of MeV-GeV gamma-ray flaring activity from the FSRQ PKS 0736+017 (z& x2004;=& x2004;0.189) with Fermi-LAT, the H.E.S.S. array of Cherenkov telescopes triggered target-of-opportunity (ToO) observations on February 18, 2015, with the goal of studying the gamma-ray emission in the VHE band. Methods. H.E.S.S. ToO observations were carried out during the nights of February 18, 19, 21, and 24, 2015. Together with Fermi-LAT, the multi-wavelength coverage of the flare includes Swift observations in soft X-ray and optical-UV bands, and optical monitoring (photometry and spectro-polarimetry) by the Steward Observatory, and the ATOM, the KAIT, and the ASAS-SN telescopes. Results. VHE emission from PKS 0736+017 was detected with H.E.S.S. only during the night of February 19, 2015. Fermi-LAT data indicate the presence of a gamma-ray flare, peaking at the time of the H.E.S.S. detection, with a flux doubling timescale of around six hours. The gamma-ray flare was accompanied by at least a 1 mag brightening of the non-thermal optical continuum. No simultaneous observations at longer wavelengths are available for the night of the H.E.S.S. detection. The gamma-ray observations with H.E.S.S. and Fermi-LAT are used to put constraints on the location of the gamma-ray emitting region during the flare: it is constrained to be just outside the radius of the broad-line region r(BLR) with a bulk Lorentz factor Gamma& x2004;similar or equal to& x2004;20, or at the level of the radius of the dusty torus r(torus) with Gamma& x2004;similar or equal to& x2004;60. Conclusions. PKS 0736+017 is the seventh FSRQ known to emit VHE photons, and at z& x2004;=& x2004;0.189 is the nearest so far. The location of the gamma-ray emitting region during the flare can be tightly constrained thanks to opacity, variability, and collimation arguments.
|
|
| 5. |
- Abdalla, H., et al.
(författare)
-
Probing the Magnetic Field in the GW170817 Outflow Using HESS Observations
- 2020
-
Ingår i: Astrophysical Journal Letters. - : Institute of Physics Publishing (IOPP). - 2041-8205 .- 2041-8213. ; 894:2, s. 1-5
-
Tidskriftsartikel (refereegranskat)abstract
- The detection of the first electromagnetic counterpart to the binary neutron star (BNS) merger remnant GW170817 established the connection between short gamma-ray bursts and BNS mergers. It also confirmed the forging of heavy elements in the ejecta (a so-called kilonova) via the r-process nucleosynthesis. The appearance of nonthermal radio and X-ray emission, as well as the brightening, which lasted more than 100 days, were somewhat unexpected. Current theoretical models attempt to explain this temporal behavior as either originating from a relativistic off-axis jet or a kilonova-like outflow. In either scenario, there is some ambiguity regarding how much energy is transported in the nonthermal electrons versus the magnetic field of the emission region. Combining the Very Large Array (radio) and Chandra (X-ray) measurements with observations in the GeV-TeV domain can help break this ambiguity, almost independently of the assumed origin of the emission. Here we report for the first time on deep H.E.S.S. observations of GW170817/GRB 170817A between 124 and 272 days after the BNS merger with the full H.E.S.S. array of telescopes, as well as on an updated analysis of the prompt (<5 days) observations with the upgraded H.E.S.S. phase-I telescopes. We discuss implications of the H.E.S.S. measurement for the magnetic field in the context of different source scenarios.
|
|
| 6. |
- Abdalla, H., et al.
(författare)
-
Resolving acceleration to very high energies along the jet of Centaurus A
- 2020
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 582:7812, s. 356-359
-
Tidskriftsartikel (refereegranskat)abstract
- The nearby radio galaxy Centaurus A belongs to a class of active galaxies that are luminous at radio wavelengths. Most show collimated relativistic outflows known as jets, which extend over hundreds of thousands of parsecs for the most powerful sources. Accretion of matter onto the central supermassive black hole is believed to fuel these jets and power their emission(1). Synchrotron radiation from relativistic electrons causes the radio emission, and it has been suggested that the X-ray emission from Centaurus A also originates in electron synchrotron processes(2-4). Another possible explanation is inverse Compton scattering with cosmic microwave background (CMB) soft photons(5-7). Synchrotron radiation needs ultrarelativistic electrons (about 50 teraelectronvolts) and, given their short cooling times, requires some continuous re-acceleration mechanism(8). Inverse Compton scattering, on the other hand, does not require very energetic electrons, but the jets must stay highly relativistic on large scales (exceeding 1 megaparsec). Some recent evidence disfavours inverse Compton-CMB models(9-12), although other work seems to be compatible with them(13,14). In principle, the detection of extended gamma-ray emission, which directly probes the presence of ultrarelativistic electrons, could distinguish between these options. At gigaelectronvolt energies there is also an unusual spectral hardening(15,16)in Centaurus A that has not yet been explained. Here we report observations of Centaurus A at teraelectronvolt energies that resolve its large-scale jet. We interpret the data as evidence for the acceleration of ultrarelativistic electrons in the jet, and favour the synchrotron explanation for the X-rays. Given that this jet is not exceptional in terms of power, length or speed, it is possible that ultrarelativistic electrons are commonplace in the large-scale jets of radio-loud active galaxies. Observations of the radio galaxy Centaurus A at teraelectronvolt energies resolve its large-scale jet and favour electron synchrotron processes as the source of its X-ray emission.
|
|
| 7. |
- Abdalla, H., et al.
(författare)
-
Resolving the Crab pulsar wind nebula at teraelectronvolt energies
- 2020
-
Ingår i: Nature Astronomy. - : Nature Publishing Group. - 2397-3366. ; 4:2, s. 167-173
-
Tidskriftsartikel (refereegranskat)abstract
- An angular extension at gamma-ray energies of 52 arcseconds is detected for the Crab nebula, revealing the emission region of the highest-energy gamma rays; simulations of the electromagnetic emission provide a non-trivial test of our understanding of particle acceleration in the Crab nebula. The Crab nebula is one of the most-studied cosmic particle accelerators, shining brightly across the entire electromagnetic spectrum up to very-high-energy gamma rays(1,2). It is known from observations in the radio to gamma-ray part of the spectrum that the nebula is powered by a pulsar, which converts most of its rotational energy losses into a highly relativistic outflow. This outflow powers a pulsar wind nebula, a region of up to ten light-years across, filled with relativistic electrons and positrons. These particles emit synchrotron photons in the ambient magnetic field and produce very-high-energy gamma rays by Compton up-scattering of ambient low-energy photons. Although the synchrotron morphology of the nebula is well established, it has not been known from which region the very-high-energy gamma rays are emitted(3-8). Here we report that the Crab nebula has an angular extension at gamma-ray energies of 52 arcseconds (assuming a Gaussian source width), much larger than at X-ray energies. This result closes a gap in the multi-wavelength coverage of the nebula, revealing the emission region of the highest-energy gamma rays. These gamma rays enable us to probe a previously inaccessible electron and positron energy range. We find that simulations of the electromagnetic emission reproduce our measurement, providing a non-trivial test of our understanding of particle acceleration in the Crab nebula.
|
|
| 8. |
- Abdalla, H., et al.
(författare)
-
Simultaneous observations of the blazar PKS 2155-304 from ultra-violet to TeV energies
- 2020
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 639, s. 1-13
-
Tidskriftsartikel (refereegranskat)abstract
- Here we report the results of the first ever contemporaneous multi-wavelength observation campaign on the BL Lac object PKS 2155-304 involving Swift, NuSTAR, Fermi-LAT, and H.E.S.S. The use of these instruments allows us to cover a broad energy range, which is important for disentangling the different radiative mechanisms. The source, observed from June 2013 to October 2013, was found in a low flux state with respect to previous observations but exhibited highly significant flux variability in the X-rays. The high-energy end of the synchrotron spectrum can be traced up to 40 keV without significant contamination by high-energy emission. A one-zone synchrotron self-Compton model was used to reproduce the broadband flux of the source for all the observations presented here but failed for previous observations made in April 2013. A lepto-hadronic solution was then explored to explain these earlier observational results.
|
|
| 9. |
- van Cappellen, W., et al.
(författare)
-
Apertif: Phased array feeds for the Westerbork Synthesis Radio Telescope: System overview and performance characteristics
- 2022
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 658
-
Tidskriftsartikel (refereegranskat)abstract
- We describe the APERture Tile In Focus (Apertif) system, a phased array feed (PAF) upgrade of the Westerbork Synthesis Radio Telescope that transforms this telescope into a high-sensitivity, wide-field-of-view L-band imaging and transient survey instrument. Using novel PAF technology, up to 40 partially overlapping beams are formed on the sky simultaneously, significantly increasing the survey speed of the telescope. With this upgraded instrument, an imaging survey covering an area of 2300 deg2 is being performed that will deliver both continuum and spectral line datasets, of which the first data have been publicly released. In addition, a time domain transient and pulsar survey covering 15 000 deg2 is in progress. An overview of the Apertif science drivers, hardware, and software of the upgraded telescope is presented, along with its key performance characteristics.
|
|
| 10. |
- Abdalla, H., et al.
(författare)
-
HESS and Fermi-LAT observations of PSR B1259-63/LS 2883 during its 2014 and 2017 periastron passages
- 2020
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 633, s. 1-14
-
Tidskriftsartikel (refereegranskat)abstract
- Context. PSR B1259-63/LS 2883 is a gamma-ray binary system consisting of a pulsar in an eccentric orbit around a bright Oe stellar-type companion star that features a dense circumstellar disc. The bright broad-band emission observed at phases close to periastron offers a unique opportunity to study particle acceleration and radiation processes in binary systems. Observations at gamma-ray energies constrain these processes through variability and spectral characterisation studies. Aims. The high- and very-high-energy (HE, VHE) gamma-ray emission from PSR B1259-63/LS 2883 around the times of its periastron passage are characterised, in particular, at the time of the HE gamma-ray flares reported to have occurred in 2011, 2014, and 2017. Short-term and average emission characteristics of PSR B1259-63/LS 2883 are determined. Super-orbital variability is searched for in order to investigate possible cycle-to-cycle VHE flux changes due to different properties of the companion star's circumstellar disc and/or the conditions under which the HE gamma-ray flares develop. Methods. Spectra and light curves were derived from observations conducted with the H.E.S.S-II array in 2014 and 2017. Phase-folded light curves are compared with the results obtained in 2004, 2007, and 2011. Fermi-LAT observations from 2010/11, 2014, and 2017 are analysed. Results. A local double-peak profile with asymmetric peaks in the VHE light curve is measured, with a flux minimum at the time of periastron t(p) and two peaks coinciding with the times at which the neutron star crosses the companion's circumstellar disc (similar to t(p) 16 d). A high VHE gamma-ray flux is also observed at the times of the HE gamma-ray flares (similar to t(p) + 30 d) and at phases before the first disc crossing (similar to t(p) - 35 d). The spectral energy range now extends to below 200 GeV and up to similar to 45 TeV. Conclusions. PSR B1259-63/LS 2883 displays periodic flux variability at VHE gamma-rays without clear signatures of super-orbital modulation in the time span covered by the monitoring of the source with the H.E.S.S. telescopes. This flux variability is most probably caused by the changing environmental conditions, particularly at times close to periastron passage at which the neutron star is thought to cross the circumstellar disc of the companion star twice. In contrast, the photon index remains unchanged within uncertainties for about 200 d around periastron. At HE gamma-rays, PSR B1259-63/LS 2883 has now been detected also before and after periastron, close to the disc crossing times. Repetitive flares with distinct variability patterns are detected in this energy range. Such outbursts are not observed at VHEs, although a relatively high emission level is measured. The spectra obtained in both energy regimes displays a similar slope, although a common physical origin either in terms of a related particle population, emission mechanism, or emitter location is ruled out.
|
|
| 11. |
- Adams, E. A. K., et al.
(författare)
-
First release of Apertif imaging survey data
- 2022
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 667
-
Tidskriftsartikel (refereegranskat)abstract
- Context. Apertif is a phased-array feed system for the Westerbork Synthesis Radio Telescope, providing forty instantaneous beams over 300 MHz of bandwidth. A dedicated survey program utilizing this upgrade started on 1 July 2019, with the last observations taken on 28 February 2022. The imaging survey component provides radio continuum, polarization, and spectral line data. Aims. Public release of data is critical for maximizing the legacy of a survey. Toward that end, we describe the release of data products from the first year of survey operations, through 30 June 2020. In particular, we focus on defining quality control metrics for the processed data products. Methods. The Apertif imaging pipeline, Apercal, automatically produces non-primary beam corrected continuum images, polarization images and cubes, and uncleaned spectral line and dirty beam cubes for each beam of an Apertif imaging observation. For this release, processed data products are considered on a beam-by-beam basis within an observation. We validate the continuum images by using metrics that identify deviations from Gaussian noise in the residual images. If the continuum image passes validation, we release all processed data products for a given beam. We apply further validation to the polarization and line data products and provide flags indicating the quality of those data products. Results. We release all raw observational data from the first year of survey observations, for a total of 221 observations of 160 independent target fields, covering approximately one thousand square degrees of sky. Images and cubes are released on a per beam basis, and 3374 beams (of 7640 considered) are released. The median noise in the continuum images is 41.4 uJy beam(-1), with a slightly lower median noise of 36.9 uJy beam(-1) in the Stokes V polarization image. The median angular resolution is 11.6 ''/sin delta. The median noise for all line cubes, with a spectral resolution of 36.6 kHz, is 1.6 mJy beam(-1), corresponding to a 3-sigma H i column density sensitivity of 1.8 x 10(20) atoms cm(-2) over 20 km s(-1) (for a median angular resolution of 24 '' x 15 ''). Line cubes at lower frequency have slightly higher noise values, consistent with the global RFI environment and overall Apertif system performance. We also provide primary beam images for each individual Apertif compound beam. The data are made accessible using a Virtual Observatory interface and can be queried using a variety of standard tools.
|
|
| 12. |
- Shupe, M. D., et al.
(författare)
-
Overview of the MOSAiC expedition : Atmosphere
- 2022
-
Ingår i: Elementa. - : University of California Press. - 2325-1026. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- With the Arctic rapidly changing, the needs to observe, understand, and model the changes are essential. To support these needs, an annual cycle of observations of atmospheric properties, processes, and interactions were made while drifting with the sea ice across the central Arctic during the Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition from October 2019 to September 2020. An international team designed and implemented the comprehensive program to document and characterize all aspects of the Arctic atmospheric system in unprecedented detail, using a variety of approaches, and across multiple scales. These measurements were coordinated with other observational teams to explore crosscutting and coupled interactions with the Arctic Ocean, sea ice, and ecosystem through a variety of physical and biogeochemical processes. This overview outlines the breadth and complexity of the atmospheric research program, which was organized into 4 subgroups: atmospheric state, clouds and precipitation, gases and aerosols, and energy budgets. Atmospheric variability over the annual cycle revealed important influences from a persistent large-scale winter circulation pattern, leading to some storms with pressure and winds that were outside the interquartile range of past conditions suggested by long-term reanalysis. Similarly, the MOSAiC location was warmer and wetter in summer than the reanalysis climatology, in part due to its close proximity to the sea ice edge. The comprehensiveness of the observational program for characterizing and analyzing atmospheric phenomena is demonstrated via a winter case study examining air mass transitions and a summer case study examining vertical atmospheric evolution. Overall, the MOSAiC atmospheric program successfully met its objectives and was the most comprehensive atmospheric measurement program to date conducted over the Arctic sea ice. The obtained data will support a broad range of coupled-system scientific research and provide an important foundation for advancing multiscale modeling capabilities in the Arctic.
|
|
| 13. |
- van Bragt, JJMH, et al.
(författare)
-
Characteristics and treatment regimens across ERS SHARP severe asthma registries
- 2020
-
Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 55:1
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
|
|
| 14. |
- Winkler, TW, et al.
(författare)
-
Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
-
Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
-
Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
|
|
| 15. |
- Zhang, X., et al.
(författare)
-
Human total, basal and activity energy expenditures are independent of ambient environmental temperature
- 2022
-
Ingår i: iScience. - : Elsevier Inc.. - 2589-0042. ; 25:8
-
Tidskriftsartikel (refereegranskat)abstract
- Lower ambient temperature (Ta) requires greater energy expenditure to sustain body temperature. However, effects of Ta on human energetics may be buffered by environmental modification and behavioral compensation. We used the IAEA DLW database for adults in the USA (n = 3213) to determine the effect of Ta (−10 to +30°C) on TEE, basal (BEE) and activity energy expenditure (AEE) and physical activity level (PAL). There were no significant relationships (p > 0.05) between maximum, minimum and average Ta and TEE, BEE, AEE and PAL. After adjustment for fat-free mass, fat mass and age, statistically significant (p < 0.01) relationships between TEE, BEE and Ta emerged in females but the effect sizes were not biologically meaningful. Temperatures inside buildings are regulated at 18–25°C independent of latitude. Hence, adults in the US modify their environments to keep TEE constant across a wide range of external ambient temperatures.
|
|
| 16. |
- Echelmeier, A., et al.
(författare)
-
Segmented flow generator for serial crystallography at the European X-ray free electron laser
- 2020
-
Ingår i: Nature Communications. - : Nature Research. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Serial femtosecond crystallography (SFX) with X-ray free electron lasers (XFELs) allows structure determination of membrane proteins and time-resolved crystallography. Common liquid sample delivery continuously jets the protein crystal suspension into the path of the XFEL, wasting a vast amount of sample due to the pulsed nature of all current XFEL sources. The European XFEL (EuXFEL) delivers femtosecond (fs) X-ray pulses in trains spaced 100 ms apart whereas pulses within trains are currently separated by 889 ns. Therefore, continuous sample delivery via fast jets wastes >99% of sample. Here, we introduce a microfluidic device delivering crystal laden droplets segmented with an immiscible oil reducing sample waste and demonstrate droplet injection at the EuXFEL compatible with high pressure liquid delivery of an SFX experiment. While achieving ~60% reduction in sample waste, we determine the structure of the enzyme 3-deoxy-D-manno-octulosonate-8-phosphate synthase from microcrystals delivered in droplets revealing distinct structural features not previously reported.
|
|
| 17. |
- Adebahr, B., et al.
(författare)
-
Apercal - The Apertif calibration pipeline
- 2022
-
Ingår i: Astronomy and Computing. - : Elsevier BV. - 2213-1337. ; 38
-
Tidskriftsartikel (refereegranskat)abstract
- Apertif (APERture Tile In Focus) is one of the Square Kilometre Array (SKA) pathfinder facilities. The Apertif project is an upgrade to the 50-year-old Westerbork Synthesis Radio Telescope (WSRT) using phased-array feed technology. The new receivers create 40 individual beams on the sky, achieving an instantaneous sky coverage of 6.5 square degrees. The primary goal of the Apertif Imaging Survey is to perform a wide survey of 3500 square degrees (AWES) and a medium deep survey of 350 square degrees (AMES) of neutral atomic hydrogen (up to a redshift of 0.26), radio continuum emission and polarisation. Each survey pointing yields 4.6 TB of correlated data. The goal of Apercal is to process this data and fully automatically generate science ready data products for the astronomical community while keeping up with the survey observations. We make use of common astronomical software packages in combination with Python based routines and parallelisation. We use an object oriented module-based approach to ensure easy adaptation of the pipeline. A Jupyter notebook based framework allows user interaction and execution of individual modules as well as a full automatic processing of a complete survey observation. If nothing interrupts processing, we are able to reduce a single pointing survey observation on our five node cluster with 24 physical cores and 256 GB of memory each within 24 h keeping up with the speed of the surveys. The quality of the generated images is sufficient for scientific usage for 44% of the recorded data products with single images reaching dynamic ranges of several thousands. Future improvements will increase this percentage to over 80%. Our design allowed development of the pipeline in parallel to the commissioning of the Apertif system.
|
|
| 18. |
- Christopoulos, Arthur, et al.
(författare)
-
THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.
- 2021
-
Ingår i: British journal of pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 178 Suppl 1
-
Forskningsöversikt (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
|
|
| 19. |
- Gorski, Mathias, et al.
(författare)
-
Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
- 2022
-
Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
-
Tidskriftsartikel (refereegranskat)abstract
- Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
|
|
| 20. |
- Alexander, Stephen P. H., et al.
(författare)
-
The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors
- 2023
-
Ingår i: BRITISH JOURNAL OF PHARMACOLOGY. - : British pharmacological society. - 0007-1188 .- 1476-5381. ; 180
-
Tidskriftsartikel (refereegranskat)abstract
- The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
|
|
| 21. |
- Ebersole, Charles R., et al.
(författare)
-
Many Labs 5: Testing Pre-Data-Collection Peer Review as an Intervention to Increase Replicability
- 2020
-
Ingår i: Advances in Methods and Practices in Psychological Science. - : Sage. - 2515-2467 .- 2515-2459. ; 3:3, s. 309-331
-
Tidskriftsartikel (refereegranskat)abstract
- Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3-9; median total sample = 1,279.5, range = 276-3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (Delta r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00-.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19-.50).
|
|
| 22. |
- Hess, K. M., et al.
(författare)
-
Apertif view of the OH megamaser IRAS 10597+5926: OH 18 cm satellite lines in wide-area H i surveys
- 2021
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 647
-
Tidskriftsartikel (refereegranskat)abstract
- We present the serendipitous detection of the two main OH maser lines at 1667 and 1665 MHz associated with IRAS 10597+5926 at zpdbl = 0.19612 in the untargeted Apertif Wide-area Extragalactic imaging Survey (AWES), and the subsequent measurement of the OH 1612 MHz satellite line in the same source. With a total OH luminosity of log(L/Lpdbl ) = 3.90 ± 0.03, IRAS 10597+5926 is the fourth brightest OH megamaser (OHM) known. We measure a lower limit for the 1667/1612 ratio of R1612 > 45.9, which is the highest limiting ratio measured for the 1612 MHz OH satellite line to date. OH satellite line measurements provide a potentially valuable constraint by which to compare detailed models of OH maser pumping mechanisms. Optical imaging shows that the galaxy is likely a late-stage merger. Based on published infrared and far ultraviolet fluxes, we find that the galaxy is an ultra-luminous infrared galaxy (ULIRG) with log(LTIR/Lpdbl) = 12.24 that is undergoing a starburst with an estimated star formation rate of 179 ± 40 Mpdbl yr-1. These host galaxy properties are consistent with the physical conditions responsible for very bright OHM emission. Finally, we provide an update on the predicted number of OH masers that may be found in AWES and estimate the total number of OH masers that will be detected in each of the individual main and satellite OH 18 cm lines.
|
|
| 23. |
- Kawahara, R., et al.
(författare)
-
Community evaluation of glycoproteomics informatics solutions reveals high-performance search strategies for serum glycopeptide analysis
- 2021
-
Ingår i: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 18, s. 1304-1316
-
Tidskriftsartikel (refereegranskat)abstract
- Glycoproteomics is a powerful yet analytically challenging research tool. Software packages aiding the interpretation of complex glycopeptide tandem mass spectra have appeared, but their relative performance remains untested. Conducted through the HUPO Human Glycoproteomics Initiative, this community study, comprising both developers and users of glycoproteomics software, evaluates solutions for system-wide glycopeptide analysis. The same mass spectrometrybased glycoproteomics datasets from human serum were shared with participants and the relative team performance for N- and O-glycopeptide data analysis was comprehensively established by orthogonal performance tests. Although the results were variable, several high-performance glycoproteomics informatics strategies were identified. Deep analysis of the data revealed key performance-associated search parameters and led to recommendations for improved 'high-coverage' and 'high-accuracy' glycoproteomics search solutions. This study concludes that diverse software packages for comprehensive glycopeptide data analysis exist, points to several high-performance search strategies and specifies key variables that will guide future software developments and assist informatics decision-making in glycoproteomics. This analysis presents the results of a community-based evaluation of existing software for large-scale glycopeptide data analysis.
|
|
| 24. |
- Lombardi, C., et al.
(författare)
-
Periodic limb movements during sleep and blood pressure changes in sleep apnoea: Data from the European Sleep Apnoea Database
- 2020
-
Ingår i: Respirology. - : Wiley. - 1323-7799 .- 1440-1843. ; 25:8, s. 872-879
-
Tidskriftsartikel (refereegranskat)abstract
- Background and objective OSA and PLMS are known to induce acute BP swings during sleep. Our current study aimed to address the independent effect of PLMS on BP in an unselected OSA patient cohort. Methods This cross‐sectional analysis included 1487 patients (1110 males, no previous hypertension diagnosis or treatment, mean age: 52.5years, mean BMI: 30.5kg/m2) with significant OSA (defined as AHI≥10) recruited from the European Sleep Apnoea Cohort. Patients underwent overnight PSG. Patients were stratified into two groups: patients with significant PLMS (PLMSI>25 events/hour of sleep) and patients without significant PLMS (PLMSI<25 events/hour of sleep). SBP, DBP and PP were the variables of interest. For each of these, a multivariate regression linear model was fitted to evaluate the relationship between PLMS and outcome adjusting for sociodemographic and clinical covariates (gender, age, BMI, AHI, ESS, diabetes, smoking and sleep efficiency). Results The univariate analysis of SBP showed an increment of BP equal to 4.70mm Hg (P<0.001) in patients with significant PLMS compared to patients without significant PLMS. This increment remained significant after implementing a multivariate regression model (2.64mm Hg, P = 0.044). No significant increment of BP was observed for DBP and PP. Conclusion PLMS is associated with a rise in SBP regardless of AHI, independent of clinical and sociodemographic confounders. A PLMS phenotype may carry an increased risk for cardiovascular disease in OSA patients.
|
|
| 25. |
|
|
| 26. |
- Hilbert, Kevin, et al.
(författare)
-
Cortical and Subcortical Brain Alterations in Specific Phobia and Its Animal and Blood-Injection-Injury Subtypes: A Mega-Analysis From the ENIGMA Anxiety Working Group.
- 2024
-
Ingår i: The American Journal of Psychiatry. - 1535-7228.
-
Tidskriftsartikel (refereegranskat)abstract
- Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults).Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis.Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents.Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.
|
|
| 27. |
- Adebahr, B., et al.
(författare)
-
The Apertif science verification campaign: Characteristics of polarised radio sources
- 2022
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 663
-
Tidskriftsartikel (refereegranskat)abstract
- Context. The characteristics of the polarised radio sky are a key ingredient in constraining evolutionary models of magnetic fields in the Universe and their role in feedback processes. The origin of the polarised emission and the characteristics of the intergalactic medium on the line of sight can be investigated using large samples of polarised sources. Ancillary infrared (IR) and optical data can be used to study the nature of the emitting objects. Aims. We analyse five early science datasets from the APERture Tile in Focus (Apertif) phased array feed system to verify the polarisation capabilities of Apertif in view of future larger data releases. We aim to characterise the source population of the polarised sky in the L-Band using polarised source information in combination with IR and optical data. Methods. We use automatic routines to generate full field-of-view Q- and U-cubes and perform rotation measure (RM)-Synthesis, source finding, and cross-matching with published radio, optical, and IR data to generate polarised source catalogues. All sources were inspected individually by eye for verification of their IR and optical counterparts. Spectral energy distribution (SED)-fitting routines were used to determine photometric redshifts, star-formation rates, and galaxy masses. IR colour information was used to classify sources as active galactic nuclei (AGN) or star-forming-dominated and early- or late-type. Results. We surveyed an area of 56 deg2 and detected 1357 polarised source components in 1170 sources. The fraction of polarised sources is 10.57% with a median fractional polarisation of 4.70 ± 0.14%. We confirmed the reliability of the Apertif measurements by comparing them with polarised cross-identified NVSS sources. Average RMs of the individual fields lie within the error of the best Milky Way foreground measurements. All of our polarised sources were found to be dominated by AGN activity in the radio regime with most of them being radio-loud (79%) and of the Fanaroff-Riley (FR)II class (87%). The host galaxies of our polarised source sample are dominated by intermediate disc and star-forming disc galaxies. The contribution of star formation to the radio emission is on the order of a few percent for 10% of the polarised sources while for 90% it is completely dominated by the AGN. We do not see any change in fractional polarisation for different star-formation rates of the AGN host galaxies. Conclusions. The Apertif system is suitable for large-area high-sensitivity polarised sky surveys. The data products of the polarisation analysis pipeline can be used to investigate the Milky Way magnetic field on projected scales of several arcminutes as well as the origin of the polarised emission in AGN and the properties of their host galaxies.
|
|
| 28. |
- Fiedler, Stephanie, et al.
(författare)
-
Interactions between atmospheric composition and climate change – progress in understanding and future opportunities from AerChemMIP, PDRMIP, and RFMIP
- 2024
-
Ingår i: Geoscientific Model Development. - 1991-959X .- 1991-9603. ; 17:6, s. 2387-2417
-
Forskningsöversikt (refereegranskat)abstract
- The climate science community aims to improve our understanding of climate change due to anthropogenic influences on atmospheric composition and the Earth's surface. Yet not all climate interactions are fully understood, and uncertainty in climate model results persists, as assessed in the latest Intergovernmental Panel on Climate Change (IPCC) assessment report. We synthesize current challenges and emphasize opportunities for advancing our understanding of the interactions between atmospheric composition, air quality, and climate change, as well as for quantifying model diversity. Our perspective is based on expert views from three multi-model intercomparison projects (MIPs) – the Precipitation Driver Response MIP (PDRMIP), the Aerosol Chemistry MIP (AerChemMIP), and the Radiative Forcing MIP (RFMIP). While there are many shared interests and specializations across the MIPs, they have their own scientific foci and specific approaches. The partial overlap between the MIPs proved useful for advancing the understanding of the perturbation–response paradigm through multi-model ensembles of Earth system models of varying complexity. We discuss the challenges of gaining insights from Earth system models that face computational and process representation limits and provide guidance from our lessons learned. Promising ideas to overcome some long-standing challenges in the near future are kilometer-scale experiments to better simulate circulation-dependent processes where it is possible and machine learning approaches where they are needed, e.g., for faster and better subgrid-scale parameterizations and pattern recognition in big data. New model constraints can arise from augmented observational products that leverage multiple datasets with machine learning approaches. Future MIPs can develop smart experiment protocols that strive towards an optimal trade-off between the resolution, complexity, and number of simulations and their length and, thereby, help to advance the understanding of climate change and its impacts.
|
|
| 29. |
- Gorski, Mathias, et al.
(författare)
-
Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
-
Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
-
Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
|
|
| 30. |
- Gunduz, C., et al.
(författare)
-
Long-term positive airway pressure therapy is associated with reduced total cholesterol levels in patients with obstructive sleep apnea: data from the European Sleep Apnea Database (ESADA)
- 2020
-
Ingår i: Sleep Medicine. - : Elsevier BV. - 1389-9457. ; 75, s. 201-209
-
Tidskriftsartikel (refereegranskat)abstract
- Background and aim: Obstructive sleep apnea (OSA) is an independent risk factor for dyslipidemia. The current study examined the effects of positive airway pressure (PAP) treatment on lipid status in the European Sleep Apnea Database (ESADA). Methods: The prospective cohort study enrolled 1564 OSA subjects (74% male, mean age 54 ± 11y, body mass index (BMI) 32.7 ± 6.6 kg/m2 and apnea-hypopnea index (AHI) 40.3 ± 24.4 n/h) undergoing PAP therapy for at least three months (mean 377.6 ± 419.5 days). Baseline and follow-up total cholesterol (TC) from nine centers were analyzed. Repeated measures and logistic regression tests (adjusted for age, sex, weight changes, lipid lowering medication, PAP compliance, and treatment duration) were used to compare changes in TC concentration. Incident risk for a coronary heart disease event (CHD) was used to compute a Framingham CHD risk score (estimated from age, BMI, blood pressure, and TC). Results: Adjusted means of TC decreased from 194.2 mg/dl to 189.3 mg/dl during follow-up (p = 0.019). A clinically significant (10%) reduction of TC at PAP follow-up was observed in 422 patients (27%). Duration of PAP therapy was identified as independent predictor for TC reduction, which implies an approximately 10% risk reduction for incident CHD events (from 26.7% to 24.1% in men and from 11.2% to 10.1% in women, p < 0.001 respectively). Conclusion: This observational study demonstrates a reduction of TC after long-term PAP treatment. The close association between TC concentration and cardiovascular (CV) mortality suggests that identification and treatment of OSA may have a beneficial effect on overall CV risk due to this mechanism. This possibility needs to be evaluated in prospective randomized studies. © 2020 Elsevier B.V.
|
|
| 31. |
- Bellouin, N., et al.
(författare)
-
Bounding Global Aerosol Radiative Forcing of Climate Change
- 2020
-
Ingår i: Reviews of geophysics. - 8755-1209 .- 1944-9208. ; 58:1
-
Forskningsöversikt (refereegranskat)abstract
- Aerosols interact with radiation and clouds. Substantial progress made over the past 40 years in observing, understanding, and modeling these processes helped quantify the imbalance in the Earth's radiation budget caused by anthropogenic aerosols, called aerosol radiative forcing, but uncertainties remain large. This review provides a new range of aerosol radiative forcing over the industrial era based on multiple, traceable, and arguable lines of evidence, including modeling approaches, theoretical considerations, and observations. Improved understanding of aerosol absorption and the causes of trends in surface radiative fluxes constrain the forcing from aerosol-radiation interactions. A robust theoretical foundation and convincing evidence constrain the forcing caused by aerosol-driven increases in liquid cloud droplet number concentration. However, the influence of anthropogenic aerosols on cloud liquid water content and cloud fraction is less clear, and the influence on mixed-phase and ice clouds remains poorly constrained. Observed changes in surface temperature and radiative fluxes provide additional constraints. These multiple lines of evidence lead to a 68% confidence interval for the total aerosol effective radiative forcing of -1.6 to -0.6Wm(-2), or -2.0 to -0.4Wm(-2) with a 90% likelihood. Those intervals are of similar width to the last Intergovernmental Panel on Climate Change assessment but shifted toward more negative values. The uncertainty will narrow in the future by continuing to critically combine multiple lines of evidence, especially those addressing industrial-era changes in aerosol sources and aerosol effects on liquid cloud amount and on ice clouds. Plain Language Summary Human activities emit into the atmosphere small liquid and solid particles called aerosols. Those aerosols change the energy budget of the Earth and trigger climate changes, by scattering and absorbing solar and terrestrial radiation and playing important roles in the formation of cloud droplets and ice crystals. But because aerosols are much more varied in their chemical composition and much more heterogeneous in their spatial and temporal distributions than greenhouse gases, their perturbation to the energy budget, called radiative forcing, is much more uncertain. This review uses traceable and arguable lines of evidence, supported by aerosol studies published over the past 40 years, to quantify that uncertainty. It finds that there are two chances out of three that aerosols from human activities have increased scattering and absorption of solar radiation by 14% to 29% and cloud droplet number concentration by 5 to 17% in the period 2005-2015 compared to the year 1850. Those increases exert a radiative forcing that offsets between a fifth and a half of the radiative forcing by greenhouse gases. The degree to which human activities affect natural aerosol levels, and the response of clouds, and especially ice clouds, to aerosol perturbations remain particularly uncertain.
|
|
| 32. |
- Goderis, Steven, et al.
(författare)
-
Globally distributed iridium layer preserved within the Chicxulub impact structure
- 2021
-
Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:9
-
Tidskriftsartikel (refereegranskat)abstract
- The Cretaceous-Paleogene (K-Pg) mass extinction is marked globally by elevated concentrations of iridium, emplaced by a hypervelocity impact event 66 million years ago. Here, we report new data from four independent laboratories that reveal a positive iridium anomaly within the peak-ring sequence of the Chicxulub impact structure, in drill core recovered by IODP-ICDP Expedition 364. The highest concentration of ultrafine meteoritic matter occurs in the post-impact sediments that cover the crater peak ring, just below the lowermost Danian pelagic limestone. Within years to decades after the impact event, this part of the Chicxulub impact basin returned to a relatively low-energy depositional environment, recording in unprecedented detail the recovery of life during the succeeding millennia. The iridium layer provides a key temporal horizon precisely linking Chicxulub to K-Pg boundary sections worldwide.
|
|
| 33. |
|
|
| 34. |
- Allentoft, Morten E., et al.
(författare)
-
Population genomics of post-glacial western Eurasia
- 2024
-
Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
-
Tidskriftsartikel (refereegranskat)abstract
- Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
|
|
| 35. |
|
|
| 36. |
- Gaertner, A, et al.
(författare)
-
The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy
- 2021
-
Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 12:6
-
Tidskriftsartikel (refereegranskat)abstract
- A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them TTN and RBM20. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in TTN (TTNtv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (RBM20) are also known to be associated with severe cardiomyopathies. TTN is one of the major RBM20 splicing targets. Most of the pathogenic RBM20 mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant RBM20. Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic TTN and RBM20 mutations. We show that the splicing of RBM20 target genes is affected in the mutation carrier. Furthermore, we reveal RBM20 haploinsufficiency presumably caused by the frameshift mutation in RBM20.
|
|
| 37. |
- Maccari, Maria Elena, et al.
(författare)
-
Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.
- 2023
-
Ingår i: The Journal of allergy and clinical immunology. - 1097-6825. ; 152:4
-
Tidskriftsartikel (refereegranskat)abstract
- Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking.This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS.Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs.The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS.APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.
|
|
| 38. |
- Mohammed Taha, Hiba, et al.
(författare)
-
The NORMAN Suspect List Exchange (NORMAN-SLE) : facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry
- 2022
-
Ingår i: Environmental Sciences Europe. - : Springer. - 2190-4707 .- 2190-4715. ; 34:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The NORMAN Association (https://www.norman-network.com/) initiated the NORMAN Suspect List Exchange (NORMAN-SLE; https://www.norman-network.com/nds/SLE/) in 2015, following the NORMAN collaborative trial on non-target screening of environmental water samples by mass spectrometry. Since then, this exchange of information on chemicals that are expected to occur in the environment, along with the accompanying expert knowledge and references, has become a valuable knowledge base for “suspect screening” lists. The NORMAN-SLE now serves as a FAIR (Findable, Accessible, Interoperable, Reusable) chemical information resource worldwide.Results: The NORMAN-SLE contains 99 separate suspect list collections (as of May 2022) from over 70 contributors around the world, totalling over 100,000 unique substances. The substance classes include per- and polyfluoroalkyl substances (PFAS), pharmaceuticals, pesticides, natural toxins, high production volume substances covered under the European REACH regulation (EC: 1272/2008), priority contaminants of emerging concern (CECs) and regulatory lists from NORMAN partners. Several lists focus on transformation products (TPs) and complex features detected in the environment with various levels of provenance and structural information. Each list is available for separate download. The merged, curated collection is also available as the NORMAN Substance Database (NORMAN SusDat). Both the NORMAN-SLE and NORMAN SusDat are integrated within the NORMAN Database System (NDS). The individual NORMAN-SLE lists receive digital object identifiers (DOIs) and traceable versioning via a Zenodo community (https://zenodo.org/communities/norman-sle), with a total of > 40,000 unique views, > 50,000 unique downloads and 40 citations (May 2022). NORMAN-SLE content is progressively integrated into large open chemical databases such as PubChem (https://pubchem.ncbi.nlm.nih.gov/) and the US EPA’s CompTox Chemicals Dashboard (https://comptox.epa.gov/dashboard/), enabling further access to these lists, along with the additional functionality and calculated properties these resources offer. PubChem has also integrated significant annotation content from the NORMAN-SLE, including a classification browser (https://pubchem.ncbi.nlm.nih.gov/classification/#hid=101).Conclusions: The NORMAN-SLE offers a specialized service for hosting suspect screening lists of relevance for the environmental community in an open, FAIR manner that allows integration with other major chemical resources. These efforts foster the exchange of information between scientists and regulators, supporting the paradigm shift to the “one substance, one assessment” approach. New submissions are welcome via the contacts provided on the NORMAN-SLE website (https://www.norman-network.com/nds/SLE/).
|
|
| 39. |
|
|
| 40. |
- Papaioannou, NE, et al.
(författare)
-
Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice
- 2021
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 464-
-
Tidskriftsartikel (refereegranskat)abstract
- Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. We further show that cDC2 in early life, despite being distinct from cDC2 in adult life, are functionally competent and can induce T cell responses. Our results thus highlight the potential of harnessing cDC2 for boosting immunity in early life.
|
|
| 41. |
|
|
| 42. |
- Uhlmann, Eric, L., et al.
(författare)
-
Subjective Evidence Evaluation Survey For Multi-Analyst Studies
- 2024
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Multi-analyst studies explore how well an empirical claim withstands plausible alternative analyses of the same data set by multiple, independent analysis teams. Conclusions from these studies typically rely on a single outcome metric (e.g., effect size) provided by each analysis team. Although informative about the range of plausible effects in a data set, a single effect size from each team does not provide a complete, nuanced understanding of how analysis choices are related to the outcome. We used the Delphi consensus technique with input from 37 experts to develop an 18-item Subjective Evidence Evaluation Survey (SEES) to evaluate how each analysis team views the methodological appropriateness of the research design and the strength of evidence for the hypothesis. We illustrate the usefulness of the SEES in providing richer evidence assessment with pilot data from a previous multi-analyst study.
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
- Ayyer, Kartik, et al.
(författare)
-
3D diffractive imaging of nanoparticle ensembles using an x-ray laser
- 2021
-
Ingår i: Optica. - : Optical Society of America. - 2334-2536. ; 8:1, s. 15-23
-
Tidskriftsartikel (refereegranskat)abstract
- Single particle imaging at x-ray free electron lasers (XFELs) has the potential to determine the structure and dynamics of single biomolecules at room temperature. Two major hurdles have prevented this potential from being reached, namely, the collection of sufficient high-quality diffraction patterns and robust computational purification to overcome structural heterogeneity. We report the breaking of both of these barriers using gold nanoparticle test samples, recording around 10 million diffraction patterns at the European XFEL and structurally and orientationally sorting the patterns to obtain better than 3-nm-resolution 3D reconstructions for each of four samples. With these new developments, integrating advancements in x-ray sources, fast-framing detectors, efficient sample delivery, and data analysis algorithms, we illuminate the path towards sub-nano meter biomolecular imaging. The methods developed here can also be extended to characterize ensembles that are inherently diverse to obtain their full structural landscape. Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License.
|
|
| 47. |
- Bethge, WA, et al.
(författare)
-
Results of a multicenter phase I/II trial of TCRαβ and CD19-depleted haploidentical hematopoietic stem cell transplantation for adult and pediatric patients
- 2022
-
Ingår i: Bone marrow transplantation. - : Springer Science and Business Media LLC. - 1476-5365 .- 0268-3369. ; 57:3, s. 423-430
-
Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cell transplantation (HSCT) from haploidentical donors is a viable option for patients lacking HLA-matched donors. Here we report the results of a prospective multicenter phase I/II trial of transplantation of TCRαβ and CD19-depleted peripheral blood stem cells from haploidentical family donors after a reduced-intensity conditioning with fludarabine, thiotepa, and melphalan. Thirty pediatric and 30 adult patients with acute leukemia (n = 43), myelodysplastic or myeloproliferative syndrome (n = 6), multiple myeloma (n = 1), solid tumors (n = 6), and non-malignant disorders (n = 4) were enrolled. TCR αβ/CD19-depleted grafts prepared decentrally at six manufacturing sites contained a median of 12.1 × 106 CD34+ cells/kg and 14.2 × 103 TCRαβ+ T-cells/kg. None of the patients developed grade lll/IV acute graft-versus-host disease (GVHD) and only six patients (10%) had grade II acute GVHD. With a median follow-up of 733 days 36/60 patients are alive. The cumulative incidence of non-relapse mortality at day 100, 1 and 2 years after HSCT was 5%, 15%, and 17% for all patients, respectively. Estimated probabilities of overall and disease-free survival at 2 years were 63% and 50%, respectively. Based on these promising results in a high-risk patient cohort, haploidentical HSCT using TCRαβ/CD19-depleted grafts represents a viable treatment option.
|
|
| 48. |
|
|
| 49. |
- Haid, Sibylle, et al.
(författare)
-
Repurposing screen identifies novel candidates for broad-spectrum coronavirus antivirals and druggable host targets
- 2024
-
Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 68:3
-
Tidskriftsartikel (refereegranskat)abstract
- Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs’ host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha- and a Betacoronavirus. This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses.
|
|
| 50. |
|
|
